<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/NCT03796533</url>
  </required_header>
  <id_info>
    <org_study_id>69HCL18_0429</org_study_id>
    <secondary_id>2018-003488-67</secondary_id>
    <nct_id>NCT03796533</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics Variability of Posaconazole (PCZ) and Its Glucuronide Metabolite During Induction and Consolidation Treatments in Patients With Acute Myeloid Leukemia (AML): a Covariate Analysis With the Tablets Formulation and Evaluation of the Potential Risk of Hepatotoxicity</brief_title>
  <acronym>Posa-Pk</acronym>
  <official_title>Pharmacokinetics Variability of Posaconazole (PCZ) and Its Glucuronide Metabolite During Induction and Consolidation Treatments in Patients With Acute Myeloid Leukemia (AML): a Covariate Analysis With the Tablets Formulation and Evaluation of the Potential Risk of Hepatotoxicity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospices Civils de Lyon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospices Civils de Lyon</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Among its authorized indications, posaconazole (PCZ) is prescribed for prophylaxis in&#xD;
      onco-hematology patients at high risk of invasive fungal infections. This azole antifungal&#xD;
      has a low bioavailability. The enteric-coated tablets form available since mid-2015 has&#xD;
      significantly improved its pharmacokinetic profile compared to the oral suspension form&#xD;
      initially used. According to the recommendations of The European Conference on Infections in&#xD;
      Leukemia (ECIL-6), the minimum serum concentration desirable for prophylaxis is 0.7 mg/L.&#xD;
      This concentration threshold was difficult to achieve in onco-hematology patients treated&#xD;
      with oral suspension.&#xD;
&#xD;
      The investigators retrospectively collected and analyzed 201 results of residual PCZ serum&#xD;
      concentrations from 91 onco-hematology patients on Noxafil® tablets prophylaxis. The median&#xD;
      concentration of PCZ was 1.08 mg/L. In this study, the pharmacokinetics of tablet-PCZ showed&#xD;
      significant inter-individual variability. Thus, while 25% of the concentrations remained&#xD;
      below the recommended threshold of 0.7 mg/L (25% percentile = 0.69 mg/L), exposure to PCZ was&#xD;
      greater than 2.63 mg/L in 10% of cases. This level of exposure, however, did not have obvious&#xD;
      hepatic repercussions. Nevertheless, further studies involving larger cohorts are needed to&#xD;
      clarify a hypothetical relationship between serum PCZ concentration and the occurrence of&#xD;
      hepatic toxicity.&#xD;
&#xD;
      In addition, the investigators found significant intra-individual variability in PCZ exposure&#xD;
      (CV = 48.8%), especially in leukemic patients. This variability is probably related to a&#xD;
      modification during the treatment of the physio-pathological conditions of the patient likely&#xD;
      to impact the pharmacokinetics of PCZ (absorption, distribution, metabolism, etc.) as well as&#xD;
      the effect of possible pharmacokinetic drug interactions.&#xD;
&#xD;
      The metabolism of PCZ is mediated primarily by the uridine diphosphate&#xD;
      (UDP)-glucuronosyltransferase 1A4 (UGT1A4) pathway. Although hepatic metabolism of PCZ is low&#xD;
      compared with other azoles (such as itraconazole or voriconazole), differences in the&#xD;
      metabolic capacity of UGT1A4 may alter PCZ exposure. A previous study of the oral suspension&#xD;
      form had shown that low concentrations of PCZ were associated with a high ratio of&#xD;
      PCZ-glucuronide / PCZ concentrations. Two genetic variants of the gene encoding UGT1A4 are&#xD;
      associated with a decrease in the metabolic clearance of glucuronide drugs via UGT1A4. A&#xD;
      recent study suggests less exposure to PCZ in the presence of UGT1A4 polymorphism.&#xD;
&#xD;
      The main objective of the investigator's project is to study prospectively in a homogeneous&#xD;
      population of patients treated by intensive chemotherapy for acute myeloid leukemia&#xD;
      (induction and consolidation) the pharmacokinetics of PCZ administered in its tablet&#xD;
      formulation, and in particular:&#xD;
&#xD;
        -  Clinical and biological tolerance of high concentrations of PCZ&#xD;
&#xD;
        -  The influence of clinical and demographic covariates on PCZ and PCZ-glucuronide ratio&#xD;
&#xD;
        -  The influence of genetic variants of UGT1A4 on PCZ metabolism (PCZ-glucuronide / PCZ&#xD;
           ratio).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 10, 2018</start_date>
  <completion_date type="Anticipated">April 10, 2023</completion_date>
  <primary_completion_date type="Anticipated">April 10, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evolution of the blood concentration of posaconazole and its metabolite from the beginning of treatment to the end of the induction phase (pharmacokinetic).</measure>
    <time_frame>Day 21</time_frame>
    <description>Posaconazole (PCZ) treatment will start at Day 1 at the beginning of induction/ consolidation therapy.&#xD;
For the pharmacokinetics study of PCZ during induction, blood samples (5 mL) will be taken on days 3, 7, 14 and 21. Predoses (just prior to a daily dose) or trough concentrations (C0) will be collected on days 3, 7, 14 and 21. A peak concentration (at 3 hours post dose) will also be collected on day 14.&#xD;
After achieving complete remission, patients receive a consolidation cure. During the consolidation cures, trough concentrations will be collected on days 3, 7, 14 and 21. A peak concentration (at 3 hours post dose) will also be collected on day 14.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Search and identification by sequencing gene variants of UGT1A4</measure>
    <time_frame>At diagnosis</time_frame>
    <description>The blood sample (5 mL) for the study of polymorphisms of the UGT1A4 gene will be performed before the initiation of induction.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Leukemia, Myeloid, Acute</condition>
  <arm_group>
    <arm_group_label>Posaconazole pharmacokinetics</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients with AML over the age of 18 years treated with intensive chemotherapy in induction and consolidation whose was under antifungal prophylaxis by PCZ formulation tablets.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Posaconazole</intervention_name>
    <description>PCZ will be used as recommended in tablet formulation at an initial dosage of 300 mg twice a day on the first day and then once a day at a dose of 300 mg the following days.&#xD;
PCZ prophylaxis will be started on the same day as the start of chemotherapy and will be continued until the end of aplasia.&#xD;
The dosage of the PCZ can be adjusted according to the results of the PCZ assay. It may be interrupted if the transaminase level is greater than 3 times higher than normal (3N) or on medical decision.</description>
    <arm_group_label>Posaconazole pharmacokinetics</arm_group_label>
    <other_name>PCZ</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient aged 18 or over&#xD;
&#xD;
          2. Patients with AML de novo or secondary to myelodysplastic syndrome or therapy-related&#xD;
             AML except acute myeloid leukemia (AML3)&#xD;
&#xD;
          3. Patient hospitalized for the treatment of leukemia (induction chemotherapy or&#xD;
             consolidation)&#xD;
&#xD;
          4. General state retained (ECOG performance scale ≤ 3)&#xD;
&#xD;
          5. alanine aminotransferase aspartate transaminase (ASAT) and alanine aminotransferase&#xD;
             (ALAT) ≤ 2.5 times the upper limit of normal (ULN), total bilirubin ≤ 2 times the ULN,&#xD;
             creatinine &lt;150 μmol / L unless these biological abnormalities are related to leukemia&#xD;
&#xD;
          6. Patients affiliated or beneficiaries of a social security scheme (Social Security or&#xD;
             Universal Medical Coverage)&#xD;
&#xD;
          7. Having read and understood the information sheet and signed the informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with acute promyelocytic leukemia (AML3)&#xD;
&#xD;
          2. History of uncontrolled cancer for at least two years&#xD;
&#xD;
          3. Patient included in another clinical study that may interfere with the objectives of&#xD;
             this study&#xD;
&#xD;
          4. Treatment with antifungal other than posaconazole&#xD;
&#xD;
          5. Severe uncontrolled infection at the time of inclusion&#xD;
&#xD;
          6. Positive serology for HIV 1 or 2 or human T-cell lymphoma virus (HTLV 1) or 2, or&#xD;
             active viral infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)&#xD;
&#xD;
          7. Pregnant woman (beta positive HCG) or breastfeeding&#xD;
&#xD;
          8. A woman of childbearing potential who can not justify the use of effective&#xD;
             contraception during treatment with Noxafil®&#xD;
&#xD;
          9. Patient incapacitated, under guardianship, curators or safeguard of justice&#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_contact>
    <last_name>Sophie Ducastelle-lepretre</last_name>
    <phone>04 78 86 22 36</phone>
    <phone_ext>+33</phone_ext>
    <email>Sophie.ducastelle-lepretre@chu-lyon.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mohamed EL HAMRI</last_name>
    <phone>04 78 86 22 20</phone>
    <phone_ext>+33</phone_ext>
    <email>mohamed.el-hamri@chu-lyon.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Centre Hospitalier Lyon Sud, Hematology department</name>
      <address>
        <city>Pierre-Bénite</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sophie DUCASTELLE-LEPRETRE, MD</last_name>
      <phone>04 78 86 22 36</phone>
      <phone_ext>+33</phone_ext>
      <email>Sophie.ducastelle-lepretre@chu-lyon.fr</email>
    </contact>
    <contact_backup>
      <last_name>Mohamed EL HAMRI, MD</last_name>
      <phone>04 78 86 22 20</phone>
      <phone_ext>+33</phone_ext>
      <email>mohamed.el-hamri@chu-lyon.fr</email>
    </contact_backup>
    <investigator>
      <last_name>Sophie Ducastelle-Lepretre, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Xavier THOMAS, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Fiorenza BARRACO, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Etienne PAUBELLE, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Hélène Labussiere-Wallet, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Eric Wattel</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Marie Virginie Larcher, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Clement Rocher, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Gaelle Fossard, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Marie Balsat, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>November 16, 2018</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>February 23, 2022</last_update_submitted>
  <last_update_submitted_qc>February 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 24, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>AML-PCZ-UGT1A4 gene</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Posaconazole</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03796533
org study id: 69HCL18_0429
secondary id: 2018-003488-67
nct id: NCT03796533
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Among its authorized indications, posaconazole (PCZ) is prescribed for prophylaxis in
      onco-hematology patients at high risk of invasive fungal infections. This azole antifungal
      has a low bioavailability. The enteric-coated tablets form available since mid-2015 has
      significantly improved its pharmacokinetic profile compared to the oral suspension form
      initially used. According to the recommendations of The European Conference on Infections in
      Leukemia (ECIL-6), the minimum serum concentration desirable for prophylaxis is 0.7 mg/L.
      This concentration threshold was difficult to achieve in onco-hematology patients treated
      with oral suspension.

      The investigators retrospectively collected and analyzed 201 results of residual PCZ serum
      concentrations from 91 onco-hematology patients on Noxafil® tablets prophylaxis. The median
      concentration of PCZ was 1.08 mg/L. In this study, the pharmacokinetics of tablet-PCZ showed
      significant inter-individual variability. Thus, while 25% of the concentrations remained
      below the recommended threshold of 0.7 mg/L (25% percentile = 0.69 mg/L), exposure to PCZ was
      greater than 2.63 mg/L in 10% of cases. This level of exposure, however, did not have obvious
      hepatic repercussions. Nevertheless, further studies involving larger cohorts are needed to
      clarify a hypothetical relationship between serum PCZ concentration and the occurrence of
      hepatic toxicity.

      In addition, the investigators found significant intra-individual variability in PCZ exposure
      (CV = 48.8%), especially in leukemic patients. This variability is probably related to a
      modification during the treatment of the physio-pathological conditions of the patient likely
      to impact the pharmacokinetics of PCZ (absorption, distribution, metabolism, etc.) as well as
      the effect of possible pharmacokinetic drug interactions.

      The metabolism of PCZ is mediated primarily by the uridine diphosphate
      (UDP)-glucuronosyltransferase 1A4 (UGT1A4) pathway. Although hepatic metabolism of PCZ is low
      compared with other azoles (such as itraconazole or voriconazole), differences in the
      metabolic capacity of UGT1A4 may alter PCZ exposure. A previous study of the oral suspension
      form had shown that low concentrations of PCZ were associated with a high ratio of
      PCZ-glucuronide / PCZ concentrations. Two genetic variants of the gene encoding UGT1A4 are
      associated with a decrease in the metabolic clearance of glucuronide drugs via UGT1A4. A
      recent study suggests less exposure to PCZ in the presence of UGT1A4 polymorphism.

      The main objective of the investigator's project is to study prospectively in a homogeneous
      population of patients treated by intensive chemotherapy for acute myeloid leukemia
      (induction and consolidation) the pharmacokinetics of PCZ administered in its tablet
      formulation, and in particular:

        -  Clinical and biological tolerance of high concentrations of PCZ

        -  The influence of clinical and demographic covariates on PCZ and PCZ-glucuronide ratio

        -  The influence of genetic variants of UGT1A4 on PCZ metabolism (PCZ-glucuronide / PCZ
           ratio).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Health Services Research
masking: None (Open Label)
measure: Evolution of the blood concentration of posaconazole and its metabolite from the beginning of treatment to the end of the induction phase (pharmacokinetic).
time frame: Day 21
description: Posaconazole (PCZ) treatment will start at Day 1 at the beginning of induction/ consolidation therapy.
For the pharmacokinetics study of PCZ during induction, blood samples (5 mL) will be taken on days 3, 7, 14 and 21. Predoses (just prior to a daily dose) or trough concentrations (C0) will be collected on days 3, 7, 14 and 21. A peak concentration (at 3 hours post dose) will also be collected on day 14.
After achieving complete remission, patients receive a consolidation cure. During the consolidation cures, trough concentrations will be collected on days 3, 7, 14 and 21. A peak concentration (at 3 hours post dose) will also be collected on day 14.
measure: Search and identification by sequencing gene variants of UGT1A4
time frame: At diagnosis
description: The blood sample (5 mL) for the study of polymorphisms of the UGT1A4 gene will be performed before the initiation of induction.
arm group label: Posaconazole pharmacokinetics
arm group type: Other
description: Patients with AML over the age of 18 years treated with intensive chemotherapy in induction and consolidation whose was under antifungal prophylaxis by PCZ formulation tablets.
intervention type: Drug
intervention name: Posaconazole
description: PCZ will be used as recommended in tablet formulation at an initial dosage of 300 mg twice a day on the first day and then once a day at a dose of 300 mg the following days.
PCZ prophylaxis will be started on the same day as the start of chemotherapy and will be continued until the end of aplasia.
The dosage of the PCZ can be adjusted according to the results of the PCZ assay. It may be interrupted if the transaminase level is greater than 3 times higher than normal (3N) or on medical decision.
arm group label: Posaconazole pharmacokinetics
other name: PCZ
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sophie Ducastelle-lepretre
phone: 04 78 86 22 36
phone ext: +33
email: Sophie.ducastelle-lepretre@chu-lyon.fr
last name: Mohamed EL HAMRI
phone: 04 78 86 22 20
phone ext: +33
email: mohamed.el-hamri@chu-lyon.fr
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Posaconazole