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.

ANRS, Emerging Infectious Diseases

Status and phase: Completed; Phase 3; Phase 2

Conditions: Hepatitis C, Chronic; Liver Fibrosis

Treatments: Drug: Ribavirin; Drug: Ribavirin-Placebo; Biological: Peginterferon alfa-2b

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00323804

2005-002937-11 (EudraCT Number)

ANRS HC15 NRfi

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 372 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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372 participants in 2 patient groups, including a placebo group

Randomised PegIFN alfa 2b + ribavirin (RBV) arm

Experimental group

Description:

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

Treatment:

Biological: Peginterferon alfa-2b

Drug: Ribavirin

Randomised PegIFN alfa 2b + ribavirin-placebo arm

Placebo Comparator group

Description:

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

Treatment:

Biological: Peginterferon alfa-2b

Drug: Ribavirin-Placebo