Study to Assess Efficacy and Safety of Grazoprevir/Elbasvir Associated With Sofosbuvir and Ribavirin in HCV Genotype 1 or 4-infected Patients Who Failed Direct Acting Antivirals (DAA) Bitherapy With Sofosbuvir

The primary objective of this study is to estimate, in HCV genotype 1 or 4-infected patients who failed a prior DAA bitherapy with Sofosbuvir, the efficacy of a treatment with Grazoprevir/Elbasvir, Sofosbuvir and Ribavirin in the two treatment groups and compare the rate of sustained virological response (SVR) 12 weeks after 16 or 24 weeks of this treatment. SVR12 is defined as HCV RNA < LLOQ (either TD[u] or TND).

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: Sofosbuvir; Drug: Ribavirin; Drug: Grazoprevir/Elbasvir

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult ≥18 years
• Infection with HCV genotype 1 or 4, confirmed by detectable HCV RNA at pre-inclusion
• Failure to a prior therapy with Sofosbuvir +/- Ribavirin associated with Simeprevir or Daclatasvir or Ledipasvir, with documented presence of NS5A or NS3/4A RAVs (Resistance Associated Variants) at the time of failure (presence of RAVs on at least one sample since the time of failure).

The proportion of patients previously treated with Simeprevir will be limited to a third of all patients included.

• Fibrosis at any stage
• Men and women of child-bearing age and their heterosexual partners must use adequate contraceptions from 15 days before their inclusion in the study up to 7 months after the end of treatment for men and up to 4 months after the end of treatment for women
• Written informed consent signed by the patient and the investigator (on the day of the pre-inclusion at the latest and before any examination required by the study) (article L1122-1-1 Public Health Code)
• Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle)

Exclusion Criteria:

• Child B or C cirrhosis (or Child A patients with history of Child B)
• Patients with documented presence of RAVs conferring resistance to sofosbuvir
• Positive HBs Antigen
• Confirmed HIV-1 or HIV-2 infection
• Pregnant or breast-feeding women or men whose female partners are pregnant
• Transplant recipients
• Any evolutive ongoing malignant disease, including hepatocellular carcinoma, which will be specifically screened for before inclusion
• History of severe rhythm disorders or cardiac disease (coronary artery disease, heart failure, arteriopathy,…): the opinion of a cardiologist is compulsory (< 6 months)
• Consumption of alcohol which, in the investigator's opinion, will be an obstacle to the patient's participation and to his/her remaining in the study
• Drug addiction which, in the investigator's opinion, will be an obstacle to the patient's participation and to his/her remaining in the study. Patients included in a programme of substitution with methadone or buprenorphine could be included. The opinion of an addictology consultant is recommended for patients presenting with current drug use or drug use in the past year
• Patients taking part in another clinical trial within 30 days prior to inclusion
• Patient under guardianship, trusteeship or judicial protection

Non-inclusion biological criteria

• Hemoglobin < 11 g/dL
• Platelets < 50 000/mm3
• INR > 1.5 unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR
• ALT or AST > 10xULN
• Creatinine clearance < 50 mL/mn (MDRD formula)
• Albumin < 30 g/L
• HbA1c > 10% (only in diabetic patients)

Criteria related to study drugs

• Contra-indication to treatment with Grazoprevir/Elbasvir, Sofosbuvir or Ribavirin including a history of hypersensitivity to one of their excipients
• Patients with a non-compliance history, who will be at risk of not complying with the study follow-up timetable
• Treatment with contra-indicated associated drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 16 weeks of treatment; Drug : Grazoprevir/Elbasvir + Sofosbuvir + Ribavirin during 16 weeks	Drug: Sofosbuvir; Other Names: Sofosbuvir is also known as Sovaldi; Drug: Ribavirin; Other Names: Ribavirin is also known as Rebetol; Drug: Grazoprevir/Elbasvir; Other Names: Grazoprevir/Elbasvir is also known as MK-5172A or Zepatier
Experimental: 24 weeks of treatment; Drug : Grazoprevir/Elbasvir + Sofosbuvir + Ribavirin during 24 weeks	Drug: Sofosbuvir; Other Names: Sofosbuvir is also known as Sovaldi; Drug: Ribavirin; Other Names: Ribavirin is also known as Rebetol; Drug: Grazoprevir/Elbasvir; Other Names: Grazoprevir/Elbasvir is also known as MK-5172A or Zepatier

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of the Sustained Virological Response 12 weeks after the end of the therapy (SVR12), i.e. at W28 or W36 for treatment duration of 16 weeks and 24 weeks respectively.	The primary endpoint is the rate of the Sustained Virological Response defined as HCV RNA < LLOQ (either TD[u] or TND) 12 weeks after the end of the therapy associating Grazoprevir/Elbasvir, Sofosbuvir and Ribavirin (SVR12), i.e. at W28 or W36 for treatment duration of 16 weeks and 24 weeks respectively.	Week 28 (W28) or Week 36 (W36)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SVR rate 4 weeks after the end of treatment (i.e. at week 20 or week 28 for treatment duration of 16 weeks and 24 weeks respectively) and 24 weeks after the end of treatment (i.e. at week 40 or week 48).		Week 20 (W20) or Week 28 (W28), and W40 or W48
HCV viral load assessment		from Day 0 (D0) to Week 40 (W40) or Week 48 (W48)
Assessment of HCV subtypic distribution at baseline		Pre-inclusion
Numbers and proportions of patients presenting variants of resistance (RAV) at baseline	The numbers and proportions of patients presenting variants of resistance (RAV) and their characteristics will be studied	Pre-inclusion
Assessment of liver fibrosis by Hepatic impulse elastometry (Fibroscan®), or biological parameters (FibroMeter® or Fibrotest®)		Pre-inclusion, Week 40 or Week 48
For cirrhotic patients, description of the risk of cirrhosis evolution (decompensation, hepatocarcinoma)	Cirrhosis evaluation (Child-Pugh)	Pre-inclusion, Day 0 (D0), Week 16 (W16), W20, W24, W28, W36, W40 or W48
For cirrhotic patients, description of the risk of cirrhosis evolution (decompensation, hepatocarcinoma)	Cirrhosis evaluation (MELD score)	Pre-inclusion, Day 0 (D0), Week 16 (W16), W20, W24, W28, W36, W40 or W48
Clinical and biological adverse events occurring during the treatment and until 24 weeks after the end of the treatment		from Day 0(D0) to Week 40 (W40) or W48
Numbers and proportions of patients who interrupted the treatments of the study		from Day 0 (D0) to Week 40 (W40) or W48
Patient's reported outcomes evaluation with questionnaires	Evaluation of patient's quality of life	Day 0 (D0), Week 4 (W4), W16, W28, W40 or D0, W4, W16, W24, W36, W48 (24 weeks treatment-arm))
Patient's reported outcomes evaluation with questionnaires	Evaluation of perceived symptoms (ANRS questionnaire)	Day 0 (D0), Week 4 (W4), W16, W28, W40 or D0, W4, W16, W24, W36, W48 (24 weeks treatment-arm))

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Investigators: Principal Investigator: Victor DE LEDINGHEN, Hôpital de Haut-Lévêque, CHU de Bordeaux; Study Chair: Eric Bellissant, Centre de Méthodologie et de Gestion, CHU de Rennes

Publications and helpful links

General Publications

• de Ledinghen V, Laforest C, Hezode C, Pol S, Renault A, Alric L, Larrey D, Metivier S, Tran A, Jezequel C, Samuel D, Zoulim F, Tual C, Pailhe A, Gibowski S, Bourliere M, Bellissant E, Pawlotsky JM. Retreatment With Sofosbuvir Plus Grazoprevir/Elbasvir Plus Ribavirin of Patients With Hepatitis C Virus Genotype 1 or 4 Who Previously Failed an NS5A- or NS3-Containing Regimen: The ANRS HC34 REVENGE Study. Clin Infect Dis. 2018 Mar 19;66(7):1013-1018. doi: 10.1093/cid/cix916.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: January 4, 2016
• First Posted (Estimate): January 6, 2016

Study Record Updates

• Last Update Posted (Actual): June 29, 2017
• Last Update Submitted That Met QC Criteria: June 28, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: HCV genotype 1 or 4; failure to DAA
• 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; Hepatitis; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Sofosbuvir; Ribavirin; Grazoprevir; Elbasvir-grazoprevir drug combination
• Other Study ID Numbers: ANRS HC34 REVENGE