<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/NCT03022747</url>
  </required_header>
  <id_info>
    <org_study_id>Allopurinol Study V3.0</org_study_id>
    <nct_id>NCT03022747</nct_id>
  </id_info>
  <brief_title>Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol</brief_title>
  <official_title>Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol Clinical Study in Children 1-19 Years on Maintenance Therapy for Acute Lymphoblastic Leukemia.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vastra Gotaland Region</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vastra Gotaland Region</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study will investigate, in children with acute lymphoblastic leukemia during maintenance&#xD;
      treatment, if addition of allopurinol to conventional oral 6-mercaptopurine and methotrexate&#xD;
      therapy, affects erythrocyte concentrations of 6-thioguanine and 6 methylmercaptopurine. The&#xD;
      effect on hematological and liver toxicity parameters in blood will also be investigated as&#xD;
      well as clinical toxicity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      After one month of conventional maintenance therapy (MT) children and adolescents, treated&#xD;
      for acute lymphoblastic leukemia on Nordic protocols and with wild type thiopurine&#xD;
      methyltransferase (TPMT) are eligible for the study. They will first receive a 12 week phase&#xD;
      with normal MT during which time repeated sampling of 6-mercaptopurine (6MP) metabolite&#xD;
      levels and other laboratory parameters will be performed. After 12 weeks, allopurinol at a&#xD;
      dose of 50 mg/sqm is added (simultaneously reducing the dose of 6MP by 50%) and during the&#xD;
      next 12 weeks patients are monitored closely for toxicity and samples for determination of&#xD;
      metabolite levels and hematological and liver toxicity are obtained regularly. If, after 4&#xD;
      weeks of allopurinol treatment, the levels of 6-thioguanine are below 200 nmol/mmol&#xD;
      hemoglobin, the dose of allopurinol will be increased to 100 mg/sqm. Allopurinol treatment is&#xD;
      continued for 12 weeks after which the patients switch to their original maintenance therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">April 2019</completion_date>
  <primary_completion_date type="Anticipated">December 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>6-thioguanine (6TG) levels in erythrocytes</measure>
    <time_frame>Up to week 25</time_frame>
    <description>The fraction of patients with 6TG levels over 200 nmol/mmol Hb at week 13 and 25 (ie after 12 weeks standard and allopurinol treatment respectively)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean level of 6-thioguanine</measure>
    <time_frame>Up to week 25</time_frame>
    <description>The mean level of 6TG at week 13 and 25</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean level of DNA-incorporated thioguanine (DNA-TGN)</measure>
    <time_frame>Up to week 25</time_frame>
    <description>The mean level of DNA-TGN at week 13 and 25</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean level of 6-methylmercaptopurine (6MMP)</measure>
    <time_frame>Up to week 25</time_frame>
    <description>The mean level of 6MMP at week 13 and 25</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean levels of platelets</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of weighted mean of platelets in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean levels of hemoglobin</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of weighted mean of hemoglobin in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean levels of absolute neutrophil count (ANC)</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of weighted mean of ANC in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean levels of white blood cells (WBC)</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of weighted mean of WBC in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glutamate pyruvate transaminase (GPT)</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of weighted means of serum GPT in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bilirubin</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of weighted means of serum bilirubin in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hypoglycemia</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of incidence of hypoglycemia and laboratory measures of metabolic disturbance during the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolic disturbance</measure>
    <time_frame>Up to week 25</time_frame>
    <description>Comparison of incidence of laboratory measures of metabolic disturbance during the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of serious adverse events (SAE)</measure>
    <time_frame>Up to week 29</time_frame>
    <description>Comparison of the frequency of SAE in the treatment phases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative dose of 6-mercaptopurine and methotrexate</measure>
    <time_frame>Up to week 29</time_frame>
    <description>Comparison of the cumulative dose of 6MP and methotrexate and days with treatment interruption in the two treatment arms</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Lymphoblastic Leukemia, Acute, Childhood</condition>
  <arm_group>
    <arm_group_label>Standard maintenance therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard maintenance therapy with 6 mercaptopurine and methotrexate</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Allopurinol treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The second 12 week phase during which allopurinol is added to oral 6-mercaptopurine and methotrexate therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Allopurinol</intervention_name>
    <description>Allopurinol is added to standard oral 6-mercaptopurine and methotrexate</description>
    <arm_group_label>Allopurinol treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard treatment</intervention_name>
    <description>Oral 6-mercaptopurine and methotrexate</description>
    <arm_group_label>Standard maintenance therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed diagnosis of acute lymphoblastic leukemia&#xD;
&#xD;
          -  Treatment according to Nordic Society for pediatric hematology/oncology (NOPHO)&#xD;
             ALL2008 based protocols&#xD;
&#xD;
          -  Age 0-18y at time of initial diagnosis&#xD;
&#xD;
          -  TPMT wild type&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Mature B cell lymphoblastic leukemia&#xD;
&#xD;
          -  t(9;22) positive acute lymphoblastic leukemia&#xD;
&#xD;
          -  Unknown TPMT status or presence of TPMT mutation (both heterozygous and homozygous)&#xD;
&#xD;
          -  Known intolerance to any of the chemotherapeutic drugs in the protocol&#xD;
&#xD;
          -  Major organ failure precluding administration of planned chemotherapy&#xD;
&#xD;
          -  Severe liver toxicity defined as persistent (≥ two weeks) elevation of either&#xD;
             S-bilirubin &gt; 50 μmol/l or S-GPT &gt; 20 x Upper normal limit (UNL) or P-Prothrombin&#xD;
             complex &gt; 1.5.&#xD;
&#xD;
          -  Reduced kidney function defined as S-creatinine ≥ 1.5 x UNL.&#xD;
&#xD;
          -  Lactating female or female of childbearing potential not using adequate contraception.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>19 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jonas Abrahamsson, PhD, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Childrens Cancer Center, Queen Silvia Children Hospital, Sahlgrenska Academy, Gothenburg, Sweden</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Riita Niinimäki, PhD, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jonas Abrahamsson, PhD, MD</last_name>
    <phone>+46 707 695159</phone>
    <email>vobjab@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Torben Ek, PhD, MD</last_name>
    <phone>+46 706 169284</phone>
    <email>torben.ek@mac.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland</name>
      <address>
        <city>Oulu</city>
        <zip>90029 OYS</zip>
        <country>Finland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Riita Niinimäki, MD, PhD</last_name>
      <phone>+358 8 3155832</phone>
      <email>riita.niinimaki@ppshp.fi</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Childrens' Cancer Centre, Queen Silvias Childrens and Adolescents Hospital</name>
      <address>
        <city>Gothenburg</city>
        <zip>416 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lene Karlsson, MD</last_name>
      <phone>+46 313435610</phone>
      <email>lene.karlsson@vgregion.se</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Linköping University Hospital, Dept of Pediatrics</name>
      <address>
        <city>Linköping</city>
        <zip>58185</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Hartmut Vogt, MD, PhD</last_name>
      <phone>+46 101031343</phone>
      <email>hartmut.vogt@regionostergotland.se</email>
    </contact>
  </location>
  <location_countries>
    <country>Finland</country>
    <country>Sweden</country>
  </location_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 9, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>January 11, 2017</last_update_submitted>
  <last_update_submitted_qc>January 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 16, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Allopurinol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03022747
org study id: Allopurinol Study V3.0
nct id: NCT03022747
lead sponsor: 
has dmc: Yes
The study will investigate, in children with acute lymphoblastic leukemia during maintenance
      treatment, if addition of allopurinol to conventional oral 6-mercaptopurine and methotrexate
      therapy, affects erythrocyte concentrations of 6-thioguanine and 6 methylmercaptopurine. The
      effect on hematological and liver toxicity parameters in blood will also be investigated as
      well as clinical toxicity.
After one month of conventional maintenance therapy (MT) children and adolescents, treated
      for acute lymphoblastic leukemia on Nordic protocols and with wild type thiopurine
      methyltransferase (TPMT) are eligible for the study. They will first receive a 12 week phase
      with normal MT during which time repeated sampling of 6-mercaptopurine (6MP) metabolite
      levels and other laboratory parameters will be performed. After 12 weeks, allopurinol at a
      dose of 50 mg/sqm is added (simultaneously reducing the dose of 6MP by 50%) and during the
      next 12 weeks patients are monitored closely for toxicity and samples for determination of
      metabolite levels and hematological and liver toxicity are obtained regularly. If, after 4
      weeks of allopurinol treatment, the levels of 6-thioguanine are below 200 nmol/mmol
      hemoglobin, the dose of allopurinol will be increased to 100 mg/sqm. Allopurinol treatment is
      continued for 12 weeks after which the patients switch to their original maintenance therapy.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 6-thioguanine (6TG) levels in erythrocytes
time frame: Up to week 25
description: The fraction of patients with 6TG levels over 200 nmol/mmol Hb at week 13 and 25 (ie after 12 weeks standard and allopurinol treatment respectively)
measure: Mean level of 6-thioguanine
time frame: Up to week 25
description: The mean level of 6TG at week 13 and 25
measure: Mean level of DNA-incorporated thioguanine (DNA-TGN)
time frame: Up to week 25
description: The mean level of DNA-TGN at week 13 and 25
measure: Mean level of 6-methylmercaptopurine (6MMP)
time frame: Up to week 25
description: The mean level of 6MMP at week 13 and 25
measure: Mean levels of platelets
time frame: Up to week 25
description: Comparison of weighted mean of platelets in the treatment phases
measure: Mean levels of hemoglobin
time frame: Up to week 25
description: Comparison of weighted mean of hemoglobin in the treatment phases
measure: Mean levels of absolute neutrophil count (ANC)
time frame: Up to week 25
description: Comparison of weighted mean of ANC in the treatment phases
measure: Mean levels of white blood cells (WBC)
time frame: Up to week 25
description: Comparison of weighted mean of WBC in the treatment phases
measure: Glutamate pyruvate transaminase (GPT)
time frame: Up to week 25
description: Comparison of weighted means of serum GPT in the treatment phases
measure: Bilirubin
time frame: Up to week 25
description: Comparison of weighted means of serum bilirubin in the treatment phases
measure: Hypoglycemia
time frame: Up to week 25
description: Comparison of incidence of hypoglycemia and laboratory measures of metabolic disturbance during the treatment phases
measure: Metabolic disturbance
time frame: Up to week 25
description: Comparison of incidence of laboratory measures of metabolic disturbance during the treatment phases
measure: Incidence of serious adverse events (SAE)
time frame: Up to week 29
description: Comparison of the frequency of SAE in the treatment phases
measure: Cumulative dose of 6-mercaptopurine and methotrexate
time frame: Up to week 29
description: Comparison of the cumulative dose of 6MP and methotrexate and days with treatment interruption in the two treatment arms
arm group label: Standard maintenance therapy
arm group type: Active Comparator
description: Standard maintenance therapy with 6 mercaptopurine and methotrexate
arm group label: Allopurinol treatment
arm group type: Experimental
description: The second 12 week phase during which allopurinol is added to oral 6-mercaptopurine and methotrexate therapy
intervention type: Drug
intervention name: Allopurinol
description: Allopurinol is added to standard oral 6-mercaptopurine and methotrexate
arm group label: Allopurinol treatment
intervention type: Drug
intervention name: Standard treatment
description: Oral 6-mercaptopurine and methotrexate
arm group label: Standard maintenance therapy
criteria: 
gender: All
minimum age: 6 Months
maximum age: 19 Years
healthy volunteers: No
last name: Jonas Abrahamsson, PhD, MD
role: Study Chair
affiliation: Childrens Cancer Center, Queen Silvia Children Hospital, Sahlgrenska Academy, Gothenburg, Sweden
last name: Riita Niinimäki, PhD, MD
role: Principal Investigator
affiliation: Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland
last name: Jonas Abrahamsson, PhD, MD
phone: +46 707 695159
email: vobjab@gmail.com
last name: Torben Ek, PhD, MD
phone: +46 706 169284
email: torben.ek@mac.com
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Finland
country: Sweden
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Allopurinol
sharing ipd: No