FORCE: Tolerance and Activity Evaluation of High Doses of Favipiravir Against Ebola Virus in the Semen

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France (Other)

Overall Status

Terminated

CT.gov ID

NCT02739477

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patient Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to evaluate favipiravir high dose tolerance in male survivor of Ebola Virus Disease (EVD) with Ebola Virus (EBOV) RNA in semen. This is a dose escalation study with 3 cohorts of 6 patients, each dose level including 2 sentinel patients.

Condition or Disease	Intervention/Treatment	Phase
Ebola Virus Survivor	Drug: Favipiravir	Phase 2

Detailed Description

Rational:

Data suggesting persistence of EBOV in semen a few months after the end of EVD and sexual transmission of EBOV
Encouraging results on favipiravir efficacy to reduce mortality of EVD in JIKI trial (NCT02329054 )
Favipiravir trough plasma concentration in JIKI trial lower than predicted by population pharmacokinetic model, suggesting an increase of dose might be necessary to achieve a therapeutically relevant exposure.

Objectives:

Primary objective: to assess clinical and biological tolerance of high-dosed favipiravir bid for 14 days
Secondary objectives: to assess the activity of favipiravir on evolution of EBOV RNA and infectious loads in semen under treatment; the trough plasma and semen concentrations of favipiravir; and genetic factors associated with favipiravir pharmacokinetic.

Dose escalation scheme:

Each patient of each cohort will receive favipiravir loading doses of 4800 mg at Day 1 (2400 mg bid), following by 3600 mg (1800 mg bid) from Day 2 to 14 (cohort 1), then 3600, 4200 or 4800 mg from Day 2 to 14 (cohort 2 and 3), depending on previous cohort results.

Escalation rules are based on the number of patient undergoing treatment-related adverse events (TRAE) of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v4.03 (CTCAE), as defined by the investigator and sponsor.

Participants will attend medical visits at Day 1, Day 3, Day 7, Day 10, Day 14, Day 21 and clinical tolerance will be assessed daily by phone call from Day 1 to Day 14.

At the end of the first cohort:

if no TRAE, cohort 2 will be given 2400 mg bid from Day 2 to 14;
if 1 or 2 TRAE is observed, cohort 2 will be given 2100 mg bid from Day 2 to Day 14;
if 3 or more TRAE is observed, cohort 2 will be given the same dose as cohort 1.

At the end of cohort 2, same rules will be apply to cohort 3, without exceed 4800 mg of favipiravir per day.

Each cohort will include 6 patients. Each dose level will comprise 2 sentinel patients.

In their own interest, patients included in a cohort with detection of EBOV RNA in semen by RT-PCR (CT<38) at Day 21, could be included in the next cohort.

Recruitment will start among PostEbogui cohort from coast Guinea.

Study Design

Study Type:

Interventional

Actual Enrollment :

2 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Tolerance and Activity Assessment of High Doses of Favipiravir in Male Survivors With Ebola Virus in the Semen

Study Start Date :

Apr 1, 2016

Actual Primary Completion Date :

Aug 1, 2016

Actual Study Completion Date :

Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Favipiravir Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)	Drug: Favipiravir Cohort 1: Day 1 (inclusion) 4800 mg (2400 mg bid). Day 2 to Day 14: 3600 mg (1800 mg bid). Cohort 2: Day 1 (inclusion) 4800 mg (2400 mg bid). Day 2 to Day 14: 3600, 4200, 4800 mg per day depending on cohort 1 results. Cohort 3: Day 1 (inclusion) 4800 mg (2400 mg bid). Day 2 to Day 14: 3600, 4200, 4800 mg per day depending on cohorts 1 and 2 results. Other Names: AVIGAN

Arm

Intervention/Treatment

Experimental: Favipiravir

Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)

Drug: Favipiravir

Cohort 1: Day 1 (inclusion) 4800 mg (2400 mg bid). Day 2 to Day 14: 3600 mg (1800 mg bid). Cohort 2: Day 1 (inclusion) 4800 mg (2400 mg bid). Day 2 to Day 14: 3600, 4200, 4800 mg per day depending on cohort 1 results. Cohort 3: Day 1 (inclusion) 4800 mg (2400 mg bid). Day 2 to Day 14: 3600, 4200, 4800 mg per day depending on cohorts 1 and 2 results.

Other Names:

AVIGAN

Outcome Measures

Primary Outcome Measures

Number of patients undergoing grade 3 or 4 clinical or biological adverse events related to Favipiravir (Common Terminology Criteria for Adverse Events, CTCAE, v4.03) [Day 14]
Day 1 is the first day of favipiravir intake

Secondary Outcome Measures

Evolution of EBOV semen RNA and infectious loads [Semen collection will be performed at least at Day 7, Day 14, Day 21 and Day 90]
From Day 14 to Day 90, semen EBOV PCR will be performed every 3 weeks until their semen tests negative for virus twice by RT-PCR, with an interval of one week between tests.
Plasma and semen trough concentrations of favipiravir [Plasma collection at Day 3, Day7, Day 10 and Day 14. Semen collection at Day 7 and Day 14]
Genetic variations associated with favipiravir exposition [Blood collection at Day 1 will be used for further genotyping.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

male survivor of biologically confirmed EVD
age >= 18 years
EBOV RT-PCR on semen with cycle threshold [Ct]<38 at Day -7 and semen aliquot available for later quantification of EBOV
signed informed consent

Non-Inclusion Criteria:

EBOV RT-PCR on blood with cycle threshold [Ct]<38 at Day -7
Biological abnormality higher than grade 2 according to CTCAE (v4.03) on following parameters: creatinine, ASAT, ALAT, alkaline phosphatase, total bilirubin
Fridericia corrected QT interval (QTc) > 450 ms
Concomitant use of QT/QTc interval-prolonging drugs or drugs that could cause electrolyte imbalance, such as: loop diuretics, thiazide diuretics or related
Previous gout attack or ongoing treatment for gout or hyperuricemia
Ongoing pyrazinamide treatment or other drug known to induce hyperuricemia
Previous hypersensitivity reaction due to nucleoside analogue
Symptom or biological value suggesting systemic disorder (renal, hepatic, cardio-vascular, pulmonary) or any medical condition that could interfere with results interpretation or compromise participants' health
Explicit refusal to comply with proper use of drug (condom use)