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).
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Asunaprevir 100 mg, 1 capsule twice a day from Day 0 to Week 24
Daclatasvir 60 mg, 1 tablet once a day from Day 0 to Week 24
Ribavirin tablets or capsules 200 mg, weight-based daily dose ( \<75 kg : 1000 mg ; ≥ 75 kg : 1200 mg), from Day 0 to Week 24
Pegylated Interferon alpha-2a, by subcutaneous injection 180µg / week, from Day 0 to Week 24
Hôpital AVICENNE
Bobigny, France
Hôpital Jean Verdier
Bondy, France
Hôpital de Haut Lévêque
Bordeaux Pessac, France
Hôpital Beaujon
Clichy, France
Centre Hospitalier Intercommunal
Créteil, France
Hôpital Henri Mondor
Créteil, France
Hôpital Albert Michallon
Grenoble, France
Hôpital Claude Huriez
Lille, France
Hôpital Dupuytren
Limoges, France
Hôpital de la Croix Rousse
Lyon, France
...and 15 more locations
SVR12 Rate
HCV RNA measured 12 weeks after the end of the HCV treatment (Week 36)
Time frame: Week 36
Number of patients with adverse events
Time frame: Up to Week 48
Treatment discontinuations
Number and causes of treatment discontinuations
Time frame: Up to Week 24
Self-reported symptoms
ANRS AC24 perceived symptoms scale
Time frame: Day 0, Week 12, Week 36
Patients' adherence
ANRS questionnaire
Time frame: Week 4, Week 12, Week 24
SVR 24 rate
Undetectable HCV RNA 24 weeks after the end of the HCV treatment
Time frame: Week 48
HCV viral load
Time frame: Day 0, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 36, 48
Number of patients with virological failure under treatment
Patients with detectable HCV viral load at Week 8, or Patients with HCV breakthrough : a) undetectable HCV viral load at Week 8 and detectable at any visit after Week 8 or b) undetectable HCV viral load at any time point before Week 8 and who presents a new confirmed detectable viral load before Week 8
Time frame: Up to Week 24
HCV subtypic distribution
Time frame: Baseline
Proportion of patients with resistance mutations to Asunaprevir and/or Daclatasvir in case of virological failure
Time frame: Up to Week 48
Cirrhosis evaluation
For cirrhotic patients : Child-Pugh and MELD scores ; cirrhosis decompensation evaluation on clinical examination
Time frame: Baseline, Week 12, Week 24, Week 36, Week 48
Insulin resistance : HOMA-IR score
Time frame: Day 0, Week 36
Metabolic syndrome parameters
Waist circumference, blood pressure, fasting glucose, triglycerides, HDL cholesterol (composite measure)
Time frame: Day 0, Week 36
Liver fibrosis
Evolution of liver fibrosis on biological parameters (Fibrotest®) and imaging (Fibroscan®)
Time frame: Between baseline and Week 48
Polymorphism of the gene of IL28B
Time frame: Day 0
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