Hepatitis C Virus Genotype 4 Infection | Therapy With Asunaprevir, Daclatasvir, Ribavirin and Pegylated Interferon Alpha-2a in HCV Genotype 4-infected Patients Who Have Failed to a Previous Therapy With Peg-Interferon/Ribavirin (ANRS HC32 QUATTRO)
Hepatitis C Virus Genotype 4 Infection research study
What is the primary objective of this study?
Success rates, after retreatment with Peg-Interferon/Ribavirin bitherapy, in patients infected with HCV (hepatitis C virus) genotype 4 and non-responders to a first standard treatment, are disappointing. The association of Asunaprevir and Daclatasvir in combination with the standard-of-care bitherapy has been shown to increase the efficacy of the treatment in non-responders genotype 1-infected patients. Given the absence of current solutions and urgent therapeutic needs for HCV genotype 4-infected patients previously treated with pegylated Interferon/Ribavirin, this pilot study aims to evaluate the efficacy and safety of a quadritherapy associating Asunaprevir, Daclatasvir, pegylated Interferon alpha-2a and Ribavirin, in this very difficult to treat population. 60 subjects will be enrolled. The primary endpoint will be the rate of sustained virological response (SVR), defined by an undetectable HCV RNA, at Week 36 (12 weeks after the end of a 24 weeks quadritherapy).
Who is eligible to participate?
Inclusion Criteria: - Adult ≥18 years - Infection with HCV genotype 4, confirmed by detectable HCV RNA ≥ 1000 IU/ml at pre-inclusion - Non-responders to a prior treatment with pegylated Interferon and Ribavirin, with non-response being defined as follows: - Null-response: reduction of less than 2 log10 IU/ml of HCV viral load between D0 of the treatment and week 12 - Partial response: reduction of at least 2 log10 IU/ml of HCV viral load between D0 of the treatment and week 12 but detectable HCV RNA at week 12 and week 24 and without an undetectable viral load by the end of treatment - Anti-HCV treatment discontinued for at least the last 3 months - Fibrosis at any stage, with documentation of the presence or absence of cirrhosis at the pre-inclusion visit: - history of liver biopsy showing cirrhosis lesions (METAVIR F4), at any time in the patient's history, and/or - good quality (length ≥ 15 mm and ≥ 6 portal spaces) liver puncture biopsy from less than 18 months to establish the METAVIR, and/or - hepatic impulse elastometry (Fibroscan®) from less than 6 months and of good quality (at least 10 measurements on an incidence with an IQR of less than 30% of the mean elastometry measured and a success rate of 60%) - Body weight ≥ 40 kg and ≤125 kg - Men and women of child-bearing age and their heterosexual partners must use two adequate contraceptions from 1 month before initiation of treatment up to 7 months after the end of treatment for men and up to 4 months after treatment for women. - Written informed consents (2) 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) - Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle) Exclusion Criteria: - CHILD B or C cirrhosis or a history of decompensated cirrhosis. If Child A cirrhosis, presence of varices presenting an hemorrhagic risk (grade II with red spots or grade III) on a fibroscopy dating from less than 3 years - Previous HCV therapy including HCV NS3 protease inhibitor, and/or HCV NS5A replication complex inhibitor and/or HCV NS5B polymerase inhibitor - Positive HBs Antigen - Confirmed HIV-1 or HIV-2 infection - Pregnant or breast-feeding women - Severe heart or lung disease - Transplant recipient - Uncontrolled dysthyroidism - Uncontrolled diabetes - Any evolutive ongoing malignant disease, including hepatocellular carcinoma, which will be specifically screened for before inclusion - Consumption of alcohol which, in the opinion of the investigator, will be an obstacle to participation of the patient and to his remaining in the study - Drug addiction which, in the the investigator's opinion, will be an obstacle to the patient's participation and to his or her remaining in the study. Patients included in a programme of substitution with methadone or buprenorphine could be included. The opinion of a consultant in addictology is recommended for patients presenting with current drug use or drug use in the past year. - Patients taking part in another clinical trial during the 30 days preceding inclusion. - Patient under guardianship, trusteeship or judicial protection - Hb < 110 g/L - Platelets < 80 000/mm3 - Polynuclear neutrophils < 1000 /mm3 (for European patients) and < 750 /mm3 (for African patients) - Kidney failure defined by creatinine clearance < 50mL/mn (MDRD formula) - Contra-indication for treatment with Ribavirin including a history of hypersensitivity to Ribavirin or to one of the excipients - Contra-indication for treatment with Daclatasvir or Asunaprevir including a history of hypersensitivity to one of the excipients - Contra-indication to treatment with Interferon including psychiatric contra-indications. A psychiatrist's opinion is compulsory in the following situations : - history of psychiatric disorders requiring hospitalisation of the patient or a consultation with a specialist - treatment with mood stabilizers or antipsychotics during the previous year - history of psychiatric disorders during prior treatment with Interferon alpha - evidence of depression episodes, a risk of suicide, bipolar disorder and/or current behavioral disorders. These patients can only be included after a psychiatric evaluation that specifically authorizes the use of Interferon. - History of previous HCV treatment premature cessation (in the first 6 months) for toxicity. Premature cessation for anemia or neutropenia will be authorized in the absence of the use of erythropoietin or polynuclear neutrophil growth factor, respectively. - Patients with a non-compliance history, who will be at risk of not complying with the study follow-up timetable - Associated treatment likely to interfere with the study drugs
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Hepatitis C Virus Genotype 4 Infection
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:AsunaprevirAsunaprevir 100 mg, 1 capsule twice a day from Day 0 to Week 24
Drug:DaclatasvirDaclatasvir 60 mg, 1 tablet once a day from Day 0 to Week 24
Drug:RibavirinRibavirin tablets or capsules 200 mg, weight-based daily dose ( <75 kg : 1000 mg ; ≥ 75 kg : 1200 mg), from Day 0 to Week 24
Drug:Pegylated Interferon alpha-2aPegylated Interferon alpha-2a, by subcutaneous injection 180µg / week, from Day 0 to Week 24
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
Asunaprevir, Daclatasvir, Ribavirin, Peg-Interferon alpha-2aQuadritherapy from Day 0 to Week 24
Start Date: November 2013
Completed Date: April 2015
Phase: Phase 2
Primary Outcome: SVR12 Rate
Secondary Outcome: Number of patients with adverse events
Study sponsors, principal investigator, and references
Principal Investigator: Dominique ROULOT, MD, PhD
Lead Sponsor: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Collaborator: Bristol-Myers Squibb