Tolerance and Activity Evaluation of High Doses of Favipiravir Against Ebola Virus in the Semen (FORCE)
Primary Purpose
Ebola Virus Survivor
Status
Terminated
Phase
Phase 2
Locations
Guinea
Study Type
Interventional
Intervention
Favipiravir
Sponsored by
About this trial
This is an interventional treatment trial for Ebola Virus Survivor focused on measuring Favipiravir, Tolerance, Survivor, Ebola Virus, Genital reservoir, Guinea
Eligibility 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)
Sites / Locations
- Conakry
- Nzérékoré
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Favipiravir
Arm Description
Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)
Outcomes
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 1 is the first day of favipiravir intake
Secondary Outcome Measures
Evolution of EBOV semen RNA and infectious loads
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
Genetic variations associated with favipiravir exposition
Full Information
NCT ID
NCT02739477
First Posted
February 24, 2016
Last Updated
October 17, 2018
Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
1. Study Identification
Unique Protocol Identification Number
NCT02739477
Brief Title
Tolerance and Activity Evaluation of High Doses of Favipiravir Against Ebola Virus in the Semen
Acronym
FORCE
Official Title
Tolerance and Activity Assessment of High Doses of Favipiravir in Male Survivors With Ebola Virus in the Semen
Study Type
Interventional
2. Study Status
Record Verification Date
May 2016
Overall Recruitment Status
Terminated
Why Stopped
End date of epidemic
Study Start Date
April 2016 (undefined)
Primary Completion Date
August 2016 (Actual)
Study Completion Date
August 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut National de la Santé Et de la Recherche Médicale, France
4. Oversight
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ebola Virus Survivor
Keywords
Favipiravir, Tolerance, Survivor, Ebola Virus, Genital reservoir, Guinea
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Favipiravir
Arm Type
Experimental
Arm Description
Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)
Intervention Type
Drug
Intervention Name(s)
Favipiravir
Other Intervention Name(s)
AVIGAN
Intervention Description
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.
Primary Outcome Measure Information:
Title
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)
Description
Day 1 is the first day of favipiravir intake
Time Frame
Day 14
Secondary Outcome Measure Information:
Title
Evolution of EBOV semen RNA and infectious loads
Description
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.
Time Frame
Semen collection will be performed at least at Day 7, Day 14, Day 21 and Day 90
Title
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
Title
Genetic variations associated with favipiravir exposition
Time Frame
Blood collection at Day 1 will be used for further genotyping.
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daouda Sissoko, Doctor
Organizational Affiliation
Inserm 897 unit, ISPED, Université de Bordeaux, Bordeaux cedex
Official's Role
Principal Investigator
Facility Information:
Facility Name
Conakry
City
Conakry
Country
Guinea
Facility Name
Nzérékoré
City
Nzérékoré
Country
Guinea
12. IPD Sharing Statement
Learn more about this trial
Tolerance and Activity Evaluation of High Doses of Favipiravir Against Ebola Virus in the Semen
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