<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01681472</url>
  </required_header>
  <id_info>
    <org_study_id>ISO-CC-002</org_study_id>
    <secondary_id>2012-000522-22</secondary_id>
    <nct_id>NCT01681472</nct_id>
  </id_info>
  <brief_title>PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in Patients With Colon Cancer</brief_title>
  <official_title>A Single-Blind, Randomized Phase I/II Study of Pharmacokinetic and Pharmacodynamic Investigation of Modufolin® (60 or 200mg/m2) Compared to Levoleucovorin (60 or 200mg/m2) in Tumor, Adjacent Mucosa and Plasma for Patients With Colon Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Isofol Medical AB</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Isofol Medical AB</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare the concentration of four different metabolites in&#xD;
      the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two&#xD;
      different doses of Modufolin (arfolitixorin) and Levoleucovorin (Isovorin®), respectively (60&#xD;
      and 200 mg/m2).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to compare the concentration of [6R] 5,10-methylene-THF,&#xD;
      5-formyl-THF, 5-methyl-THF and THF in the tumor, in adjacent mucosa and in plasma in patients&#xD;
      with colon cancer receiving two different does of Modufolin® and Levoleucovorin (Isovorin®),&#xD;
      respectively (60 and 200 mg/m2).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">August 2013</completion_date>
  <primary_completion_date type="Actual">August 2013</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Concentration of [6R]-5,10-methylene-THF in Tumor Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6S]-5-THF in Tumor Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6S]-5-THF in Adjacent Mucosa Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6S]-5-methyl-THF in Tumor Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6S]-5-formyl-THF in Tumor Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue</measure>
    <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
    <description>Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AUC(0-2h) of [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-2h) of [6S]-5-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-2h) of [6S]-5-methyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: [6S]-5-methyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-2h) of [6SR]-5-formyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-formyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(Last) of [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(Last) of [6S]-5-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(Last) of [6S]-5-methyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-methyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(Last) of [6S]-5-formyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-formyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of [6S]-5-THF in Plasma</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of [6S]-5-methyl-THF in Plasma</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of [6S]-5-formyl-THF in Plasma</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R] 5,10- methylene-THF and the metabolites: [6S]-5-THF, [6S]-5-methyl-THF, and [6S]-5-formyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of [6S]-5-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of [6S]-5-methyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of [6S]-5-formyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(1/2) of [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Terminal plasma elimination half-life time for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(1/2) of [6S]-5-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(1/2) of [6S]-5-methyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(1/2) of [6S]-5-formyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(Last) of [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>The time-point for the last measurable concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(Last) of [6S]-5-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>The time-point for the last measurable concentration for the metabolite [6S]-5-TH in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(Last) of [6S]-5-methyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>The time-point for the last measurable concentration for the metabolite [6S]-5-methyl-THF in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T(Last) of [6S]-5-formyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
    <description>The time-point for the last measurable concentration for the metabolite [6S]-5-formyl-THF in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Correlation between the exposure of [6R]-5,10-methylene-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6R]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Correlation between the exposure of [6S]-5-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-THF in the tumor or adjacent mucosa at surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Correlation between the exposure of [6S]-5-methyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-methyl-THF in the tumor or adjacent mucosa at surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF</measure>
    <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
    <description>Correlation between the exposure of [6S]-5-formyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-formyl-THF in the tumor or adjacent mucosa at surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gene Expression Ratios (Mucosa:Tumor)</measure>
    <time_frame>Sample taken Day 1 (Day of Surgery)</time_frame>
    <description>Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of Gene Expression in Tumor and Adjacent Mucosa</measure>
    <time_frame>Sample taken Day 1 (Day of Surgery)</time_frame>
    <description>Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Homocystein Concentration</measure>
    <time_frame>Samples taken at Screening visit, Day 2, and End of Study (Day 5)</time_frame>
    <description>Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>S-Folate Concentration</measure>
    <time_frame>Samples taken at Screening visit, Day 2 and End of Study (Day 5)</time_frame>
    <description>Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Homocystein Concentration From Screening</measure>
    <time_frame>Samples taken at Screening visit, Day 2 and End of Study (Day 5)</time_frame>
    <description>Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.&#xD;
The criteria for assessment categories &quot;normal&quot;, &quot;low&quot; and &quot;high&quot; were based on the reference ranges for plasma-Homocystein as follows: &quot;low&quot; &lt;4,7 mcmol/L; &quot;normal&quot; =&gt; 4,7 and &lt;=16 mcmol/L; &quot;high&quot; &gt;16 mcmol/L. Values were applicable for both male and female adults.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in S-Folate Concentration From Screening</measure>
    <time_frame>Samples taken at Screening visit, Day 2 and End of Study (Day 5)</time_frame>
    <description>Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of AEs Per Severity</measure>
    <time_frame>Screening visit until end of study, Day 5</time_frame>
    <description>Number of reported AEs per treatment with respect to severity</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Colonic Neoplasms</condition>
  <arm_group>
    <arm_group_label>Levoleucovorin 200 mg/m2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One i.v. bolus injection of study drug after the patient has been anaesthetized.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Levoleucovorin 60 mg/m2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One i.v. bolus injection of study drug after the patient has been anaesthetized.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>6R-MTHF 200 mg/m2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One i.v. bolus injection of study drug after the patient has been anaesthetized.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>6R-MTHF 60 mg/m2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One i.v. bolus injection of study drug after the patient has been anaesthetized.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6R-MTHF (arfolitixorin) 200 mg/m2</intervention_name>
    <description>i.v. bolus injection</description>
    <arm_group_label>6R-MTHF 200 mg/m2</arm_group_label>
    <other_name>Modufolin®</other_name>
    <other_name>ISO-901</other_name>
    <other_name>[6R] 5,10-methylenetetrahydrofolate</other_name>
    <other_name>arfolitixorin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levoleucovorin 200 mg/m2</intervention_name>
    <description>i.v. bolus injection</description>
    <arm_group_label>Levoleucovorin 200 mg/m2</arm_group_label>
    <other_name>Isovorin®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6R-MTHF (arfolitixorin) 60 mg/m2</intervention_name>
    <description>i.v. bolus injection</description>
    <arm_group_label>6R-MTHF 60 mg/m2</arm_group_label>
    <other_name>Modufolin®</other_name>
    <other_name>ISO-901</other_name>
    <other_name>[6R] 5,10-methylenetetrahydrofolate</other_name>
    <other_name>arfolitixorin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levoleucovorin 60 mg/m2</intervention_name>
    <description>i.v. bolus injection</description>
    <arm_group_label>Levoleucovorin 60 mg/m2</arm_group_label>
    <other_name>Isovorin®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Main Inclusion Criteria:&#xD;
&#xD;
          -  Operable colon cancer amenable to curative surgery.&#xD;
&#xD;
          -  Performance status of 0 to 1&#xD;
&#xD;
          -  Informed consent form&#xD;
&#xD;
          -  Patients must be at least 18 years of age.&#xD;
&#xD;
        Main Exclusion Criteria:&#xD;
&#xD;
          -  Any concurrent other anti-tumor therapy&#xD;
&#xD;
          -  Any prohibited concomitant medication within 30 days of surgery&#xD;
&#xD;
          -  Pregnancy or breast-feeding.&#xD;
&#xD;
          -  Second primary malignancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristoffer Derwinger, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sahlgrenska University Hospital, Sweden</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sahlgrenska University Hospital</name>
      <address>
        <city>Gothenburg</city>
        <zip>461 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>September 5, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <results_first_submitted>May 21, 2015</results_first_submitted>
  <results_first_submitted_qc>June 23, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">July 17, 2015</results_first_posted>
  <last_update_submitted>September 7, 2020</last_update_submitted>
  <last_update_submitted_qc>September 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Colon cancer</keyword>
  <keyword>5,10-methylenetetrahydrofolate</keyword>
  <keyword>Rectal Neoplasms</keyword>
  <keyword>Colorectal Neoplasms</keyword>
  <keyword>Intestinal Neoplasms</keyword>
  <keyword>Gastrointestinal Neoplasms</keyword>
  <keyword>Digestive System Neoplasms</keyword>
  <keyword>Gastrointestinal Diseases</keyword>
  <keyword>Therapeutic Uses</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pharmacodynamics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Colonic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Tetrahydrofolates</mesh_term>
    <mesh_term>Levoleucovorin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Levoleucovorin 200 mg/m2</title>
          <description>Levoleucovorin: i.v. bolus injection</description>
        </group>
        <group group_id="P2">
          <title>Levoleucovorin 60 mg/m2</title>
          <description>Levoleucovorin: i.v. bolus injection</description>
        </group>
        <group group_id="P3">
          <title>6R-MTHF 200 mg/m2</title>
          <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
        </group>
        <group group_id="P4">
          <title>6R-MTHF 60 mg/m2</title>
          <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Levoleucovorin 200 mg/m2</title>
          <description>Levoleucovorin: i.v. bolus injection</description>
        </group>
        <group group_id="B2">
          <title>Levoleucovorin 60 mg/m2</title>
          <description>Levoleucovorin: i.v. bolus injection</description>
        </group>
        <group group_id="B3">
          <title>Modufolin 200 mg/m2</title>
          <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
        </group>
        <group group_id="B4">
          <title>Modufolin 60 mg/m2</title>
          <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="8"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="8"/>
            <count group_id="B4" value="8"/>
            <count group_id="B5" value="32"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="6"/>
                    <measurement group_id="B5" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="80.5" spread="9.15"/>
                    <measurement group_id="B2" value="66.71" spread="16.89"/>
                    <measurement group_id="B3" value="72" spread="15"/>
                    <measurement group_id="B4" value="71.75" spread="11.25"/>
                    <measurement group_id="B5" value="72.74" spread="13.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Sweden</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6R]-5,10-methylene-THF in Tumor Tissue</title>
        <description>Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6R]-5,10-methylene-THF in Tumor Tissue</title>
          <description>Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1871" spread="1159"/>
                    <measurement group_id="O2" value="959" spread="417"/>
                    <measurement group_id="O3" value="4725" spread="2210"/>
                    <measurement group_id="O4" value="2393" spread="1920"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0323</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1336</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.8622</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0074</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1752</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue</title>
        <description>Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue</title>
          <description>Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1333" spread="852"/>
                    <measurement group_id="O2" value="626" spread="439"/>
                    <measurement group_id="O3" value="5099" spread="3927"/>
                    <measurement group_id="O4" value="3481" spread="3926"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1480</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0034</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0177</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0019</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0118</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6S]-5-THF in Tumor Tissue</title>
        <description>Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6S]-5-THF in Tumor Tissue</title>
          <description>Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1329" spread="720"/>
                    <measurement group_id="O2" value="933" spread="598"/>
                    <measurement group_id="O3" value="4175" spread="3127"/>
                    <measurement group_id="O4" value="2219" spread="1995"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1182</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0538</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5244</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0081</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0313</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4777</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6S]-5-THF in Adjacent Mucosa Tissue</title>
        <description>Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6S]-5-THF in Adjacent Mucosa Tissue</title>
          <description>Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1333" spread="852"/>
                    <measurement group_id="O2" value="626" spread="439"/>
                    <measurement group_id="O3" value="5099" spread="3927"/>
                    <measurement group_id="O4" value="3481" spread="3926"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2716</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0124</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0728</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0039</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0454</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6S]-5-methyl-THF in Tumor Tissue</title>
        <description>Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6S]-5-methyl-THF in Tumor Tissue</title>
          <description>Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3574" spread="2415"/>
                    <measurement group_id="O2" value="1904" spread="918"/>
                    <measurement group_id="O3" value="4396" spread="1858"/>
                    <measurement group_id="O4" value="1882" spread="1204"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0092</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.8303</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1182</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0081</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3184</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1752</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue</title>
        <description>Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue</title>
          <description>Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3667" spread="2043"/>
                    <measurement group_id="O2" value="1216" spread="455"/>
                    <measurement group_id="O3" value="2494" spread="765"/>
                    <measurement group_id="O4" value="2066" spread="1517"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0728</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2246</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0428</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0003</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4309</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0055</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6S]-5-formyl-THF in Tumor Tissue</title>
        <description>Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6S]-5-formyl-THF in Tumor Tissue</title>
          <description>Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3611" spread="3899"/>
                    <measurement group_id="O2" value="512" spread="259"/>
                    <measurement group_id="O3" value="100" spread="47"/>
                    <measurement group_id="O4" value="57" spread="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0728</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0034</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0055</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue</title>
        <description>Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.</description>
        <time_frame>Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue</title>
          <description>Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>pmol/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5456" spread="3963"/>
                    <measurement group_id="O2" value="1403" spread="640"/>
                    <measurement group_id="O3" value="82" spread="77"/>
                    <measurement group_id="O4" value="42" spread="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0240</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0058</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0014</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0338</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-2h) of [6R]-5,10-methylene-THF</title>
        <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-2h) of [6R]-5,10-methylene-THF</title>
          <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="326.40261" spread="61.98416"/>
                    <measurement group_id="O2" value="239.90076" spread="0"/>
                    <measurement group_id="O3" value="7734.09113" spread="1557.76552"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-2h) of [6S]-5-THF</title>
        <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-2h) of [6S]-5-THF</title>
          <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="827.1083" spread="178.23243"/>
                    <measurement group_id="O2" value="640.0489" spread="0"/>
                    <measurement group_id="O3" value="19408.1712" spread="3000.64794"/>
                    <measurement group_id="O4" value="5639.2700" spread="885.82223"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-2h) of [6S]-5-methyl-THF</title>
        <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: [6S]-5-methyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-2h) of [6S]-5-methyl-THF</title>
          <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: [6S]-5-methyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2336.24432" spread="829.18634"/>
                    <measurement group_id="O2" value="1258.60184" spread="247.51353"/>
                    <measurement group_id="O3" value="2277.89290" spread="1132.95603"/>
                    <measurement group_id="O4" value="997.74091" spread="413.68052"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0728</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2246</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0166</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1752</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.9581</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0118</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-2h) of [6SR]-5-formyl-THF</title>
        <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-formyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-2h) of [6SR]-5-formyl-THF</title>
          <description>Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-formyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29911.9184" spread="6924.78031"/>
                    <measurement group_id="O2" value="7595.4599" spread="764.27650"/>
                    <measurement group_id="O3" value="0" spread="0"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(Last) of [6R]-5,10-methylene-THF</title>
        <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(Last) of [6R]-5,10-methylene-THF</title>
          <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="462.10746" spread="221.85761"/>
                    <measurement group_id="O2" value="239.90076" spread="0"/>
                    <measurement group_id="O3" value="7910.61038" spread="1623.24300"/>
                    <measurement group_id="O4" value="2272.78010" spread="448.01407"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0022</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(Last) of [6S]-5-THF</title>
        <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(Last) of [6S]-5-THF</title>
          <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2231.1443" spread="1051.06650"/>
                    <measurement group_id="O2" value="640.0489" spread="0"/>
                    <measurement group_id="O3" value="28466.5389" spread="5303.28705"/>
                    <measurement group_id="O4" value="6766.9104" spread="1484.91243"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(Last) of [6S]-5-methyl-THF</title>
        <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-methyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(Last) of [6S]-5-methyl-THF</title>
          <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-methyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32206.2771" spread="9121.1818"/>
                    <measurement group_id="O2" value="7689.0921" spread="5164.6098"/>
                    <measurement group_id="O3" value="21737.2428" spread="21757.1545"/>
                    <measurement group_id="O4" value="5495.1924" spread="6110.0065"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0240</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1336</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2725</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1893</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(Last) of [6S]-5-formyl-THF</title>
        <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-formyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(Last) of [6S]-5-formyl-THF</title>
          <description>Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-formyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>mcg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43429.1885" spread="12411.2844"/>
                    <measurement group_id="O2" value="9637.0308" spread="1637.2118"/>
                    <measurement group_id="O3" value="75.6174" spread="69.2176"/>
                    <measurement group_id="O4" value="50.1858" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0142</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0085</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax of [6R]-5,10-methylene-THF</title>
        <description>Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of [6R]-5,10-methylene-THF</title>
          <description>Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>µg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="195.0000" spread="40.76763"/>
                    <measurement group_id="O2" value="123.0000" spread="0"/>
                    <measurement group_id="O3" value="22087.5000" spread="5635.45853"/>
                    <measurement group_id="O4" value="6452.8571" spread="559.18477"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0014</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0021</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0014</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax of [6S]-5-THF in Plasma</title>
        <description>Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of [6S]-5-THF in Plasma</title>
          <description>Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>µg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="577.6250" spread="190.74436"/>
                    <measurement group_id="O2" value="335.0000" spread="0"/>
                    <measurement group_id="O3" value="13372.5000" spread="2108.15932"/>
                    <measurement group_id="O4" value="5015.7143" spread="427.35064"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax of [6S]-5-methyl-THF in Plasma</title>
        <description>Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of [6S]-5-methyl-THF in Plasma</title>
          <description>Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>µg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2786.25000" spread="822.6253"/>
                    <measurement group_id="O2" value="1078.00000" spread="275.26206"/>
                    <measurement group_id="O3" value="2020.50000" spread="1142.25116"/>
                    <measurement group_id="O4" value="800.42857" spread="396.41849"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0240</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1336</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1551</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1563</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax of [6S]-5-formyl-THF in Plasma</title>
        <description>Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R] 5,10- methylene-THF and the metabolites: [6S]-5-THF, [6S]-5-methyl-THF, and [6S]-5-formyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of [6S]-5-formyl-THF in Plasma</title>
          <description>Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R] 5,10- methylene-THF and the metabolites: [6S]-5-THF, [6S]-5-methyl-THF, and [6S]-5-formyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>µg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32962.5000" spread="8594.17369"/>
                    <measurement group_id="O2" value="10168.3333" spread="2271.47896"/>
                    <measurement group_id="O3" value="252.7500" spread="141.51178"/>
                    <measurement group_id="O4" value="261.0000" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0142</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0085</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0024</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax of [6R]-5,10-methylene-THF</title>
        <description>Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of [6R]-5,10-methylene-THF</title>
          <description>Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.14285857" spread="0.53079605"/>
                    <measurement group_id="O2" value="1.00000000" spread="0"/>
                    <measurement group_id="O3" value="0.08333000" spread="0.00000000"/>
                    <measurement group_id="O4" value="0.08333000" spread="0.00000000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>1.0000</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0010</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0005</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax of [6S]-5-THF</title>
        <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of [6S]-5-THF</title>
          <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.02083375" spread="1.03677360"/>
                    <measurement group_id="O2" value="1.50000000" spread="0"/>
                    <measurement group_id="O3" value="0.38541750" spread="0.24775936"/>
                    <measurement group_id="O4" value="0.09523571" spread="0.03149956"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0056</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0010</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0014</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax of [6S]-5-methyl-THF</title>
        <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of [6S]-5-methyl-THF</title>
          <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.75000000" spread="1.38873015"/>
                    <measurement group_id="O2" value="2.41666667" spread="0.66458007"/>
                    <measurement group_id="O3" value="3.75000000" spread="1.16496475"/>
                    <measurement group_id="O4" value="2.92857143" spread="0.93222724"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1796</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3243</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0263</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0268</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2041</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0061</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax of [6S]-5-formyl-THF</title>
        <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of [6S]-5-formyl-THF</title>
          <description>Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.12499750" spread="0.08908753"/>
                    <measurement group_id="O2" value="0.08333000" spread="0.00000000"/>
                    <measurement group_id="O3" value="0.10416500" spread="0.04167000"/>
                    <measurement group_id="O4" value="0.08333000" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(1/2) of [6R]-5,10-methylene-THF</title>
        <description>Terminal plasma elimination half-life time for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(1/2) of [6R]-5,10-methylene-THF</title>
          <description>Terminal plasma elimination half-life time for the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.07069184" spread="2.48958159"/>
                    <measurement group_id="O2" value="9.12204918" spread="0"/>
                    <measurement group_id="O3" value="0.90893994" spread="0.62586420"/>
                    <measurement group_id="O4" value="0.34368840" spread="0.06725217"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0268</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0227</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0933</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(1/2) of [6S]-5-THF</title>
        <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(1/2) of [6S]-5-THF</title>
          <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.59459251" spread="1.76982092"/>
                    <measurement group_id="O2" value="0" spread="0"/>
                    <measurement group_id="O3" value="1.24808943" spread="0.23995973"/>
                    <measurement group_id="O4" value="0.96378070" spread="0.19174152"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0177</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0058</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0043</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(1/2) of [6S]-5-methyl-THF</title>
        <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(1/2) of [6S]-5-methyl-THF</title>
          <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.0955575" spread="1.18981597"/>
                    <measurement group_id="O2" value="10.7281060" spread="8.80812064"/>
                    <measurement group_id="O3" value="9.0743346" spread="3.84317226"/>
                    <measurement group_id="O4" value="8.5121573" spread="2.80644764"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(1/2) of [6S]-5-formyl-THF</title>
        <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(1/2) of [6S]-5-formyl-THF</title>
          <description>Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.51328500" spread="0.34108131"/>
                    <measurement group_id="O2" value="0.98944069" spread="0.20217367"/>
                    <measurement group_id="O3" value="0.23180085" spread="0.13438901"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0668</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0502</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0081</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(Last) of [6R]-5,10-methylene-THF</title>
        <description>The time-point for the last measurable concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(Last) of [6R]-5,10-methylene-THF</title>
          <description>The time-point for the last measurable concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.00000000" spread="1.41421356"/>
                    <measurement group_id="O2" value="2.00000000" spread="0"/>
                    <measurement group_id="O3" value="3.25000000" spread="1.38873015"/>
                    <measurement group_id="O4" value="1.35714286" spread="0.24397502"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0011</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.6691</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(Last) of [6S]-5-THF</title>
        <description>The time-point for the last measurable concentration for the metabolite [6S]-5-TH in plasma</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(Last) of [6S]-5-THF</title>
          <description>The time-point for the last measurable concentration for the metabolite [6S]-5-TH in plasma</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.75000000" spread="1.48804762"/>
                    <measurement group_id="O2" value="2.00000000" spread="0"/>
                    <measurement group_id="O3" value="5.75000000" spread="0.70710678"/>
                    <measurement group_id="O4" value="3.42857143" spread="0.78679579"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0015</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0640</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1213</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(Last) of [6S]-5-methyl-THF</title>
        <description>The time-point for the last measurable concentration for the metabolite [6S]-5-methyl-THF in plasma</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(Last) of [6S]-5-methyl-THF</title>
          <description>The time-point for the last measurable concentration for the metabolite [6S]-5-methyl-THF in plasma</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.0000000" spread="0.00000000"/>
                    <measurement group_id="O2" value="12.0000000" spread="9.29516003"/>
                    <measurement group_id="O3" value="15.0000000" spread="9.62140471"/>
                    <measurement group_id="O4" value="8.5714286" spread="6.80336051"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1791</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4945</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0014</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5990</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0303</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0107</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T(Last) of [6S]-5-formyl-THF</title>
        <description>The time-point for the last measurable concentration for the metabolite [6S]-5-formyl-THF in plasma</description>
        <time_frame>Samples taken Day 1 (Day of surgery) and Day 2</time_frame>
        <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
        <group_list>
          <group group_id="O1">
            <title>L-LV(200)</title>
            <description>Levoleucovorin 200 mg/m2</description>
          </group>
          <group group_id="O2">
            <title>L-LV(60)</title>
            <description>Levoleucovorin 60 mg/m2</description>
          </group>
          <group group_id="O3">
            <title>Mod(200)</title>
            <description>Modufolin 200 mg/m2</description>
          </group>
          <group group_id="O4">
            <title>Mod(60)</title>
            <description>Modufolin 60 mg/m2</description>
          </group>
        </group_list>
        <measure>
          <title>T(Last) of [6S]-5-formyl-THF</title>
          <description>The time-point for the last measurable concentration for the metabolite [6S]-5-formyl-THF in plasma</description>
          <population>Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.</population>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.00000000" spread="0.00000000"/>
                    <measurement group_id="O2" value="8.33333333" spread="7.73735528"/>
                    <measurement group_id="O3" value="0.33333500" spread="0.23570226"/>
                    <measurement group_id="O4" value="0.16667000" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0125</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0017</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5286</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF</title>
        <description>Correlation between the exposure of [6R]-5,10-methylene-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6R]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF</title>
          <description>Correlation between the exposure of [6R]-5,10-methylene-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6R]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>correlation coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AUC(0-2h) vs. conc in tumor</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.54039"/>
                    <measurement group_id="O2" value="NA">Only one observation available for AUC(0-2h)</measurement>
                    <measurement group_id="O3" value="-0.21666"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AUC(0-2h) vs. conc in adjacent mucosa</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.68223"/>
                    <measurement group_id="O2" value="NA">Only one observation available for AUC(0-2h)</measurement>
                    <measurement group_id="O3" value="0.27618"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.6063</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.21666</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2105</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.54039</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5079</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.27618</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0913</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.68223</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF</title>
        <description>Correlation between the exposure of [6S]-5-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-THF in the tumor or adjacent mucosa at surgery.</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF</title>
          <description>Correlation between the exposure of [6S]-5-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-THF in the tumor or adjacent mucosa at surgery.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>correlation coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AUC(0-2h) vs. conc in tumor</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.02188"/>
                    <measurement group_id="O2" value="NA">Only one observation available for AUC(0-2h)</measurement>
                    <measurement group_id="O3" value="0.27018"/>
                    <measurement group_id="O4" value="0.38298"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AUC(0-2h) vs. conc in adjacent mucosa</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.07937"/>
                    <measurement group_id="O2" value="NA">Only one observation available for AUC(0-2h)</measurement>
                    <measurement group_id="O3" value="0.34905"/>
                    <measurement group_id="O4" value="0.45404"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3964</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.38298</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5175</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.27018</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.9590</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.02188</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3061</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.45404</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3967</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.34905</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.8518</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.07937</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF</title>
        <description>Correlation between the exposure of [6S]-5-methyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-methyl-THF in the tumor or adjacent mucosa at surgery.</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF</title>
          <description>Correlation between the exposure of [6S]-5-methyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-methyl-THF in the tumor or adjacent mucosa at surgery.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>correlation coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AUC(0-2h) vs. conc in tumor</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.73743"/>
                    <measurement group_id="O2" value="0.44757"/>
                    <measurement group_id="O3" value="0.03292"/>
                    <measurement group_id="O4" value="0.09033"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AUC(0-2h) vs. conc in adjacent mucosa</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.76502"/>
                    <measurement group_id="O2" value="0.34496"/>
                    <measurement group_id="O3" value="-0.66295"/>
                    <measurement group_id="O4" value="0.36854"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0586</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.73743</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2661</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.44757</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.9506</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.03292</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.8315</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.09033</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0451</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.76502</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.4027</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.34496</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1513</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.66295</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3690</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.36854</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF</title>
        <description>Correlation between the exposure of [6S]-5-formyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-formyl-THF in the tumor or adjacent mucosa at surgery.</description>
        <time_frame>Samples taken Day 1 (Day of surgery)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF</title>
          <description>Correlation between the exposure of [6S]-5-formyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-formyl-THF in the tumor or adjacent mucosa at surgery.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>correlation coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AUC(0-2h) vs. conc in tumor</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="6"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.68778"/>
                    <measurement group_id="O2" value="0.11512"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AUC(0-2h) vs. conc in adjacent mucosa</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.23512"/>
                    <measurement group_id="O2" value="0.02576"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5751</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.23512</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. concentration in adjacent mucosa</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.9672</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.02576</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0594</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.68778</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>AUC(0-2h) vs. conc in tumor</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.8281</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.11512</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Gene Expression Ratios (Mucosa:Tumor)</title>
        <description>Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.</description>
        <time_frame>Sample taken Day 1 (Day of Surgery)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Gene Expression Ratios (Mucosa:Tumor)</title>
          <description>Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>Ratio</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AMT</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.35"/>
                    <measurement group_id="O2" value="5.60"/>
                    <measurement group_id="O3" value="1.86"/>
                    <measurement group_id="O4" value="3.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PCFT</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.03"/>
                    <measurement group_id="O2" value="2.75"/>
                    <measurement group_id="O3" value="2.92"/>
                    <measurement group_id="O4" value="2.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>FPGS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.47"/>
                    <measurement group_id="O2" value="0.70"/>
                    <measurement group_id="O3" value="0.63"/>
                    <measurement group_id="O4" value="0.83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MTHFS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51"/>
                    <measurement group_id="O2" value="0.87"/>
                    <measurement group_id="O3" value="0.83"/>
                    <measurement group_id="O4" value="0.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ABCC3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.83"/>
                    <measurement group_id="O2" value="3.37"/>
                    <measurement group_id="O3" value="2.48"/>
                    <measurement group_id="O4" value="4.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>GGH</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50"/>
                    <measurement group_id="O2" value="0.47"/>
                    <measurement group_id="O3" value="0.35"/>
                    <measurement group_id="O4" value="0.31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ABCC1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.41"/>
                    <measurement group_id="O2" value="0.55"/>
                    <measurement group_id="O3" value="0.77"/>
                    <measurement group_id="O4" value="0.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MTHFD1L</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.15"/>
                    <measurement group_id="O2" value="0.24"/>
                    <measurement group_id="O3" value="0.29"/>
                    <measurement group_id="O4" value="0.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SHMT1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.89"/>
                    <measurement group_id="O2" value="1.13"/>
                    <measurement group_id="O3" value="0.72"/>
                    <measurement group_id="O4" value="2.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SHMT2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.31"/>
                    <measurement group_id="O2" value="0.34"/>
                    <measurement group_id="O3" value="0.38"/>
                    <measurement group_id="O4" value="0.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RFC-1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.48"/>
                    <measurement group_id="O2" value="0.66"/>
                    <measurement group_id="O3" value="0.53"/>
                    <measurement group_id="O4" value="1.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0451</p_value>
            <method>pearson</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlation of Gene Expression in Tumor and Adjacent Mucosa</title>
        <description>Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.</description>
        <time_frame>Sample taken Day 1 (Day of Surgery)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Correlation of Gene Expression in Tumor and Adjacent Mucosa</title>
          <description>Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>Normalized concentration</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AMT</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.47193"/>
                    <measurement group_id="O2" value="-0.70730"/>
                    <measurement group_id="O3" value="0.75404"/>
                    <measurement group_id="O4" value="0.42972"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PCFT</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.11497"/>
                    <measurement group_id="O2" value="0.89976"/>
                    <measurement group_id="O3" value="0.58502"/>
                    <measurement group_id="O4" value="0.88128"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>FPGS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.17664"/>
                    <measurement group_id="O2" value="-0.64743"/>
                    <measurement group_id="O3" value="0.88682"/>
                    <measurement group_id="O4" value="0.97624"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MTHFS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.95840"/>
                    <measurement group_id="O2" value="0.58419"/>
                    <measurement group_id="O3" value="0.43194"/>
                    <measurement group_id="O4" value="0.94364"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ABCC3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.00322"/>
                    <measurement group_id="O2" value="0.77700"/>
                    <measurement group_id="O3" value="-0.25891"/>
                    <measurement group_id="O4" value="-0.38987"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>GGH</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.78928"/>
                    <measurement group_id="O2" value="-0.09737"/>
                    <measurement group_id="O3" value="0.46883"/>
                    <measurement group_id="O4" value="0.93711"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ABCC1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.74757"/>
                    <measurement group_id="O2" value="0.14436"/>
                    <measurement group_id="O3" value="-0.16724"/>
                    <measurement group_id="O4" value="0.82963"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MTHFD1L</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.74459"/>
                    <measurement group_id="O2" value="0.20955"/>
                    <measurement group_id="O3" value="0.37160"/>
                    <measurement group_id="O4" value="0.32113"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SHMT1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.59183"/>
                    <measurement group_id="O2" value="0.05531"/>
                    <measurement group_id="O3" value="0.67853"/>
                    <measurement group_id="O4" value="0.50966"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SHMT2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.55508"/>
                    <measurement group_id="O2" value="-0.71666"/>
                    <measurement group_id="O3" value="0.86266"/>
                    <measurement group_id="O4" value="0.81040"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RFC-1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.64565"/>
                    <measurement group_id="O2" value="-0.02450"/>
                    <measurement group_id="O3" value="0.23312"/>
                    <measurement group_id="O4" value="0.31800"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for AMT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3359</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.42972</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for AMT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0307</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.75404</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for AMT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1160</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.70730</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for AMT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2377</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.47193</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for PCFT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0087</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.88128</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for PCFT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1277</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.58502</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for PCFT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0146</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.89976</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for PCFT gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.7863</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.11497</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for FPGS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0002</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.97624</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for FPGS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0033</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.88682</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for FPGS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1645</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.64743</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for FPGS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.6756</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.17664</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0014</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.94364</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2852</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.43194</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2234</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.58419</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFS gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0002</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.95840</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC3 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3873</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.38987</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC3 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5358</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.25891</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC3 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0691</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.77700</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC3 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.9940</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.00322</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for GGH gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0018</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.93711</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for GGH gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2413</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.46883</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for GGH gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.8544</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.09737</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for GGH gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0199</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.78928</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0209</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.82963</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.6922</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.16724</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.7850</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.14436</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for ABCC1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0330</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.74757</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFD1L gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.4825</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.32113</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFD1L gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3647</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.37160</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFD1L gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.6903</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.20955</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for MTHFD1L gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0341</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.74459</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2426</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.50966</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0643</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.67853</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.9171</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.05531</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1222</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.59183</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT2 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0271</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.81040</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT2 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0058</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.86266</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT2 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1090</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.71666</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for SHMT2 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1533</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.55508</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Correlation for RFC-1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.4870</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.31800</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Correlation for RFC-1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5785</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.23312</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Correlation for RFC-1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.9632</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>-0.02450</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation for RFC-1 gene expression</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0838</p_value>
            <method>Pearson Correlation</method>
            <param_type>Correlation factor</param_type>
            <param_value>0.64565</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Homocystein Concentration</title>
        <description>Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).</description>
        <time_frame>Samples taken at Screening visit, Day 2, and End of Study (Day 5)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Homocystein Concentration</title>
          <description>Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>μmol/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Concentration at Screening</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.59" spread="4.28"/>
                    <measurement group_id="O2" value="11.27" spread="3.98"/>
                    <measurement group_id="O3" value="14.53" spread="6.22"/>
                    <measurement group_id="O4" value="13.80" spread="3.83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Concentration at Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.41" spread="2.32"/>
                    <measurement group_id="O2" value="6.40" spread="3.10"/>
                    <measurement group_id="O3" value="7.06" spread="1.97"/>
                    <measurement group_id="O4" value="8.14" spread="2.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Concentration at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.04" spread="2.53"/>
                    <measurement group_id="O2" value="9.18" spread="4.65"/>
                    <measurement group_id="O3" value="10.20" spread="3.34"/>
                    <measurement group_id="O4" value="10.10" spread="2.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>S-Folate Concentration</title>
        <description>Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).</description>
        <time_frame>Samples taken at Screening visit, Day 2 and End of Study (Day 5)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>S-Folate Concentration</title>
          <description>Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>nmol/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Concentration at Screening</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.75" spread="8.88"/>
                    <measurement group_id="O2" value="21.00" spread="6.54"/>
                    <measurement group_id="O3" value="15.03" spread="5.20"/>
                    <measurement group_id="O4" value="18.71" spread="7.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Concentration at Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.00" spread="0.00"/>
                    <measurement group_id="O2" value="45.00" spread="0.00"/>
                    <measurement group_id="O3" value="45.00" spread="0.00"/>
                    <measurement group_id="O4" value="45.00" spread="0.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Concentration at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.75" spread="0.71"/>
                    <measurement group_id="O2" value="40.80" spread="9.39"/>
                    <measurement group_id="O3" value="44.14" spread="2.27"/>
                    <measurement group_id="O4" value="40.29" spread="3.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Homocystein Concentration From Screening</title>
        <description>Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.&#xD;
The criteria for assessment categories &quot;normal&quot;, &quot;low&quot; and &quot;high&quot; were based on the reference ranges for plasma-Homocystein as follows: &quot;low&quot; &lt;4,7 mcmol/L; &quot;normal&quot; =&gt; 4,7 and &lt;=16 mcmol/L; &quot;high&quot; &gt;16 mcmol/L. Values were applicable for both male and female adults.</description>
        <time_frame>Samples taken at Screening visit, Day 2 and End of Study (Day 5)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Homocystein Concentration From Screening</title>
          <description>Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.&#xD;
The criteria for assessment categories &quot;normal&quot;, &quot;low&quot; and &quot;high&quot; were based on the reference ranges for plasma-Homocystein as follows: &quot;low&quot; &lt;4,7 mcmol/L; &quot;normal&quot; =&gt; 4,7 and &lt;=16 mcmol/L; &quot;high&quot; &gt;16 mcmol/L. Values were applicable for both male and female adults.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Normal at Screen and Normal at Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shift from Normal at Screen to Low at Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shift from High at Screen to Normal at Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal at Screen and Normal at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shift from Normal at Screen to Low at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shift from High at Screen and Normal at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Missing data Screen to Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in S-Folate Concentration From Screening</title>
        <description>Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.</description>
        <time_frame>Samples taken at Screening visit, Day 2 and End of Study (Day 5)</time_frame>
        <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>Modufolin 60 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Change in S-Folate Concentration From Screening</title>
          <description>Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.</description>
          <population>The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Shift from Normal at Screen to High at Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="8"/>
                    <measurement group_id="O3" value="5"/>
                    <measurement group_id="O4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Missing data Screen to Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal at Screening and Normal at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shift from Normal at Screen to High at Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="6"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Missing data Screen to Day 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of AEs Per Severity</title>
        <description>Number of reported AEs per treatment with respect to severity</description>
        <time_frame>Screening visit until end of study, Day 5</time_frame>
        <population>The safety population contained 31 of the 32 enrolled patients. One patient randomized to L-LV 60 mg/m2 was withdrawn prior to study drug administration and thus excluded from the safety analysis set.</population>
        <group_list>
          <group group_id="O1">
            <title>Levoleucovorin 200 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O2">
            <title>Levoleucovorin 60 mg/m2</title>
            <description>Levoleucovorin: i.v. bolus injection</description>
          </group>
          <group group_id="O3">
            <title>Modufolin 200 mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
          <group group_id="O4">
            <title>Modufolin mg/m2</title>
            <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
          </group>
        </group_list>
        <measure>
          <title>Number of AEs Per Severity</title>
          <description>Number of reported AEs per treatment with respect to severity</description>
          <population>The safety population contained 31 of the 32 enrolled patients. One patient randomized to L-LV 60 mg/m2 was withdrawn prior to study drug administration and thus excluded from the safety analysis set.</population>
          <units>Events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AEs of mild severity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AEs of moderate severity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="7"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AEs of severe severity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Levoleucovorin 200 mg/m2</title>
          <description>Levoleucovorin: i.v. bolus injection</description>
        </group>
        <group group_id="E2">
          <title>Levoleucovorin 60 mg/m2</title>
          <description>Levoleucovorin: i.v. bolus injection</description>
        </group>
        <group group_id="E3">
          <title>6R-MTHF 200 mg/m2</title>
          <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
        </group>
        <group group_id="E4">
          <title>6R-MTHF 60 mg/m2</title>
          <description>[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute mycardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Postoperative wound complication</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Anastomotic leak</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Mouth haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Paralysis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Anders Rabbe</name_or_title>
      <organization>Isofol Medical</organization>
      <phone>+46 (0)707 64 65 00</phone>
      <email>anders.rabbe@isofolmedical.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01681472
org study id: ISO-CC-002
secondary id: 2012-000522-22
nct id: NCT01681472
lead sponsor: 
has dmc: No
The purpose of this study is to compare the concentration of four different metabolites in
      the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two
      different doses of Modufolin (arfolitixorin) and Levoleucovorin (Isovorin®), respectively (60
      and 200 mg/m2).
The purpose of this study is to compare the concentration of [6R] 5,10-methylene-THF,
      5-formyl-THF, 5-methyl-THF and THF in the tumor, in adjacent mucosa and in plasma in patients
      with colon cancer receiving two different does of Modufolin® and Levoleucovorin (Isovorin®),
      respectively (60 and 200 mg/m2).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Concentration of [6R]-5,10-methylene-THF in Tumor Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.
measure: Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.
measure: Concentration of [6S]-5-THF in Tumor Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.
measure: Concentration of [6S]-5-THF in Adjacent Mucosa Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.
measure: Concentration of [6S]-5-methyl-THF in Tumor Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.
measure: Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.
measure: Concentration of [6S]-5-formyl-THF in Tumor Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.
measure: Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue
time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
description: Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.
measure: AUC(0-2h) of [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: [6R]-5,10-methylene-THF
measure: AUC(0-2h) of [6S]-5-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-THF
measure: AUC(0-2h) of [6S]-5-methyl-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: [6S]-5-methyl-THF
measure: AUC(0-2h) of [6SR]-5-formyl-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-formyl-THF
measure: AUC(Last) of [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: [6R]-5,10-methylene-THF
measure: AUC(Last) of [6S]-5-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-THF
measure: AUC(Last) of [6S]-5-methyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-methyl-THF
measure: AUC(Last) of [6S]-5-formyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-formyl-THF
measure: Cmax of [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R]-5,10-methylene-THF
measure: Cmax of [6S]-5-THF in Plasma
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF
measure: Cmax of [6S]-5-methyl-THF in Plasma
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF
measure: Cmax of [6S]-5-formyl-THF in Plasma
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R] 5,10- methylene-THF and the metabolites: [6S]-5-THF, [6S]-5-methyl-THF, and [6S]-5-formyl-THF
measure: Tmax of [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: [6R]-5,10-methylene-THF
measure: Tmax of [6S]-5-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF
measure: Tmax of [6S]-5-methyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF
measure: Tmax of [6S]-5-formyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF
measure: T(1/2) of [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Terminal plasma elimination half-life time for the active substance in Modufolin: [6R]-5,10-methylene-THF
measure: T(1/2) of [6S]-5-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Terminal plasma elimination half-life time for the metabolite [6S]-5-THF
measure: T(1/2) of [6S]-5-methyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF
measure: T(1/2) of [6S]-5-formyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF
measure: T(Last) of [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: The time-point for the last measurable concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF
measure: T(Last) of [6S]-5-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: The time-point for the last measurable concentration for the metabolite [6S]-5-TH in plasma
measure: T(Last) of [6S]-5-methyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: The time-point for the last measurable concentration for the metabolite [6S]-5-methyl-THF in plasma
measure: T(Last) of [6S]-5-formyl-THF
time frame: Samples taken Day 1 (Day of surgery) and Day 2
description: The time-point for the last measurable concentration for the metabolite [6S]-5-formyl-THF in plasma
measure: Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Correlation between the exposure of [6R]-5,10-methylene-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6R]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.
measure: Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Correlation between the exposure of [6S]-5-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-THF in the tumor or adjacent mucosa at surgery.
measure: Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Correlation between the exposure of [6S]-5-methyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-methyl-THF in the tumor or adjacent mucosa at surgery.
measure: Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF
time frame: Samples taken Day 1 (Day of surgery)
description: Correlation between the exposure of [6S]-5-formyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-formyl-THF in the tumor or adjacent mucosa at surgery.
measure: Gene Expression Ratios (Mucosa:Tumor)
time frame: Sample taken Day 1 (Day of Surgery)
description: Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.
measure: Correlation of Gene Expression in Tumor and Adjacent Mucosa
time frame: Sample taken Day 1 (Day of Surgery)
description: Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.
measure: Homocystein Concentration
time frame: Samples taken at Screening visit, Day 2, and End of Study (Day 5)
description: Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).
measure: S-Folate Concentration
time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
description: Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).
measure: Change in Homocystein Concentration From Screening
time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
description: Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.
The criteria for assessment categories "normal", "low" and "high" were based on the reference ranges for plasma-Homocystein as follows: "low" <4,7 mcmol/L; "normal" => 4,7 and <=16 mcmol/L; "high" >16 mcmol/L. Values were applicable for both male and female adults.
measure: Change in S-Folate Concentration From Screening
time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
description: Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.
measure: Number of AEs Per Severity
time frame: Screening visit until end of study, Day 5
description: Number of reported AEs per treatment with respect to severity
arm group label: Levoleucovorin 200 mg/m2
arm group type: Active Comparator
description: One i.v. bolus injection of study drug after the patient has been anaesthetized.
arm group label: Levoleucovorin 60 mg/m2
arm group type: Active Comparator
description: One i.v. bolus injection of study drug after the patient has been anaesthetized.
arm group label: 6R-MTHF 200 mg/m2
arm group type: Experimental
description: One i.v. bolus injection of study drug after the patient has been anaesthetized.
arm group label: 6R-MTHF 60 mg/m2
arm group type: Experimental
description: One i.v. bolus injection of study drug after the patient has been anaesthetized.
intervention type: Drug
intervention name: 6R-MTHF (arfolitixorin) 200 mg/m2
description: i.v. bolus injection
arm group label: 6R-MTHF 200 mg/m2
other name: Modufolin®
other name: ISO-901
other name: [6R] 5,10-methylenetetrahydrofolate
other name: arfolitixorin
intervention type: Drug
intervention name: Levoleucovorin 200 mg/m2
description: i.v. bolus injection
arm group label: Levoleucovorin 200 mg/m2
other name: Isovorin®
intervention type: Drug
intervention name: 6R-MTHF (arfolitixorin) 60 mg/m2
description: i.v. bolus injection
arm group label: 6R-MTHF 60 mg/m2
other name: Modufolin®
other name: ISO-901
other name: [6R] 5,10-methylenetetrahydrofolate
other name: arfolitixorin
intervention type: Drug
intervention name: Levoleucovorin 60 mg/m2
description: i.v. bolus injection
arm group label: Levoleucovorin 60 mg/m2
other name: Isovorin®
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kristoffer Derwinger, MD PhD
role: Principal Investigator
affiliation: Sahlgrenska University Hospital, Sweden
facility: 
country: Sweden
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Colonic Neoplasms
mesh term: Leucovorin
mesh term: Tetrahydrofolates
mesh term: Levoleucovorin
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 