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

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

Status and phase: Terminated; Phase 2

Conditions: Ebola Virus Survivor

Treatments: Drug: Favipiravir

Study type: Interventional

Funder types: Other

Identifiers

NCT02739477

C15-101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 2 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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)

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

---

2 participants in 1 patient group

Favipiravir

Experimental group

Description:

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

Treatment:

Drug: Favipiravir