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

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ClinicalTrials.gov Identifier: NCT02739477
Recruitment Status : Terminated (End date of epidemic)
First Posted : April 15, 2016
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

Tracking Information
First Submitted Date  ICMJE February 24, 2016
First Posted Date  ICMJE April 15, 2016
Last Update Posted Date October 18, 2018
Study Start Date  ICMJE April 2016
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 15, 2016)
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
Original Primary Outcome Measures  ICMJE
 (submitted: April 12, 2016)
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 21 of the last patient of the cohort ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2016)
  • 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.
  • 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 ]
  • Genetic variations associated with favipiravir exposition [ Time Frame: Blood collection at Day 1 will be used for further genotyping. ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tolerance and Activity Evaluation of High Doses of Favipiravir Against Ebola Virus in the Semen
Official Title  ICMJE Tolerance and Activity Assessment of High Doses of Favipiravir in Male Survivors With Ebola Virus in the Semen
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Ebola Virus Survivor
Intervention  ICMJE 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 Name: AVIGAN
Study Arms  ICMJE Experimental: Favipiravir
Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)
Intervention: Drug: Favipiravir
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 17, 2018)
2
Original Estimated Enrollment  ICMJE
 (submitted: April 12, 2016)
18
Actual Study Completion Date  ICMJE August 2016
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Guinea
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02739477
Other Study ID Numbers  ICMJE C15-101
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institut National de la Santé Et de la Recherche Médicale, France
Study Sponsor  ICMJE Institut National de la Santé Et de la Recherche Médicale, France
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Daouda Sissoko, Doctor Inserm 897 unit, ISPED, Université de Bordeaux, Bordeaux cedex
PRS Account Institut National de la Santé Et de la Recherche Médicale, France
Verification Date May 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP