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

October 17, 2018 updated by: Institut National de la Santé Et de la Recherche Médicale, France

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Guinea
      • Conakry, Guinea
        • Conakry
      • Nzérékoré, Guinea
        • Nzérékoré

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
Time Frame: Day 14
Day 1 is the first day of favipiravir intake
Day 14

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evolution of EBOV semen RNA and infectious loads
Time Frame: 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.
Semen collection will be performed at least at Day 7, Day 14, Day 21 and Day 90
Plasma and semen trough concentrations of favipiravir
Time Frame: Plasma collection at Day 3, Day7, Day 10 and Day 14. Semen collection at Day 7 and Day 14
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
Time Frame: Blood collection at Day 1 will be used for further genotyping.
Blood collection at Day 1 will be used for further genotyping.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Investigators

  • Principal Investigator: Daouda Sissoko, Doctor, Inserm 897 unit, ISPED, Université de Bordeaux, Bordeaux cedex

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2016

Primary Completion (Actual)

August 1, 2016

Study Completion (Actual)

August 1, 2016

Study Registration Dates

First Submitted

February 24, 2016

First Submitted That Met QC Criteria

April 12, 2016

First Posted (Estimate)

April 15, 2016

Study Record Updates

Last Update Posted (Actual)

October 18, 2018

Last Update Submitted That Met QC Criteria

October 17, 2018

Last Verified

May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • C15-101

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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