Feasibility, Tolerance and Efficacy of Interferon-free, Antiviral Treatment With Sofosbuvir + Ribavirin for the Treatment of Genotype 2 and Sofosbuvir/Ledipasvir for the Treatment of Genotype 1 and 4 Hepatitis C Virus-infected Patients in West and Central Africa (TAC)

TAC (Treatment Africa Hepatitis C) : Feasibility, Tolerance and Efficacy of Interferon-free, Antiviral Treatment With Sofosbuvir + Ribavirin for the Treatment of Genotype 2 and Sofosbuvir/Ledipasvir for the Treatment of Genotype 1 and 4 Hepatitis C Virus-infected Patients in West and Central Africa

Primary Objective:

To evaluate the efficacy (sustained virological response 12 weeks after end-of-treatment [SVR12]) of 12-week course of an interferon-free regimen combining sofosbuvir and weight-dosed ribavirin (genotype 2), or sofosbuvir and ledipasvir (genotype 1 or 4) in treatment-naïve patients infected with HCV genotype 1, 2 or 4 in West and Central Africa

Secondary Objectives:

1. To estimate the study treatment SVR24 rate
2. To evaluate the clinical and biological tolerance of study treatment
3. To describe HCV kinetics under HCV treatment, and identify associated factors
4. To describe the evolution of HIV disease under HCV treatment in HVC-HIV co-infected patients
5. To describe the changes of liver fibrosis based on non-invasive tests between treatment initiation, week 24, and week 36 after treatment, and estimate its association with SVR12 or SVR24
6. To identify factors associated with SVR12 and SVR24 (including HIV status)
7. To evaluate the performance of a nanodevice for rapid diagnosis of HCV viral load and genotypying and for assessing response to treatment (SVR12 and SVR24)
8. Facilitate the detection and treatment of those infected with HCV by supporting national initiatives for access to strategies without interferon
9. To set up a HCV clinical research network across French and English-speaking African countries, able to run large-scale comparative randomized clinical trials in a near future.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Hepatitis C
• Intervention / Treatment: Drug: Sofosbuvir; Drug: Ribavirin; Drug: Sofosbuvir; Drug: Ledipasvir

Detailed Description

Study design Multicenter, phase IIb, non randomized, open-label trial involving 3 groups of HCV-mono infected or HCV-HIV co-infected patients: group G1 (patients infected with HCV genotype 1), group G2 (patients infected with HCV genotype 2), and group G4 (patients infected with HCV genotype 4).

Number of Subjects A sample size of 40 patients per group will allow to demonstrate that the SVR12 is >70% ("expected efficacy" in difficult-to-treat patients, according to SPARE interim results), with the lower bound of the confidence interval being >50% ("unacceptable" efficacy). The overall sample size is 3x40=120 patients.

Participating Countries 3 countries from West Africa (Senegal, Côte d'Ivoire) and Central Africa (Cameroon) Number of Sites 5 clinical sites:

• Côte d'Ivoire: Hepatology Departementat the Yopougon University Teaching Hospital, , Abidjan; and Blood Donors clinic (CMSDS) at the National Blood Bank (CNTS), Abidjan
• Senegal: CRCF (Centre Régional de Recherche et de Formation), and Fann University Teaching Hospital
• Cameroon: Clinique de la Cathédrale

Duration of Recruitment : 6 months

Duration of Treatment : 12 weeks

Duration of follow-up : 36 weeks

Anticipated Start Date / Anticipated End Date: November 2015 - October 2016

Target Population /Demographics : Patients >18 years, living with chronic hepatitis C genotype 1, 2 or 4, in West and Central Africa. In each genotype group approx. 50% of patients will be HCV-HIV co-infected, and 50% of patients will be mono-infected with HCV

This study will enable us to assess the feasibility, tolerance and efficacy of such a strategy in resource-constrained settings with considerable treatment needs.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Cameroon
  • Yaoundé, Cameroon
    • Clinique de la Cathédrale
• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • Centre de suivi des donneurs de sang
  • Abidjan, Côte D'Ivoire
    • CHU de Youpougon - Service de Gastro-entéro-hépatologie
• Senegal
  • Dakar, Senegal
    • CHU Fann, Service des Maladies Infectieuses

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age≥18 years
• Confirmed G1, G2 or G4 HCV infection
• Plasma HCV-RNA ≥1000 IU/mL
• No history of HCV treatment of any kind
• Willingness to use a birth control method (hormonal or intrauterine device for women, condoms for men), starting before HCV treatment initiation and continued until 4months (women) and 7 months (men) after end of treatment.
• Weight ≥40 kg and ≤125 kg

For patients infected with HIV :

• Confirmed HIV-1 infection
• Stable HIV treatment for at least 8 weeks with two NRTIs (tenofovir or abacavir, and lamivudine or emtricitabine) and a third agent (raltegravir, lopinavir/ritonavir, atazanavir/ritonavir, darunavir/ritonavir, efavirenz, nevirapine)
• Current CD4+ lymphocytes count ≥100/mm3
• Current plasma HIV-1 RNA <200 copies/mL

Exclusion Criteria:

For each patient:

• Cirrhosis classified Child-Pugh B or C
• Co-infection by the Hepatitis B virus
• Pregnant or breastfeeding ongoing
• History of transplantation of organs or tissues
• Progressive Cancer, including hepatocellular carcinoma
• Epilepsy
• Sickle Cell Disease
• A history of myocardial infarction or other severe heart disease
• Excessive consumption of alcohol or drug users, in the absence of substitution by methadone, a stable weaning for more than three months should be required
• Ongoing Participation in another clinical trial
• Contraindications to the Sofosbuvir as defined in the Summary of Product Characteristics
• At least one of the following laboratory abnormalities:

Haemoglobin <10 g / 100 ml (woman) <11 g / 100 ml (man) Platelet count <50,000 / mm3 polymorphonuclear neutrophils rate <750 / mm3 Creatinine clearance <50ml / min

For patients infected with HIV:

• Severe opportunistic infections in the last 6 months
• Poor adherence to antiretroviral treatment history
• Use of antiretroviral drugs other than those permitted in the test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sofosbuvir+Ribavirin; Sofosbuvir 400mg QD (Sovaldi®) + Ribavirin weight-adjusted dosing (1000mg BID in patients < 75kg and 1200mg BID in patients ≥ 75kg) in treatment-naïve patients infected with HCV genotype 2 (12-week course)	Drug: Sofosbuvir; Sofosbuvir 400mg QD (Sovaldi®) in treatment-naïve patients infected with HCV genotype 2 (12-week course); Other Names: Sovaldi®; Drug: Ribavirin; Ribavirin weight-adjusted dosing (1000mg BID in patients < 75kg and 1200mg BID in patients ≥ 75kg) in treatment-naïve patients infected with HCV genotype 2 (12-week course); Drug: Sofosbuvir; Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course); Other Names: Harvoni®
EXPERIMENTAL: Sofosbuvir+Ledipasvir; Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course)	Drug: Sofosbuvir; Sofosbuvir 400mg QD (Sovaldi®) in treatment-naïve patients infected with HCV genotype 2 (12-week course); Other Names: Sovaldi®; Drug: Sofosbuvir; Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course); Other Names: Harvoni®; Drug: Ledipasvir; Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course); Other Names: Harvoni®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Sustained Viral Load Response (SVR)	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance	Grade 1, 2, 3 and 4 clinical or biological events (ACTG grading table), Adverse events-related HCV treatment discontinuation Adverse events-related ARV treatment modification	36 weeks
Viral kinetics as measured by SVR 24 and HCV-RNA	SVR 24 and HCV-RNA	W0, W2, W4, W12, W24, W36
HIV treatment clinical parameters	Number, nature and incidence of severe morbid events related to HIV, and clinical and biological events of grade 3 or 4 (ANRS scale) related to the ARV treatment	36 weeks
Liver fibrosis	Elastometry score and only for cirrhotic patients : Child-Pugh score	W0, W24 and W36
Adherence measured by number of remaining tablets at each visit based on the number of tablets should have been taken as a percentage of the total dose	Number of remaining tablets at each visit based on the number of tablets should have been taken as a percentage of the total dose	W4, W8, W12
Quality of life	proportion of people reporting symptoms in the scale of symptoms experienced (scale of side effects perception SF12)	36 weeks
Performance of an unit of nanotechnology	calculation of sensitivity / specificity / positive predictive value and negative of each of the steps that will be performed (genotype, viral load) compared to the reference measurement (PCR for viral load and sequencing to genotype).	36 weeks
Setting up the network:	number of network meetings that have taken place before the end of the trial, the number of training sessions (on site or online) and the numbers enrolled in the network active partners. The ultimate goal is the establishment of an e-learning platform that will be an ancillary project.	36 weeks
Integration Access initiatives evaluated by the number of patients off protocol that will have access to new anti-HCV treatment due to "ACCESS" programs of pharmaceutical companies conducting such programs in Sub-Saharan Africa	It will be evaluated by the number of patients off protocol that will have access to new anti-HCV treatment due to "ACCESS" programs of pharmaceutical companies conducting such programs in Sub-Saharan Africa	36 weeks
Biological events	Plasma HIV-RNA and CD4 count	W0, W24 and W36

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Investigators: Study Director: Raoul Moh, Dr, Programme PACCI; Study Director: Babacar Sylla, Institut de Médecine et d'Epidémiologie Appliquée

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2015
• Primary Completion (ACTUAL): July 1, 2017
• Study Completion (ACTUAL): November 1, 2017

Study Registration Dates

• First Submitted: February 20, 2015
• First Submitted That Met QC Criteria: March 27, 2015
• First Posted (ESTIMATE): April 1, 2015

Study Record Updates

• Last Update Posted (ACTUAL): December 13, 2017
• Last Update Submitted That Met QC Criteria: December 12, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: HIV; Adults; Africa; Hepatitis C; HCV genotype 4; HCV genotype 1; Antiviral treatment; HCV genotype 2
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Sofosbuvir; Ribavirin; Ledipasvir, sofosbuvir drug combination; Ledipasvir
• Other Study ID Numbers: ANRS 12311 TAC