<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/NCT03254394</url>
  </required_header>
  <id_info>
    <org_study_id>201705166</org_study_id>
    <nct_id>NCT03254394</nct_id>
  </id_info>
  <brief_title>Lidocaine for Oxaliplatin-induced Neuropathy</brief_title>
  <official_title>Intravenous Lidocaine for Preventing Painful Oxaliplatin-induced Peripheral Neuropathy (OIPN)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Oxaliplatin-induced neuropathy is a major dose-limiting side effect in patients with&#xD;
      colorectal cancer treated with the FOLFOX chemotherapy regimen. Hypersensitivity to cold is&#xD;
      the sensory hallmark of oxaliplatin-induced neuropathy, and it can predict the development of&#xD;
      long-term neuropathy. In this study, the investigators aim to determine whether intravenous&#xD;
      lidocaine can prevent oxaliplatin-induced cold hypersensitivity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Colorectal cancer is the third leading cause of cancer death in the United States, with an&#xD;
      estimated incidence of 130.000 cases per year. Oxaliplatin is the first-line chemotherapy&#xD;
      regimen for gastro-intestinal cancers. Despite its efficacy, oxaliplatin causes peripheral&#xD;
      neuropathy in 72% of the treated patients. Acute oxaliplatin-induced peripheral neuropathy&#xD;
      [OIPN] is the most common dose-limiting side effect of oxaliplatin and characterized by&#xD;
      profound cold allodynia in the extremities. In about 21% of the patients acute OIPN&#xD;
      exacerbates into chronic neuropathic pain, which is treatment resistant to currently approved&#xD;
      drugs, pointing towards a great need to identify an effective strategy in preventing OIPN.&#xD;
      Recent literature suggests that certain methods of assessing sensory nerve function in&#xD;
      neuropathic pain patients may provide a prediction to an individual analgesic response;&#xD;
      however, no placebo-controlled studies have been performed with the primary goal of&#xD;
      identifying treatment response predictors in preventing OIPN.&#xD;
&#xD;
      In this pilot study we will both determine the tolerability and the efficacy of intravenous&#xD;
      Lidocaine, for preventing oxaliplatin-induced cold hypersensitivity in the setting of&#xD;
      mFOLFOX6 chemotherapy for advanced colorectal cancer.&#xD;
&#xD;
      The proposed study will be conducted in two phases. The tolerability phase is an open-label&#xD;
      study to determine the tolerable dose regimen of IV lidocaine in patients with advanced&#xD;
      colorectal cancer receiving oxaliplatin chemotherapy. The efficacy pilot phase is a&#xD;
      randomized, double-blinded, controlled study comparing the outcomes between IV lidocaine&#xD;
      versus placebo in the same setting of colorectal cancer. Consented subjects will attend a&#xD;
      screening visit and six intervention visits, during which they will undergo sensory testing&#xD;
      and receive intravenous lidocaine or placebo infusion. Cold hypersensitivity and spontaneous&#xD;
      pain will be assessed at baseline, daily for 12 weeks and at follow-up visits. At enrollment,&#xD;
      each patient will be assigned a study number, which will match a previously prepared&#xD;
      computer-generated list of randomization numbers to determine the interventions lidocaine or&#xD;
      placebo. The participants and all other study personnel will be blinded to the treatment&#xD;
      allocation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 15, 2017</start_date>
  <completion_date type="Actual">April 1, 2021</completion_date>
  <primary_completion_date type="Actual">September 28, 2020</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>
    <intervention_model_description>Tolerability phase: prospective, open-label Efficacy pilot study: randomized, parallel, double blind, placebo controlled</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>At enrollment, each patient will be assigned a study number, which will match a previously prepared computer-generated list of randomization numbers to determine the interventions. The participants and all other study personnel will be blinded to the treatment allocation.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time</measure>
    <time_frame>14 weeks</time_frame>
    <description>The intensity of cold pain and cold unpleasantness is evaluated separately, assessed daily on a 0-10 scale, upon holding a pre-cooled (~8°C) metal cylinder for 10 seconds. the area under the curve of cold pain and cold unpleasantness vs time is calculated per chemotherapy cycle (every two weeks) and serves as a primary outcome measure.&#xD;
For intervention (lidocaine+FOLFOX) and control (placebo+FOLFOX) groups, the average of cold pain AUC and cold unpleasantness AUC over 7 cycles was calculated. The average AUCs over 7 cycles were compared between study arms.&#xD;
The AUC is measured as a score on a 0-10 scale multiplied by 14 days and may range between 0 and 140. Higher AUC values represent more intense cold pain/unpleasantness.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CIPN Score on EORTC QLQ-CIPN20</measure>
    <time_frame>12 weeks and 34-36 weeks</time_frame>
    <description>Change in CIPN (Chemotherapy-induced peripheral Neuropathy) score (on EORTC QLQ-CIPN20 tool ) from baseline to the Cycle 6 (12 weeks), and from baseline to last follow-up (34-36 weeks). EORTC QLQ-CIPN20 ranges from 0 (no symptoms) to 100 (worst symptoms). A higher score represents worse neuropathy. The changes in scores are compared between study arms.&#xD;
EORTC QLQ-CIPN20 tool is a quality of life questionnaire (QLQ) from the European Organization for Research and Treatment of Cancer (EORTC) for evaluation of CIPN.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in NPSI Score.</measure>
    <time_frame>6 weeks, 12 weeks, 34-36 weeks</time_frame>
    <description>Changes in Neuropathic Pain Symptom Inventory (NPSI) descriptors of neuropathic pain over time from baseline to cycle 3(6 weeks), cycle 6 (12 weeks), and the last follow-up (34-36 weeks). The total NPSI score ranges from 0 to 100; a higher NPSI total score represents a worse neuropathy outcome. The changes in scores from baseline are compared between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Cumulative Dose of Oxaliplatin</measure>
    <time_frame>24 weeks</time_frame>
    <description>The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6 treatment regimen. It corresponds to the absolute summed up quantity of Oxaliplatin administered to the patient over time. There is no range for this measure. Since this is a dose-limiting neuropathy prevention study, the higher value can be interpreted as better outcome.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Neuropathy, Painful</condition>
  <condition>Chemotherapy-induced Peripheral Neuropathy</condition>
  <condition>Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Placebo + FOLFOX</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lidocaine + FOLFOX</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lidocaine Hydrochloride</intervention_name>
    <description>Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.</description>
    <arm_group_label>Lidocaine + FOLFOX</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Dextrose 5% in water will be administered as active comparator.</description>
    <arm_group_label>Placebo + FOLFOX</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FOLFOX regimen</intervention_name>
    <description>Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
    <arm_group_label>Lidocaine + FOLFOX</arm_group_label>
    <arm_group_label>Placebo + FOLFOX</arm_group_label>
    <other_name>mFOLFOX6</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stage III and IV colorectal cancer.&#xD;
&#xD;
          -  Scheduled for oxaliplatin treatment in mFOLFOX6-based chemotherapy regimen.&#xD;
&#xD;
          -  Able to understand and willing to sign an IRB-approved written informed consent&#xD;
             document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Renal insufficiency (defined as calculated Creatinine clearance &lt; 30mL/min)&#xD;
&#xD;
          -  Moderate to severe liver failure (defined as ALT or AST &gt; 3 times upper limit of&#xD;
             normal if no liver metastases are present; ALT or AST &gt; 5 times upper limit of normal&#xD;
             if liver metastases are present).&#xD;
&#xD;
          -  Presence of brain metastases.&#xD;
&#xD;
          -  Patients with currently uncontrolled cardiac arrhythmias (non-sinus rhythm).&#xD;
&#xD;
          -  Patients with history of arrhythmias under pharmacological/pacemaker control will be&#xD;
             allowed, except if receiving antiarrhythmic medication listed in &quot;contra-indicated&#xD;
             medications&quot;.&#xD;
&#xD;
          -  Contraindication or allergy to intravenous lidocaine.&#xD;
&#xD;
          -  Pre-existing symmetric peripheral painful neuropathy.&#xD;
&#xD;
          -  Treated with chemotherapy within the past 12 months.&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Currently treated with any of the following contraindicated medications: Saquinavir,&#xD;
             Lopinavir, Amprenavir, Atazanavir, Delavirdine, Mexiletine (and other types of&#xD;
             sodium-channel blocker antiarrhythmics), Phenytoin, Carbamazepine, Oxcarbazepine,&#xD;
             Lamotrigine, Amiodarone, Dronedarone, Dihydroergotamine, Cimetidine&#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>Simon Haroutounian, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine/Barnes Jewish Hospital</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014 Dec;155(12):2461-2470. doi: 10.1016/j.pain.2014.09.020. Epub 2014 Sep 23.</citation>
    <PMID>25261162</PMID>
  </reference>
  <reference>
    <citation>Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology. 2004 Jan 27;62(2):218-25. doi: 10.1212/01.wnl.0000103237.62009.77.</citation>
    <PMID>14745057</PMID>
  </reference>
  <reference>
    <citation>Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D. Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology. 2000 Feb 8;54(3):564-74. doi: 10.1212/wnl.54.3.564.</citation>
    <PMID>10680784</PMID>
  </reference>
  <results_reference>
    <citation>Ventzel L, Madsen CS, Jensen AB, Jensen AR, Jensen TS, Finnerup NB. Assessment of acute oxaliplatin-induced cold allodynia: a pilot study. Acta Neurol Scand. 2016 Feb;133(2):152-155. doi: 10.1111/ane.12443. Epub 2015 Jun 2.</citation>
    <PMID>26032776</PMID>
  </results_reference>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>August 9, 2017</study_first_submitted>
  <study_first_submitted_qc>August 15, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 18, 2017</study_first_posted>
  <results_first_submitted>September 15, 2021</results_first_submitted>
  <results_first_submitted_qc>February 10, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 9, 2022</results_first_posted>
  <last_update_submitted>February 10, 2022</last_update_submitted>
  <last_update_submitted_qc>February 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Washington University School of Medicine</investigator_affiliation>
    <investigator_full_name>simon.haroutounian</investigator_full_name>
    <investigator_title>Assistant Professor of Anesthesiology</investigator_title>
  </responsible_party>
  <keyword>Oxaliplatin</keyword>
  <keyword>Cold hypersensitivity</keyword>
  <keyword>Neuropathy</keyword>
  <keyword>Colorectal cancer</keyword>
  <keyword>CIPN</keyword>
  <keyword>Neuropathic Pain</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Peripheral Nervous System Diseases</mesh_term>
    <mesh_term>Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lidocaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD will be shared 6 months after publication of the results in a peer-reviewed journal, upon submission of a robust data analysis plan to the study investigators.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>6 months after publication</ipd_time_frame>
    <ipd_access_criteria>IPD will be shared 6 months after publication of the results in a peer-reviewed journal, upon submission of a robust data analysis plan to the study investigators.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 12, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03254394/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Placebo + FOLFOX</title>
          <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
        </group>
        <group group_id="P2">
          <title>Lidocaine + FOLFOX</title>
          <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>This includes only patients who are enrolled and randomized into 2 groups.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo + FOLFOX</title>
          <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
        </group>
        <group group_id="B2">
          <title>Lidocaine + FOLFOX</title>
          <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
        </group>
        <group group_id="B3">
          <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="12"/>
            <count group_id="B2" value="14"/>
            <count group_id="B3" value="26"/>
          </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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </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="52.3" spread="16.4"/>
                    <measurement group_id="B2" value="50.9" spread="13.2"/>
                    <measurement group_id="B3" value="51.5" spread="14.5"/>
                  </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="6"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time</title>
        <description>The intensity of cold pain and cold unpleasantness is evaluated separately, assessed daily on a 0-10 scale, upon holding a pre-cooled (~8°C) metal cylinder for 10 seconds. the area under the curve of cold pain and cold unpleasantness vs time is calculated per chemotherapy cycle (every two weeks) and serves as a primary outcome measure.&#xD;
For intervention (lidocaine+FOLFOX) and control (placebo+FOLFOX) groups, the average of cold pain AUC and cold unpleasantness AUC over 7 cycles was calculated. The average AUCs over 7 cycles were compared between study arms.&#xD;
The AUC is measured as a score on a 0-10 scale multiplied by 14 days and may range between 0 and 140. Higher AUC values represent more intense cold pain/unpleasantness.</description>
        <time_frame>14 weeks</time_frame>
        <population>data for 14 days following the 6th cycle was collected and analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo + FOLFOX</title>
            <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
          <group group_id="O2">
            <title>Lidocaine + FOLFOX</title>
            <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time</title>
          <description>The intensity of cold pain and cold unpleasantness is evaluated separately, assessed daily on a 0-10 scale, upon holding a pre-cooled (~8°C) metal cylinder for 10 seconds. the area under the curve of cold pain and cold unpleasantness vs time is calculated per chemotherapy cycle (every two weeks) and serves as a primary outcome measure.&#xD;
For intervention (lidocaine+FOLFOX) and control (placebo+FOLFOX) groups, the average of cold pain AUC and cold unpleasantness AUC over 7 cycles was calculated. The average AUCs over 7 cycles were compared between study arms.&#xD;
The AUC is measured as a score on a 0-10 scale multiplied by 14 days and may range between 0 and 140. Higher AUC values represent more intense cold pain/unpleasantness.</description>
          <population>data for 14 days following the 6th cycle was collected and analyzed.</population>
          <units>score on a scale*days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>pain AUC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.4" spread="18.3"/>
                    <measurement group_id="O2" value="9.5" spread="14.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>unpleasantness AUC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.1" spread="27.8"/>
                    <measurement group_id="O2" value="25.4" spread="22.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis: Average AUC of cold pain score over 14 days of a chemotherapy cycle in the Control group is equal or lower than that of the experimental group. The comparison is for average AUC values over 7 cycles of chemotherapy per patient</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.318</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>6.88</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-7.09</ci_lower_limit>
            <ci_upper_limit>20.85</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis: Cold hypersensitivity counted as unpleasantness score for 14 days after cycle (AUC) in the Control group is less than that of the experimental group. The difference was calculated for the Cycle 6 visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.466</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>7.67</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-13.76</ci_lower_limit>
            <ci_upper_limit>29.10</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>CIPN Score on EORTC QLQ-CIPN20</title>
        <description>Change in CIPN (Chemotherapy-induced peripheral Neuropathy) score (on EORTC QLQ-CIPN20 tool ) from baseline to the Cycle 6 (12 weeks), and from baseline to last follow-up (34-36 weeks). EORTC QLQ-CIPN20 ranges from 0 (no symptoms) to 100 (worst symptoms). A higher score represents worse neuropathy. The changes in scores are compared between study arms.&#xD;
EORTC QLQ-CIPN20 tool is a quality of life questionnaire (QLQ) from the European Organization for Research and Treatment of Cancer (EORTC) for evaluation of CIPN.</description>
        <time_frame>12 weeks and 34-36 weeks</time_frame>
        <population>Patients in each group who had corresponding visit data</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo + FOLFOX</title>
            <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
          <group group_id="O2">
            <title>Lidocaine + FOLFOX</title>
            <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
        </group_list>
        <measure>
          <title>CIPN Score on EORTC QLQ-CIPN20</title>
          <description>Change in CIPN (Chemotherapy-induced peripheral Neuropathy) score (on EORTC QLQ-CIPN20 tool ) from baseline to the Cycle 6 (12 weeks), and from baseline to last follow-up (34-36 weeks). EORTC QLQ-CIPN20 ranges from 0 (no symptoms) to 100 (worst symptoms). A higher score represents worse neuropathy. The changes in scores are compared between study arms.&#xD;
EORTC QLQ-CIPN20 tool is a quality of life questionnaire (QLQ) from the European Organization for Research and Treatment of Cancer (EORTC) for evaluation of CIPN.</description>
          <population>Patients in each group who had corresponding visit data</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2" lower_limit="0" upper_limit="8.3"/>
                    <measurement group_id="O2" value="4" lower_limit="0" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>34-36 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.0" lower_limit="5.5" upper_limit="39.8"/>
                    <measurement group_id="O2" value="37.0" lower_limit="7.4" upper_limit="47.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>the null hypothesis is EORTC QLQ-CIPN20 sensory score change in the Control group is equal to or less than that of the experimental group for the last follow-up study visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.338</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>20</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is EORTC QLQ-CIPN20 sensory score change in the Control group is equal to or less than that of the experimental group for the cycle 6 (12 weeks) follow-up study visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.759</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>2</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in NPSI Score.</title>
        <description>Changes in Neuropathic Pain Symptom Inventory (NPSI) descriptors of neuropathic pain over time from baseline to cycle 3(6 weeks), cycle 6 (12 weeks), and the last follow-up (34-36 weeks). The total NPSI score ranges from 0 to 100; a higher NPSI total score represents a worse neuropathy outcome. The changes in scores from baseline are compared between study arms.</description>
        <time_frame>6 weeks, 12 weeks, 34-36 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo + FOLFOX</title>
            <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
          <group group_id="O2">
            <title>Lidocaine + FOLFOX</title>
            <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in NPSI Score.</title>
          <description>Changes in Neuropathic Pain Symptom Inventory (NPSI) descriptors of neuropathic pain over time from baseline to cycle 3(6 weeks), cycle 6 (12 weeks), and the last follow-up (34-36 weeks). The total NPSI score ranges from 0 to 100; a higher NPSI total score represents a worse neuropathy outcome. The changes in scores from baseline are compared between study arms.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>6 weeks visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="O2" value="0" lower_limit="0" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 weeks visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="O2" value="0" lower_limit="0" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>last follow-up visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" lower_limit="0.8" upper_limit="7.3"/>
                    <measurement group_id="O2" value="13.5" lower_limit="0" upper_limit="17.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is NPSI total score in the Control group is equal to or less than that of the experimental group for the C3 (6 weeks) study visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.581</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is NPSI total score in the Control group is equal to or less than that of the experimental group for the C6 (12 weeks) study visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.962</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is NPSI total score in the Control group is equal to or less than that of the experimental group for the last follow-up study visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.365</p_value>
            <p_value_desc>p-value was not adjusted for any parameter.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>10.50</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Cumulative Dose of Oxaliplatin</title>
        <description>The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6 treatment regimen. It corresponds to the absolute summed up quantity of Oxaliplatin administered to the patient over time. There is no range for this measure. Since this is a dose-limiting neuropathy prevention study, the higher value can be interpreted as better outcome.</description>
        <time_frame>24 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo + FOLFOX</title>
            <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
          <group group_id="O2">
            <title>Lidocaine + FOLFOX</title>
            <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
          </group>
        </group_list>
        <measure>
          <title>The Cumulative Dose of Oxaliplatin</title>
          <description>The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6 treatment regimen. It corresponds to the absolute summed up quantity of Oxaliplatin administered to the patient over time. There is no range for this measure. Since this is a dose-limiting neuropathy prevention study, the higher value can be interpreted as better outcome.</description>
          <units>mg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1161.8" spread="300.2"/>
                    <measurement group_id="O2" value="1294.8" spread="221.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is Oxaliplatin cumulative dose in the Control group is equal to or higher than that of the experimental group.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.730</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>57.68</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1771</ci_lower_limit>
            <ci_upper_limit>1886</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>16 weeks</time_frame>
      <desc>Adverse Event: any unfavorable medical occurrence in a human subject including any abnormal sign, symptom, or disease.&#xD;
For the purposes of this protocol, all adverse events will be collected and documented on CRFs by questionnaire.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo + FOLFOX</title>
          <description>Intravenous infusion of D5W solution over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Placebo: Dextrose 5% in water will be administered as active comparator.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
        </group>
        <group group_id="E2">
          <title>Lidocaine + FOLFOX</title>
          <description>Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.&#xD;
FOLFOX:&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.&#xD;
Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.&#xD;
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.&#xD;
FOLFOX regimen: Each cycle (repeated every 14 days):&#xD;
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>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="6" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Arrhythmia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="12" subjects_affected="6" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="14" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E2" events="14" subjects_affected="4" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="5" subjects_affected="2" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Lightheadedness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Itching</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Due to the COVID-19 pandemic, the study finished earlier than planned. The total number of patients enrolled was 26 instead of 30.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Simon Haroutounian, PhD. Associate Professor</name_or_title>
      <organization>Washington University in St Louis</organization>
      <phone>3132861715</phone>
      <email>sharout@wustl.edu</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/NCT03254394
org study id: 201705166
nct id: NCT03254394
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Oxaliplatin-induced neuropathy is a major dose-limiting side effect in patients with
      colorectal cancer treated with the FOLFOX chemotherapy regimen. Hypersensitivity to cold is
      the sensory hallmark of oxaliplatin-induced neuropathy, and it can predict the development of
      long-term neuropathy. In this study, the investigators aim to determine whether intravenous
      lidocaine can prevent oxaliplatin-induced cold hypersensitivity.
Colorectal cancer is the third leading cause of cancer death in the United States, with an
      estimated incidence of 130.000 cases per year. Oxaliplatin is the first-line chemotherapy
      regimen for gastro-intestinal cancers. Despite its efficacy, oxaliplatin causes peripheral
      neuropathy in 72% of the treated patients. Acute oxaliplatin-induced peripheral neuropathy
      [OIPN] is the most common dose-limiting side effect of oxaliplatin and characterized by
      profound cold allodynia in the extremities. In about 21% of the patients acute OIPN
      exacerbates into chronic neuropathic pain, which is treatment resistant to currently approved
      drugs, pointing towards a great need to identify an effective strategy in preventing OIPN.
      Recent literature suggests that certain methods of assessing sensory nerve function in
      neuropathic pain patients may provide a prediction to an individual analgesic response;
      however, no placebo-controlled studies have been performed with the primary goal of
      identifying treatment response predictors in preventing OIPN.

      In this pilot study we will both determine the tolerability and the efficacy of intravenous
      Lidocaine, for preventing oxaliplatin-induced cold hypersensitivity in the setting of
      mFOLFOX6 chemotherapy for advanced colorectal cancer.

      The proposed study will be conducted in two phases. The tolerability phase is an open-label
      study to determine the tolerable dose regimen of IV lidocaine in patients with advanced
      colorectal cancer receiving oxaliplatin chemotherapy. The efficacy pilot phase is a
      randomized, double-blinded, controlled study comparing the outcomes between IV lidocaine
      versus placebo in the same setting of colorectal cancer. Consented subjects will attend a
      screening visit and six intervention visits, during which they will undergo sensory testing
      and receive intravenous lidocaine or placebo infusion. Cold hypersensitivity and spontaneous
      pain will be assessed at baseline, daily for 12 weeks and at follow-up visits. At enrollment,
      each patient will be assigned a study number, which will match a previously prepared
      computer-generated list of randomization numbers to determine the interventions lidocaine or
      placebo. The participants and all other study personnel will be blinded to the treatment
      allocation.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Tolerability phase: prospective, open-label Efficacy pilot study: randomized, parallel, double blind, placebo controlled
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: At enrollment, each patient will be assigned a study number, which will match a previously prepared computer-generated list of randomization numbers to determine the interventions. The participants and all other study personnel will be blinded to the treatment allocation.
measure: Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time
time frame: 14 weeks
description: The intensity of cold pain and cold unpleasantness is evaluated separately, assessed daily on a 0-10 scale, upon holding a pre-cooled (~8°C) metal cylinder for 10 seconds. the area under the curve of cold pain and cold unpleasantness vs time is calculated per chemotherapy cycle (every two weeks) and serves as a primary outcome measure.
For intervention (lidocaine+FOLFOX) and control (placebo+FOLFOX) groups, the average of cold pain AUC and cold unpleasantness AUC over 7 cycles was calculated. The average AUCs over 7 cycles were compared between study arms.
The AUC is measured as a score on a 0-10 scale multiplied by 14 days and may range between 0 and 140. Higher AUC values represent more intense cold pain/unpleasantness.
measure: CIPN Score on EORTC QLQ-CIPN20
time frame: 12 weeks and 34-36 weeks
description: Change in CIPN (Chemotherapy-induced peripheral Neuropathy) score (on EORTC QLQ-CIPN20 tool ) from baseline to the Cycle 6 (12 weeks), and from baseline to last follow-up (34-36 weeks). EORTC QLQ-CIPN20 ranges from 0 (no symptoms) to 100 (worst symptoms). A higher score represents worse neuropathy. The changes in scores are compared between study arms.
EORTC QLQ-CIPN20 tool is a quality of life questionnaire (QLQ) from the European Organization for Research and Treatment of Cancer (EORTC) for evaluation of CIPN.
measure: Changes in NPSI Score.
time frame: 6 weeks, 12 weeks, 34-36 weeks
description: Changes in Neuropathic Pain Symptom Inventory (NPSI) descriptors of neuropathic pain over time from baseline to cycle 3(6 weeks), cycle 6 (12 weeks), and the last follow-up (34-36 weeks). The total NPSI score ranges from 0 to 100; a higher NPSI total score represents a worse neuropathy outcome. The changes in scores from baseline are compared between study arms.
measure: The Cumulative Dose of Oxaliplatin
time frame: 24 weeks
description: The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6 treatment regimen. It corresponds to the absolute summed up quantity of Oxaliplatin administered to the patient over time. There is no range for this measure. Since this is a dose-limiting neuropathy prevention study, the higher value can be interpreted as better outcome.
arm group label: Placebo + FOLFOX
arm group type: Placebo Comparator
description: Intravenous infusion of D5W solution over a 130 minute period.
FOLFOX:
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
arm group label: Lidocaine + FOLFOX
arm group type: Active Comparator
description: Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period.
FOLFOX:
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
intervention type: Drug
intervention name: Lidocaine Hydrochloride
description: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW.
If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.
arm group label: Lidocaine + FOLFOX
intervention type: Drug
intervention name: Placebo
description: Dextrose 5% in water will be administered as active comparator.
arm group label: Placebo + FOLFOX
intervention type: Drug
intervention name: FOLFOX regimen
description: Each cycle (repeated every 14 days):
Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
arm group label: Lidocaine + FOLFOX
arm group label: Placebo + FOLFOX
other name: mFOLFOX6
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Simon Haroutounian, PhD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
citation: Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014 Dec;155(12):2461-2470. doi: 10.1016/j.pain.2014.09.020. Epub 2014 Sep 23.
PMID: 25261162
citation: Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology. 2004 Jan 27;62(2):218-25. doi: 10.1212/01.wnl.0000103237.62009.77.
PMID: 14745057
citation: Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D. Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology. 2000 Feb 8;54(3):564-74. doi: 10.1212/wnl.54.3.564.
PMID: 10680784
citation: Ventzel L, Madsen CS, Jensen AB, Jensen AR, Jensen TS, Finnerup NB. Assessment of acute oxaliplatin-induced cold allodynia: a pilot study. Acta Neurol Scand. 2016 Feb;133(2):152-155. doi: 10.1111/ane.12443. Epub 2015 Jun 2.
PMID: 26032776
responsible party type: Principal Investigator
investigator affiliation: Washington University School of Medicine
investigator full name: simon.haroutounian
investigator title: Assistant Professor of Anesthesiology
mesh term: Colorectal Neoplasms
mesh term: Peripheral Nervous System Diseases
mesh term: Pain
mesh term: Lidocaine
sharing ipd: Yes
ipd description: IPD will be shared 6 months after publication of the results in a peer-reviewed journal, upon submission of a robust data analysis plan to the study investigators.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: 6 months after publication
ipd access criteria: IPD will be shared 6 months after publication of the results in a peer-reviewed journal, upon submission of a robust data analysis plan to the study investigators.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Due to the COVID-19 pandemic, the study finished earlier than planned. The total number of patients enrolled was 26 instead of 30.
point of contact: 