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

• ClinicalTrials.gov Identifier: NCT06024421
• Recruitment Status: Recruiting
• First Posted: September 6, 2023
• Last Update Posted: April 9, 2024
• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborator: FUJIFILM Toyama Chemical Co., Ltd.
• Information provided by (Responsible Party): Institut National de la Santé Et de la Recherche Médicale, France

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).

Condition or disease	Intervention/treatment	Phase
Infectious Disease; Pharmacology	Drug: favipiravir; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Dose-escalation trial
• 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.
• Primary Purpose: Treatment
• Official Title: EVALUATION DE LA TOLERANCE ET DU PROFIL PHARMACOCINETIQUE DE DOSES ELEVEES DE FAVIPIRAVIR CHEZ LE VOLONTAIRE SAIN
• Estimated Study Start Date: April 2024
• Estimated Primary Completion Date: May 2027
• Estimated Study Completion Date: October 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: level 1: experimental; D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning	Drug: favipiravir; Light yellow, film-coated tablet, each containing 200 mg of favipiravir
Experimental: level 2: experimental; D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning	Drug: favipiravir; Light yellow, film-coated tablet, each containing 200 mg of favipiravir
Experimental: level 3: experimental; D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning	Drug: favipiravir; Light yellow, film-coated tablet, each containing 200 mg of favipiravir
Placebo Comparator: level 1: placebo; D1: 2400 mg BID; D2 to D13: 1600 mg BID and D14: 1600 mg in the morning	Drug: Placebo; Light yellow, film-coated tablet
Placebo Comparator: level 2: placebo; D1: 2400 mg BID; D2 to D13: 2000 mg BID and D14: 2000 mg in the morning	Drug: Placebo; Light yellow, film-coated tablet
Placebo Comparator: level 3: placebo; D1: 2400 mg BID; D2 to D13: 2400 mg BID andD14: 2400 mg in the morning	Drug: Placebo; Light yellow, film-coated tablet

Outcome Measures

Primary Outcome Measures :

1. Tolerance [ Time Frame: Months 6 ]

   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 :

1. 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) ]
   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.
2. Genetic [ Time Frame: Days 1 ]
   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.
3. Sperm pharmacology [ Time Frame: Day 14, day 28 ]
   For participating men: favipiravir concentration in sperm at D14 and D28.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Man between 50 and 75 years old without any desire to have children or woman between 18 and 75 years old ;
2. Subject considered healthy after a thorough general examination (questioning, physical examination);
3. For men: acceptance of semen collection by masturbation;
4. For men: acceptance of condom use from initiation of the investigational drug until 1 month after stopping the investigational drug;
5. 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;

6. 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.

7. Urine dipstick (biochemistry: leukocyturia, proteinuria and hematuria) without clinically significant abnormality;
8. Urine tox screen negative (amphetamines/metamphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates);
9. Ability to take the investigational drug orally and adherence to the dosage of the investigational drug;
10. Acceptance and signing of the informed consent;
11. Membership in a social security plan or beneficiary of such a plan;
12. Adherence to lifestyle considerations (see section 5.5) during participation in this research.

Exclusion Criteria:

1. 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)
2. History of amiodarone use within 6 months prior to inclusion
3. History of gout or current treatment for gout or hyperuricemia
4. Treatment with pyrazinamide or any other drug known to induce hyperuricemia
5. History of hypersensitivity reaction to a nucleoside analog targeting viral RNA polymerase
6. Known hypersensitivity to any of the components (favipiravir or placebo)
7. Pregnant or breastfeeding women
8. For men: history of vasectomy or known history of infertility.
9. Refusal of the subject to complete all the visits, clinical and paraclinical examinations planned by the study
10. On ECG: PR >200ms, QRS >100ms QTc >450ms and morphological appearance of abnormal repolarization
11. PAS <100 mmHg
12. 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
13. Personal or family history of long QT syndrome, torsades de pointes or sudden death
14. Patient with severe hepatic impairment
15. Gastrointestinal pathology such as ileus, colitis or enterocolitis
16. Treatment with another investigational drug or other investigational procedure (clinical trial, clinical investigation of a medical device, category 1 or 2 research involving humans);
17. A person who is subject to a legal protection measure (safeguard of justice, curatorship, guardianship);
18. Person placed in administrative detention;
19. 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
20. Person who cannot be contacted in an emergency
21. 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:

1. Positive nasopharyngeal antigen test for SARS-CoV-2 at D1 (prior to treatment initiation)
2. Blood potassium levels outside the normal laboratory range within 8 days prior to treatment initiation (D1)
3. ECG: PR >200ms, QRS >100ms QTc >450ms and morphological appearance of abnormal repolarization on Day 1
4. Positive pregnancy test on Day 1 (before initiation of treatment)

Contacts and Locations

Contacts

Contact: France MENTRE; +33 1 40 25 79 31; france.mentre@inserm.fr

Contact: Cedric LAOUNAN; +33 1 40 25 79 31; cedric.laouenan@inserm.fr

Locations

France

University Hospital Bichat - Claude Bernard; Recruiting

Paris, France, 75018

Contact: Xavier Duval

Principal Investigator: Xavier Duval

Sponsors and Collaborators

Institut National de la Santé Et de la Recherche Médicale, France

FUJIFILM Toyama Chemical Co., Ltd.

Investigators

• Study Chair: Denis MALVY; CHU de Bordeaux & INSERM, Université de Bordeaux, France
• Principal Investigator: Xavier DUVAL; APHP Hôpital Bichat Claude Bernard
• Study Director: Helene ESPEROU; Institut National de la Santé Et de la Recherche Médicale, France

More Information

• Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
• ClinicalTrials.gov Identifier: NCT06024421
• Other Study ID Numbers: C18-47; 2022-502871-49-00 ( Other Identifier: EU CT )
• First Posted: September 6, 2023
• Last Update Posted: April 9, 2024
• Last Verified: April 2024

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:

healthy volunteer; dose escalation; tolerance; pharmacokinetics; favipiravir

Additional relevant MeSH terms:

Communicable Diseases; Infections; Disease Attributes; Pathologic Processes; Favipiravir; Antiviral Agents; Anti-Infective Agents