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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Grazoprevir/Elbasvir
* Drug: Sofosbuvir
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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)) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV genotype 1 or 4, failure to DAA