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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).
Full description
The population studied presents the maximum of factors of non-response to the retreatment of hepatitis C: non-response to well followed prior treatment with pegylated Interferon and Ribavirin, infection with HCV genotype 4, and the presence of cirrhosis (in less than 50% of the included patients) that could diminish the chances of SVR to a standard bitherapy.
The likelihood of SVR with standard bitherapy in this study population is thus considered low, around 15%.
The principal objective of this multicentric, national, single-arm, open-labeled, non-randomized phase II pilot study in 60 patients, is to assess the rate of SVR 12 weeks after 24 weeks of quadritherapy and to determine whether this rate is significantly greater than 20%.
The proportion of patients presenting with cirrhosis (defined by a METAVIR F4 score on liver biopsy or with hepatic impulse elastometry ≥ 15 kPa) will be limited to 50% of all patients included.
Enrollment
Sex
Ages
Volunteers
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:
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:
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 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
Primary purpose
Allocation
Interventional model
Masking
60 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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