xml: <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/NCT06024421</url>
    </required_header>
    <id_info>
      <org_study_id>C18-47</org_study_id>
      <secondary_id>2022-502871-49-00</secondary_id>
      <nct_id>NCT06024421</nct_id>
    </id_info>
    <brief_title>Evaluation of Tolerance and Pharmacokinetic Profile of High Doses of Favipiravir in Healthy Volunteers</brief_title>
    <acronym>FAVIDOSE</acronym>
    <official_title>EVALUATION DE LA TOLERANCE ET DU PROFIL PHARMACOCINETIQUE DE DOSES ELEVEES DE FAVIPIRAVIR CHEZ LE VOLONTAIRE SAIN</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>FUJIFILM Toyama Chemical Co., Ltd.</agency>
        <agency_class>Industry</agency_class>
      </collaborator>
    </sponsors>
    <source>Institut National de la Santé Et de la Recherche Médicale, France</source>
    <oversight_info>
      <has_dmc>Yes</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>
        FAVIDOSE trial is a Phase I randomized, double blind controlled, monocentric, dose escalation&#xD;
        clinical trial. The primary purpose of this trial is to evaluate tolerance of high doses of&#xD;
        favipiravir for 14 days in healthy volunteers. This trial also looks to characterize&#xD;
        favipiravir pharmacokinetics in blood and favipiravir levels in sperm. A pharmacogenetics&#xD;
        analysis will be conducted in an attempt to identify genetic variants of metabolism and&#xD;
        transport enzymes of favipiravir to explain the inter-individual variability of&#xD;
        pharmacokinetic parameters of favipiravir.&#xD;
  &#xD;
        Three sequential dose levels including distinctive participants:&#xD;
  &#xD;
          -  level 1: D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning;&#xD;
  &#xD;
          -  level 2: D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning;&#xD;
  &#xD;
          -  level 3: D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning.&#xD;
  &#xD;
        Three study groups of maximum of 8 participants, 6 receiving favipiravir and 2 receiving&#xD;
        placebo per dose level, three dose levels proposed. Seven additional participants with the&#xD;
        same follow up will be included and randomized (6:1 ratio) at the maximum tolerated dose&#xD;
        level to allow a satisfactory accurate characterization of pharmacokinetics and&#xD;
        pharmacogenetics of favipiravir and their determinants (maximum 39 participants in total,&#xD;
        taking into account 8 participants - 2 per dose level - replaced because loss of follow-up&#xD;
        before the end of treatment).&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">November 2023</start_date>
    <completion_date type="Anticipated">June 2027</completion_date>
    <primary_completion_date type="Anticipated">January 2027</primary_completion_date>
    <phase>Phase 1</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>Dose-escalation trial</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
      <masking_description>Active and placebo will not be visually distinguishable. Packaging and labeling of active and placebo tablets will be done in such a way as to not allow unblinding without access to the randomization list or the investigational drug unit list.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Tolerance</measure>
      <time_frame>Months 6</time_frame>
      <description>Tolerance of high doses of favipiravir, defined by the number of participants with at least one adverse medical event considered as related to favipiravir (AER)-as determined and validated by the sponsor- clinical stage 3 or 4 according to the CTCAE (v5.0) not found at inclusion at same level and biological AER de stage 3 or 4 not found at inclusion in the same level. AER are collected daily until D15 and at D21 and D28, as well as at M3 and M6 for participating men.&#xD;
  D1 is the first day of favipiravir or placebo intake.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Plasma concentration of favipiravir</measure>
      <time_frame>Day 1 (Hour 0; Hour 0.5 ; Hour 1; Hour 2; Hour 5; Hour 8), Day 3 (Hour 0 ; Hour 0.5; Hour 2), Day 7 (Hour 0; Hour 0.5 ; Hour 1; Hour 2; Hour 5; Hour 8), Day 10 (Hour 0), Day 14 (Hour 0; Hour 0.5 ; Hour 1; Hour 2; Hour 5; Hour 8), Day 15 (Hour 0)</time_frame>
      <description>Construction of the pharmacokinetic model and the estimation of its parameters will be realized by a population pharmacokinetic analysis integrating all available data on plasma concentration.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Genetic</measure>
      <time_frame>Days 1</time_frame>
      <description>Genetic variants associated with favipiravir exposure. Targeted genotyping of variants of the gene encoding the enzyme responsible for transport and metabolism of favipiravir (aldehyde deshydrogenase) will be performed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Sperm pharmacology</measure>
      <time_frame>Day 14, day 28</time_frame>
      <description>For participating men: favipiravir concentration in sperm at D14 and D28.</description>
    </secondary_outcome>
    <number_of_arms>6</number_of_arms>
    <enrollment type="Anticipated">39</enrollment>
    <condition>Infectious Disease</condition>
    <condition>Pharmacology</condition>
    <arm_group>
      <arm_group_label>level 1: experimental</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning</description>
    </arm_group>
    <arm_group>
      <arm_group_label>level 2: experimental</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning</description>
    </arm_group>
    <arm_group>
      <arm_group_label>level 3: experimental</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning</description>
    </arm_group>
    <arm_group>
      <arm_group_label>level 1: placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning</description>
    </arm_group>
    <arm_group>
      <arm_group_label>level 2: placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning</description>
    </arm_group>
    <arm_group>
      <arm_group_label>level 3: placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>favipiravir</intervention_name>
      <description>Light yellow, film-coated tablet, each containing 200 mg of favipiravir</description>
      <arm_group_label>level 1: experimental</arm_group_label>
      <arm_group_label>level 2: experimental</arm_group_label>
      <arm_group_label>level 3: experimental</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Light yellow, film-coated tablet</description>
      <arm_group_label>level 1: placebo</arm_group_label>
      <arm_group_label>level 2: placebo</arm_group_label>
      <arm_group_label>level 3: placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Man between 50 and 75 years old without any desire to have children or woman between&#xD;
               18 and 75 years old ;&#xD;
  &#xD;
            2. Subject considered healthy after a thorough general examination (questioning, physical&#xD;
               examination);&#xD;
  &#xD;
            3. For men: acceptance of semen collection by masturbation;&#xD;
  &#xD;
            4. For men: acceptance of condom use from initiation of the investigational drug until 1&#xD;
               month after stopping the investigational drug;&#xD;
  &#xD;
            5. For women of childbearing potential: effective contraceptive method combining two&#xD;
               methods of contraception (one female contraceptive method combined with male condom&#xD;
               use) from the inclusion visit until 1 month after discontinuation of the&#xD;
               investigational drug;&#xD;
  &#xD;
            6. Blood chemistry:&#xD;
  &#xD;
                 -  Kalemia, Calcemia, Prothrombin rate (PT), Activated partial thromboplastin time&#xD;
                    (APTT): values within laboratory normal;&#xD;
  &#xD;
                 -  ALT, ASAT, Uricemia: values below the upper limit of the laboratory normal;&#xD;
  &#xD;
                 -  Other biological results (Blood count; Natremia; Phosphoremia; Chloremia; Fasting&#xD;
                    blood glucose; Gamma glutamyl transpeptidase; Urea; Total bilirubin; Creatinine;&#xD;
                    CPK; Lactate dehydrogenase; Albuminemia; Proteinemia; Triglycerides; C-reactive&#xD;
                    protein; Albumin/Globulin ratio; Alkaline phosphatase) with no clinically&#xD;
                    significant abnormality.&#xD;
  &#xD;
               NB: A parameter outside the usual values considered clinically significant may, at the&#xD;
               investigator's discretion, be tested a second time on another sample taken outside of&#xD;
               a visit planned in the protocol before the initiation of the experimental drug.&#xD;
  &#xD;
            7. Urine dipstick (biochemistry: leukocyturia, proteinuria and hematuria) without&#xD;
               clinically significant abnormality;&#xD;
  &#xD;
            8. Urine tox screen negative (amphetamines/metamphetamines, barbiturates,&#xD;
               benzodiazepines, cannabis, cocaine, opiates);&#xD;
  &#xD;
            9. Ability to take the investigational drug orally and adherence to the dosage of the&#xD;
               investigational drug;&#xD;
  &#xD;
           10. Acceptance and signing of the informed consent;&#xD;
  &#xD;
           11. Membership in a social security plan or beneficiary of such a plan;&#xD;
  &#xD;
           12. Adherence to lifestyle considerations (see section 5.5) during participation in this&#xD;
               research.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Concomitant use or within 15 days prior to inclusion of another QT/QTc prolonging drug&#xD;
               or drugs that may disrupt electrolyte levels, among others: loop diuretics, thiazide&#xD;
               diuretics and related drugs (see list www.crediblemeds.org)&#xD;
  &#xD;
            2. History of amiodarone use within 6 months prior to inclusion&#xD;
  &#xD;
            3. History of gout or current treatment for gout or hyperuricemia&#xD;
  &#xD;
            4. Treatment with pyrazinamide or any other drug known to induce hyperuricemia&#xD;
  &#xD;
            5. History of hypersensitivity reaction to a nucleoside analog targeting viral RNA&#xD;
               polymerase&#xD;
  &#xD;
            6. Known hypersensitivity to any of the components (favipiravir or placebo)&#xD;
  &#xD;
            7. Pregnant or breastfeeding women&#xD;
  &#xD;
            8. For men: history of vasectomy or known history of infertility.&#xD;
  &#xD;
            9. Refusal of the subject to complete all the visits, clinical and paraclinical&#xD;
               examinations planned by the study&#xD;
  &#xD;
           10. On ECG: PR &gt;200ms, QRS &gt;100ms QTc &gt;450ms and morphological appearance of abnormal&#xD;
               repolarization&#xD;
  &#xD;
           11. PAS &lt;100 mmHg&#xD;
  &#xD;
           12. Any history or active cardiovascular, pulmonary, intestinal, hepatic, renal,&#xD;
               metabolic, hematologic, neurologic, bone, joint, muscular, psychiatric, systemic,&#xD;
               ocular, gynecologic, andrologic, or infectious disease (including active HIV, HCV, or&#xD;
               HBV infection), or any acute condition, which in the judgment of the investigator&#xD;
               could be detrimental to the volunteer and/or interfere with or limit the protocol&#xD;
               evaluation and data analysis&#xD;
  &#xD;
           13. Personal or family history of long QT syndrome, torsades de pointes or sudden death&#xD;
  &#xD;
           14. Patient with severe hepatic impairment&#xD;
  &#xD;
           15. Gastrointestinal pathology such as ileus, colitis or enterocolitis&#xD;
  &#xD;
           16. Treatment with another investigational drug or other investigational procedure&#xD;
               (clinical trial, clinical investigation of a medical device, category 1 or 2 research&#xD;
               involving humans);&#xD;
  &#xD;
           17. A person who is subject to a legal protection measure (safeguard of justice,&#xD;
               curatorship, guardianship);&#xD;
  &#xD;
           18. Person placed in administrative detention;&#xD;
  &#xD;
           19. Person who, in the judgment of the investigating physician, may be non-observant&#xD;
               during the study, or unable to communicate due to a language barrier or mental&#xD;
               disorder&#xD;
  &#xD;
           20. Person who cannot be contacted in an emergency&#xD;
  &#xD;
           21. Person with at least one first-degree relative from East Asia or Southeast Asia.&#xD;
  &#xD;
          Secondary Exclusion Criteria&#xD;
  &#xD;
          Participants with at least one of the following criteria will not start the experimental&#xD;
          treatment at D1 if they are already randomized:&#xD;
  &#xD;
            1. Positive nasopharyngeal antigen test for SARS-CoV-2 at D1 (prior to treatment&#xD;
               initiation)&#xD;
  &#xD;
            2. Blood potassium levels outside the normal laboratory range within 8 days prior to&#xD;
               treatment initiation (D1)&#xD;
  &#xD;
            3. ECG: PR &gt;200ms, QRS &gt;100ms QTc &gt;450ms and morphological appearance of abnormal&#xD;
               repolarization on Day 1&#xD;
  &#xD;
            4. Positive pregnancy test on Day 1 (before initiation of treatment)&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>75 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Denis MALVY</last_name>
      <role>Study Chair</role>
      <affiliation>CHU de Bordeaux &amp; INSERM, Université de Bordeaux, France</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Xavier DUVAL</last_name>
      <role>Principal Investigator</role>
      <affiliation>APHP Hôpital Bichat Claude Bernard</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Helene ESPEROU</last_name>
      <role>Study Director</role>
      <affiliation>Institut National de la Santé Et de la Recherche Médicale, France</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>France MENTRE</last_name>
      <phone>+33 1 40 25 79 31</phone>
      <email>france.mentre@inserm.fr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Cedric LAOUNAN</last_name>
      <phone>+33 1 40 25 79 31</phone>
      <email>cedric.laouenan@inserm.fr</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>University Hospital Bichat - Claude Bernard</name>
        <address>
          <city>Paris</city>
          <zip>75018</zip>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Xavier Duval</last_name>
      </contact>
      <investigator>
        <last_name>Xavier Duval</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 7, 2023</study_first_submitted>
    <study_first_submitted_qc>August 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 6, 2023</study_first_posted>
    <last_update_submitted>August 31, 2023</last_update_submitted>
    <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 6, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>healthy volunteer</keyword>
    <keyword>dose escalation</keyword>
    <keyword>tolerance</keyword>
    <keyword>pharmacokinetics</keyword>
    <keyword>favipiravir</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Communicable Diseases</mesh_term>
      <mesh_term>Infections</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Favipiravir</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06024421
  org study id: C18-47
  secondary id: 2022-502871-49-00
  nct id: NCT06024421
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  FAVIDOSE trial is a Phase I randomized, double blind controlled, monocentric, dose escalation
        clinical trial. The primary purpose of this trial is to evaluate tolerance of high doses of
        favipiravir for 14 days in healthy volunteers. This trial also looks to characterize
        favipiravir pharmacokinetics in blood and favipiravir levels in sperm. A pharmacogenetics
        analysis will be conducted in an attempt to identify genetic variants of metabolism and
        transport enzymes of favipiravir to explain the inter-individual variability of
        pharmacokinetic parameters of favipiravir.
  
        Three sequential dose levels including distinctive participants:
  
          -  level 1: D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning;
  
          -  level 2: D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning;
  
          -  level 3: D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning.
  
        Three study groups of maximum of 8 participants, 6 receiving favipiravir and 2 receiving
        placebo per dose level, three dose levels proposed. Seven additional participants with the
        same follow up will be included and randomized (6:1 ratio) at the maximum tolerated dose
        level to allow a satisfactory accurate characterization of pharmacokinetics and
        pharmacogenetics of favipiravir and their determinants (maximum 39 participants in total,
        taking into account 8 participants - 2 per dose level - replaced because loss of follow-up
        before the end of treatment).
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Dose-escalation trial
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  masking description: Active and placebo will not be visually distinguishable. Packaging and labeling of active and placebo tablets will be done in such a way as to not allow unblinding without access to the randomization list or the investigational drug unit list.
  measure: Tolerance
  time frame: Months 6
  description: Tolerance of high doses of favipiravir, defined by the number of participants with at least one adverse medical event considered as related to favipiravir (AER)-as determined and validated by the sponsor- clinical stage 3 or 4 according to the CTCAE (v5.0) not found at inclusion at same level and biological AER de stage 3 or 4 not found at inclusion in the same level. AER are collected daily until D15 and at D21 and D28, as well as at M3 and M6 for participating men.
  D1 is the first day of favipiravir or placebo intake.
  measure: Plasma concentration of favipiravir
  time frame: Day 1 (Hour 0; Hour 0.5 ; Hour 1; Hour 2; Hour 5; Hour 8), Day 3 (Hour 0 ; Hour 0.5; Hour 2), Day 7 (Hour 0; Hour 0.5 ; Hour 1; Hour 2; Hour 5; Hour 8), Day 10 (Hour 0), Day 14 (Hour 0; Hour 0.5 ; Hour 1; Hour 2; Hour 5; Hour 8), Day 15 (Hour 0)
  description: Construction of the pharmacokinetic model and the estimation of its parameters will be realized by a population pharmacokinetic analysis integrating all available data on plasma concentration.
  measure: Genetic
  time frame: Days 1
  description: Genetic variants associated with favipiravir exposure. Targeted genotyping of variants of the gene encoding the enzyme responsible for transport and metabolism of favipiravir (aldehyde deshydrogenase) will be performed.
  measure: Sperm pharmacology
  time frame: Day 14, day 28
  description: For participating men: favipiravir concentration in sperm at D14 and D28.
  arm group label: level 1: experimental
  arm group type: Experimental
  description: D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning
  arm group label: level 2: experimental
  arm group type: Experimental
  description: D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning
  arm group label: level 3: experimental
  arm group type: Experimental
  description: D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning
  arm group label: level 1: placebo
  arm group type: Placebo Comparator
  description: D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning
  arm group label: level 2: placebo
  arm group type: Placebo Comparator
  description: D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning
  arm group label: level 3: placebo
  arm group type: Placebo Comparator
  description: D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning
  intervention type: Drug
  intervention name: favipiravir
  description: Light yellow, film-coated tablet, each containing 200 mg of favipiravir
  arm group label: level 1: experimental
  arm group label: level 2: experimental
  arm group label: level 3: experimental
  intervention type: Drug
  intervention name: Placebo
  description: Light yellow, film-coated tablet
  arm group label: level 1: placebo
  arm group label: level 2: placebo
  arm group label: level 3: placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 75 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Denis MALVY
  role: Study Chair
  affiliation: CHU de Bordeaux & INSERM, Université de Bordeaux, France
  last name: Xavier DUVAL
  role: Principal Investigator
  affiliation: APHP Hôpital Bichat Claude Bernard
  last name: Helene ESPEROU
  role: Study Director
  affiliation: Institut National de la Santé Et de la Recherche Médicale, France
  last name: France MENTRE
  phone: +33 1 40 25 79 31
  email: france.mentre@inserm.fr
  last name: Cedric LAOUNAN
  phone: +33 1 40 25 79 31
  email: cedric.laouenan@inserm.fr
  facility: 
  contact: 
  investigator: 
  country: France
  responsible party type: Sponsor
  mesh term: Communicable Diseases
  mesh term: Infections
  mesh term: Favipiravir