Interest of Ribavirin in the Maintenance Treatment of Liver Fibrosis Using Low Dose Pegylated Interferon alpha2b in Patients With Chronic Hepatitis C Non Responders to Previous Antiviral Therapy.

Study Overview
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Brief Summary
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Patients with chronic hepatitis C who did not respond to previous antiviral treatment develop liver fibrosis leading to cirrhosis. Maintenance low dose pegylated interferon therapy of fibrosis is currently under investigation in large multicenter trials. The aim of our study is to assess if peginterferon alpha2b plus ribavirin is more efficient than peginterferon alpha2b alone. 454 patients will be randomized between the 2 arms and the efficacy will be assessed, after 3 years of treatment, on Metavir liver fibrosis score improvement.

Detailed Description
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Up to 45% of patients with chronic hepatitis C do not respond to pegylated interferon/ribavirin combination therapy. These patients are prone to develop liver fibrosis leading to cirrhosis and its complications. Interferon has proven to be efficient in liver fibrosis treatment even in case of virological non response. Maintenance low dose pegylated interferon therapy is currently under investigation in large multicenter trials. The aim of our study is to assess wether peginterferon alpha 2 b (0.5 µg/kg/week) plus ribavirin (800-1200 mg according to body weight) is more efficient than peginterferon alpha 2 b alone in a long term 3 years treatment of liver fibrosis. 454 patients, non responders (VHC RNA positive after 24 weeks of treatment or absence of ≥ 2 log HCV RNA drop after 12 weeks of treatment) to a previous peginterferon/ribavirin antiviral treatment will be randomized between the 2 arms, with a double-blind masking of ribavirin. The efficacy will be assessed on Metavir liver fibrosis score improvement between pre and post therapeutic liver biopsy.

Official Title
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Randomized, Double-blind, Placebo-controlled Multicenter Study Evaluating the Interest of a Long-term (3 Years) Treatment With Peginterferon Alfa-2b and Ribavirin on Liver Fibrosis in Non-responder Chronic Hepatitis C Patients.

Conditions
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Hepatitis C, Chronic, Liver Fibrosis

Intervention / Treatment
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* Biological: Peginterferon alfa-2b
* Drug: Ribavirin
* Drug: Ribavirin-Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults over 18 With a hepatitis C virus infection (HCV RNA and anti-HCV antibodies in serum) Not responders to a previous antiviral treatment using the interferon plus ribavirin combination With a wash-out of treatment for at least 6 months With an active chronic hepatitis C and a Metavir fibrosis score ≥ 2 Serum ALT levels > upper limit of the laboratory on two occasions within 6 months before inclusion Accepting to undergo a liver biopsy at the end of the study Negative pregnancy test for women With a social security cover Written informed consent Exclusion Criteria: History of hepatic complications History of transplantation History of severe seizures History of severe psychiatric disorders Drug addiction within the last 12 months Associated condition susceptible to be responsible for liver fibrosis Hepatocellular carcinoma Cardiovascular disease unstable under treatment Uncontrolled diabetes Retinopathy Thyroid disease unstable under treatment Epilepsy and/or central nervous system functional disorders Autoimmune disease Regular alcohol consumption Pregnancy, breast-feeding or absence of contraception Haemoglobin <12 g/dl platelets <50000/mm3 Neutrophils < 1200/ mm3 Severe hepatocellular failure (prothrombin index lower than 60%) Renal failure (creatinine clearance lower than 50 mL/Mn) Associated immunosuppressive drugs, corticosteroids, antiviral drugs (other than study ones) Treatment with drugs likely to have an effect on fibrosis Anticonvulsants Inability to tolerate interferon

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomised PegIFN alfa 2b + ribavirin (RBV) arm<br>Combination of ribavirin capsules 200 mg, weight-based daily dose ( <75 kg : 1000 mg ; ≥ 75 kg : 1200 mg), and low-dose PegIFN alfa 2b by subcutaneous injection 0.5 μg / kg / week, from day 0 to M36 | Biological: Peginterferon alfa-2b<br>* PegIFN alfa 2b in addition to ribavirin or ribavirin-placebo, from day 0 to M36<br>Drug: Ribavirin<br>* Ribavirin in addition to PegIFN alfa 2b, from day 0 to M36<br>|
| Placebo Comparator: Randomised PegIFN alfa 2b + ribavirin-placebo arm<br>Combination of ribavirin-placebo capsules 200 mg, weight-based daily dose ( <75 kg : 1000 mg ; ≥ 75 kg : 1200 mg), and low-dose PegIFN alfa 2b by subcutaneous injection 0.5 μg / kg / week, from day 0 to M36 | Biological: Peginterferon alfa-2b<br>* PegIFN alfa 2b in addition to ribavirin or ribavirin-placebo, from day 0 to M36<br>Drug: Ribavirin-Placebo<br>* Ribavirin-placebo in addition to PegIFN alfa 2b, from day 0 to M36<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with at least a one point improvement in Metavir fibrosis score between the inclusion and the end-of-study liver biopsies. |  | Screen visit and M36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of the Metavir scoring on the end-of-study biopsy |  | M36 | 
| Distribution of the Chevallier fibrosis score |  | Screen visit and M36 | 
| Evolution of the area of fibrosis between the inclusion and the end-of -study biopsies |  | Screen visit and M36 | 
| Fibrosis serum markers |  | Screen, day0, M6, M12, M24, M36 | 
| Liver elasticity before and after treatment |  | Screen,M12, M24, M36 | 
| Safety of treatment and quality of life |  | day0, M6, M12, M24, M36 | 
| Frequency of occurrence of hepatic complications and/or liver transplantations |  | Day 0 to M36 | 
| Evolution of the hepatitis C viral load |  | Screen to M36 | 
| Rate of patients with loss of detectable hepatitis C virus RNA |  | Day 0 to M36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maintenance therapy, Non-responder patients, Ribavirin/peginterferon combination therapy, Hepatitis C, Chronic