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Evaluation of Tolerance and Pharmacokinetic Profile of High Doses of Favipiravir in Healthy Volunteers (FAVIDOSE)

Primary Purpose

Infectious Disease, Pharmacology

Status
Not yet recruiting
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
favipiravir
Placebo
Sponsored by
Institut National de la Santé Et de la Recherche Médicale, France
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infectious Disease focused on measuring healthy volunteer, dose escalation, tolerance, pharmacokinetics, favipiravir

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Man between 50 and 75 years old without any desire to have children or woman between 18 and 75 years old ; Subject considered healthy after a thorough general examination (questioning, physical examination); For men: acceptance of semen collection by masturbation; For men: acceptance of condom use from initiation of the investigational drug until 1 month after stopping the investigational drug; For women of childbearing potential: effective contraceptive method combining two methods of contraception (one female contraceptive method combined with male condom use) from the inclusion visit until 1 month after discontinuation of the investigational drug; Blood chemistry: Kalemia, Calcemia, Prothrombin rate (PT), Activated partial thromboplastin time (APTT): values within laboratory normal; ALT, ASAT, Uricemia: values below the upper limit of the laboratory normal; Other biological results (Blood count; Natremia; Phosphoremia; Chloremia; Fasting blood glucose; Gamma glutamyl transpeptidase; Urea; Total bilirubin; Creatinine; CPK; Lactate dehydrogenase; Albuminemia; Proteinemia; Triglycerides; C-reactive protein; Albumin/Globulin ratio; Alkaline phosphatase) with no clinically significant abnormality. NB: A parameter outside the usual values considered clinically significant may, at the investigator's discretion, be tested a second time on another sample taken outside of a visit planned in the protocol before the initiation of the experimental drug. Urine dipstick (biochemistry: leukocyturia, proteinuria and hematuria) without clinically significant abnormality; Urine tox screen negative (amphetamines/metamphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates); Ability to take the investigational drug orally and adherence to the dosage of the investigational drug; Acceptance and signing of the informed consent; Membership in a social security plan or beneficiary of such a plan; Adherence to lifestyle considerations (see section 5.5) during participation in this research. Exclusion Criteria: Concomitant use or within 15 days prior to inclusion of another QT/QTc prolonging drug or drugs that may disrupt electrolyte levels, among others: loop diuretics, thiazide diuretics and related drugs (see list www.crediblemeds.org) History of amiodarone use within 6 months prior to inclusion History of gout or current treatment for gout or hyperuricemia Treatment with pyrazinamide or any other drug known to induce hyperuricemia History of hypersensitivity reaction to a nucleoside analog targeting viral RNA polymerase Known hypersensitivity to any of the components (favipiravir or placebo) Pregnant or breastfeeding women For men: history of vasectomy or known history of infertility. Refusal of the subject to complete all the visits, clinical and paraclinical examinations planned by the study On ECG: PR >200ms, QRS >100ms QTc >450ms and morphological appearance of abnormal repolarization PAS <100 mmHg Any history or active cardiovascular, pulmonary, intestinal, hepatic, renal, metabolic, hematologic, neurologic, bone, joint, muscular, psychiatric, systemic, ocular, gynecologic, andrologic, or infectious disease (including active HIV, HCV, or HBV infection), or any acute condition, which in the judgment of the investigator could be detrimental to the volunteer and/or interfere with or limit the protocol evaluation and data analysis Personal or family history of long QT syndrome, torsades de pointes or sudden death Patient with severe hepatic impairment Gastrointestinal pathology such as ileus, colitis or enterocolitis Treatment with another investigational drug or other investigational procedure (clinical trial, clinical investigation of a medical device, category 1 or 2 research involving humans); A person who is subject to a legal protection measure (safeguard of justice, curatorship, guardianship); Person placed in administrative detention; Person who, in the judgment of the investigating physician, may be non-observant during the study, or unable to communicate due to a language barrier or mental disorder Person who cannot be contacted in an emergency Person with at least one first-degree relative from East Asia or Southeast Asia. Secondary Exclusion Criteria Participants with at least one of the following criteria will not start the experimental treatment at D1 if they are already randomized: Positive nasopharyngeal antigen test for SARS-CoV-2 at D1 (prior to treatment initiation) Blood potassium levels outside the normal laboratory range within 8 days prior to treatment initiation (D1) ECG: PR >200ms, QRS >100ms QTc >450ms and morphological appearance of abnormal repolarization on Day 1 Positive pregnancy test on Day 1 (before initiation of treatment)

Sites / Locations

  • University Hospital Bichat - Claude Bernard

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Placebo Comparator

Placebo Comparator

Arm Label

level 1: experimental

level 2: experimental

level 3: experimental

level 1: placebo

level 2: placebo

level 3: placebo

Arm Description

D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning

D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning

D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning

D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning

D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning

D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning

Outcomes

Primary Outcome Measures

Tolerance
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.

Secondary Outcome Measures

Plasma concentration of favipiravir
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.
Genetic
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.
Sperm pharmacology
For participating men: favipiravir concentration in sperm at D14 and D28.

Full Information

First Posted
July 7, 2023
Last Updated
August 31, 2023
Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
Collaborators
FUJIFILM Toyama Chemical Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT06024421
Brief Title
Evaluation of Tolerance and Pharmacokinetic Profile of High Doses of Favipiravir in Healthy Volunteers
Acronym
FAVIDOSE
Official Title
EVALUATION DE LA TOLERANCE ET DU PROFIL PHARMACOCINETIQUE DE DOSES ELEVEES DE FAVIPIRAVIR CHEZ LE VOLONTAIRE SAIN
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 2023 (Anticipated)
Primary Completion Date
January 2027 (Anticipated)
Study Completion Date
June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
Collaborators
FUJIFILM Toyama Chemical Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infectious Disease, Pharmacology
Keywords
healthy volunteer, dose escalation, tolerance, pharmacokinetics, favipiravir

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Dose-escalation trial
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
39 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
level 1: experimental
Arm Type
Experimental
Arm Description
D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning
Arm Title
level 2: experimental
Arm Type
Experimental
Arm Description
D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning
Arm Title
level 3: experimental
Arm Type
Experimental
Arm Description
D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning
Arm Title
level 1: placebo
Arm Type
Placebo Comparator
Arm Description
D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning
Arm Title
level 2: placebo
Arm Type
Placebo Comparator
Arm Description
D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning
Arm Title
level 3: placebo
Arm Type
Placebo Comparator
Arm Description
D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning
Intervention Type
Drug
Intervention Name(s)
favipiravir
Intervention Description
Light yellow, film-coated tablet, each containing 200 mg of favipiravir
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Light yellow, film-coated tablet
Primary Outcome Measure Information:
Title
Tolerance
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.
Time Frame
Months 6
Secondary Outcome Measure Information:
Title
Plasma concentration of favipiravir
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.
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)
Title
Genetic
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.
Time Frame
Days 1
Title
Sperm pharmacology
Description
For participating men: favipiravir concentration in sperm at D14 and D28.
Time Frame
Day 14, day 28

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Man between 50 and 75 years old without any desire to have children or woman between 18 and 75 years old ; Subject considered healthy after a thorough general examination (questioning, physical examination); For men: acceptance of semen collection by masturbation; For men: acceptance of condom use from initiation of the investigational drug until 1 month after stopping the investigational drug; For women of childbearing potential: effective contraceptive method combining two methods of contraception (one female contraceptive method combined with male condom use) from the inclusion visit until 1 month after discontinuation of the investigational drug; Blood chemistry: Kalemia, Calcemia, Prothrombin rate (PT), Activated partial thromboplastin time (APTT): values within laboratory normal; ALT, ASAT, Uricemia: values below the upper limit of the laboratory normal; Other biological results (Blood count; Natremia; Phosphoremia; Chloremia; Fasting blood glucose; Gamma glutamyl transpeptidase; Urea; Total bilirubin; Creatinine; CPK; Lactate dehydrogenase; Albuminemia; Proteinemia; Triglycerides; C-reactive protein; Albumin/Globulin ratio; Alkaline phosphatase) with no clinically significant abnormality. NB: A parameter outside the usual values considered clinically significant may, at the investigator's discretion, be tested a second time on another sample taken outside of a visit planned in the protocol before the initiation of the experimental drug. Urine dipstick (biochemistry: leukocyturia, proteinuria and hematuria) without clinically significant abnormality; Urine tox screen negative (amphetamines/metamphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates); Ability to take the investigational drug orally and adherence to the dosage of the investigational drug; Acceptance and signing of the informed consent; Membership in a social security plan or beneficiary of such a plan; Adherence to lifestyle considerations (see section 5.5) during participation in this research. Exclusion Criteria: Concomitant use or within 15 days prior to inclusion of another QT/QTc prolonging drug or drugs that may disrupt electrolyte levels, among others: loop diuretics, thiazide diuretics and related drugs (see list www.crediblemeds.org) History of amiodarone use within 6 months prior to inclusion History of gout or current treatment for gout or hyperuricemia Treatment with pyrazinamide or any other drug known to induce hyperuricemia History of hypersensitivity reaction to a nucleoside analog targeting viral RNA polymerase Known hypersensitivity to any of the components (favipiravir or placebo) Pregnant or breastfeeding women For men: history of vasectomy or known history of infertility. Refusal of the subject to complete all the visits, clinical and paraclinical examinations planned by the study On ECG: PR >200ms, QRS >100ms QTc >450ms and morphological appearance of abnormal repolarization PAS <100 mmHg Any history or active cardiovascular, pulmonary, intestinal, hepatic, renal, metabolic, hematologic, neurologic, bone, joint, muscular, psychiatric, systemic, ocular, gynecologic, andrologic, or infectious disease (including active HIV, HCV, or HBV infection), or any acute condition, which in the judgment of the investigator could be detrimental to the volunteer and/or interfere with or limit the protocol evaluation and data analysis Personal or family history of long QT syndrome, torsades de pointes or sudden death Patient with severe hepatic impairment Gastrointestinal pathology such as ileus, colitis or enterocolitis Treatment with another investigational drug or other investigational procedure (clinical trial, clinical investigation of a medical device, category 1 or 2 research involving humans); A person who is subject to a legal protection measure (safeguard of justice, curatorship, guardianship); Person placed in administrative detention; Person who, in the judgment of the investigating physician, may be non-observant during the study, or unable to communicate due to a language barrier or mental disorder Person who cannot be contacted in an emergency Person with at least one first-degree relative from East Asia or Southeast Asia. Secondary Exclusion Criteria Participants with at least one of the following criteria will not start the experimental treatment at D1 if they are already randomized: Positive nasopharyngeal antigen test for SARS-CoV-2 at D1 (prior to treatment initiation) Blood potassium levels outside the normal laboratory range within 8 days prior to treatment initiation (D1) ECG: PR >200ms, QRS >100ms QTc >450ms and morphological appearance of abnormal repolarization on Day 1 Positive pregnancy test on Day 1 (before initiation of treatment)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
France MENTRE
Phone
+33 1 40 25 79 31
Email
france.mentre@inserm.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Cedric LAOUNAN
Phone
+33 1 40 25 79 31
Email
cedric.laouenan@inserm.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Denis MALVY
Organizational Affiliation
CHU de Bordeaux & INSERM, Université de Bordeaux, France
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Xavier DUVAL
Organizational Affiliation
APHP Hôpital Bichat Claude Bernard
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Helene ESPEROU
Organizational Affiliation
Institut National de la Santé Et de la Recherche Médicale, France
Official's Role
Study Director
Facility Information:
Facility Name
University Hospital Bichat - Claude Bernard
City
Paris
ZIP/Postal Code
75018
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xavier Duval
First Name & Middle Initial & Last Name & Degree
Xavier Duval

12. IPD Sharing Statement

Learn more about this trial

Evaluation of Tolerance and Pharmacokinetic Profile of High Doses of Favipiravir in Healthy Volunteers

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