High Dose Ribavirin in the Treatment of Chronic Hepatitis C

Study Overview
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Brief Summary
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Treatment of patients with chronic hepatitis C infected with genotype 1 hepatitis C virus (HCV) consists of combined peginterferon/ribavirin for 48 weeks. Approximately 50% of patients experience sustained virological response which equals cure. All other patients either do not respond or experience recurrence of HCV virus and chronic hepatitis. Important predictors of successful treatment are sustained dosing of both peginterferon and ribavirin. With regard to the latter, clinical evidence indicates that higher ribavirin doses may in fact even improve treatment outcome. However, high ribavirin doses cause hemolytic anemia which require dose reductions. Recent clinical experience show that erythropoetic growth factors, including erythropoetin, can counteract hemolytic anemia caused by antiviral treatment in chronic hepatitis C patients. Therefore, the current trial aims to test whether higher ribavirin doses adapted to a target plasma concentrations instead of a weight-based dosing result in better healing rates, and whether ribavirin-associated hemolytic anemia can be compensated by concommitant erythropoetin treatment. Using a randomized, controlled, open-label design, the investigators hypothesize that patients with high ribavirin doses adapted to plasma levels experience better viral clearance than patients treated with standard weight-based ribavirin doses. In addition, the investigators hypothesize that erythropoetin treatment will counteract hemolytic anemia induced by ribavirin thereby allowing maintenance of target plasma concentrations without ribavirin dose reductions.

Detailed Description
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Background Prevalence and incidence of chronic hepatitis C (CHC) are rising worldwide. Complications include chronic liver failure and hepatocellular carcinoma, and chronic hepatitis C is a major indication for liver transplantation. Effective treatment is required to prevent these outcomes. Current treatment consists of a combination of peginterferon (PegIFN) and ribavirin (RBV) given for 24 or 48 weeks depending on the viral genotype. While genotypes 2 and 3 respond well to 24 weeks of PegIFN/RBV with approximately 80% viral clearance, genotype 1 infected patients only achieve about 40-50% sustained viral response (SVR) with 48 weeks of combination therapy. RBV is a nucleoside analog with structural similarities to guanosine, which modulates RNA and DNA synthesis. RBV reveals antiviral activity against respiratory syncytial (RS)-virus, influenza virus, Lassa virus uand others. The exact mode of antiviral activity is yet unknown but believed to relate to reducing survival of HCV-infected hepatocytes thereby allowing for elimination of infected cells by interferon-stimulated immune mechanisms. Generally, RBV is well tolerated. With standard daily doses between 1.000 and 1.200mg, irritability, sleeping abnormalities, cough and pruritus. The most prevalent and typical side effect of RBV is a dose-dependent hemolytical anemia which responds well to dose reduction or interruption of RBV therapy. RBV-associated anemia impairs quality of life and, overall, 25-36% of patients require dose reductions and/or RBV cessation. However, reduction/cessation of RBV is associated with a significant drop of SVR and measures to maintain RBV doses are clearly warranted. Several recent studies have shown that erythropoetin can counteract RBV-induced hemolytic anemia, and improve quality of life. The relevance of RBV dose with regard to therapeutic response to combination therapy is well-established and currently, RBV is dosed according to weight: patients with CHC genotype 1 are treated with 1.000mg if body weight is <65kg, and receive 1.200mg if >65kg. Retrospective studies have shown that relapsers and non-responders to antiviral treatment with RBV had lower RBV levels than those who had a SVR. In a retrospective analysis of 4 studies investigating a total of 1105 patients treated with RBV, RBV plasma concentrations measured at 4 weeks of treatment correlated with viral clearance: SVR was 31.8% in those with RBV levels <1,000ng/ml, and increased to 62.5% with RBV concentrations at >4,000ng/ml. A pilot trial from Sweden investigated whether dosing RBV according to a plasma level of 15mcmol/l (3.7mcg/ml) in 10 patients. Median RBV dose was 2.540mg/day and all patients received erythropoetin.SVR was achieved in 9 of 10 patients. So far, a randomized, controlled trial comparing weight-based RBV (standard) vs. RBV dosed according to kidney function and plasma levels. Objective Comparison of efficacy and tolerability of treatment with PegIFN-alpha 2a + RBV dosed according plasma concentrations vs PegIFN-alpha 2a + weight-based RBV in patients with chronic hepatitis C genotype 1 Methods Prospective, controlled, open label randomized human trial

Official Title
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Prospective, Open-label, Randomised Controlled Trial on Efficacy and Tolerability of PegIFN-alpha 2a + Serum Level-adapted RBV vs. PegIFN-alpha 2a + Weight-based RBV in Treatment-naive Patients With Chronic Hepatitis C Genotype 1

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: High ribavirin dose
* Drug: Standard ribavirin dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 18-65 years Elevated liver enzymes levels Compensated liver disease Available liver histology confirming METAVIR F2 fibrosis Written consent to participation Exclusion Criteria Age <18, >65 Prior ribavirin treatment Intolerance towards ribavirin, PegIFN or erythropoetin Pregnancy or breast feeding Relevant cardiovascular or pulmonary disease Kidney insufficiency (creatinine clearance <50ml/min) Coinfection with HIV or hepatitis B virus Hepatic comorbidities (hemochromatosis, Wilson's disease, autoimmune disorders) Alcohol consumption > 40g/day Psychiatric disorders Malignancy (except for basalioma) Active consumption of illicit drugs Participation in another trial shorter than 3 months prior to inclusion Lack of consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>PegIFN-alpha 2a + RBV (commenced according to kidney function) adjusted to plasma levels. Treatment with erythropoetin 3x3,000IU/week up to 3x10,000IU/week in case of hemolytic anemia | Drug: High ribavirin dose<br>* Ribavirin dose started according to kidney function (usually 1,800mg) and adapted according to plasma level during follow-up<br>|
| Active Comparator: B<br>PegIFN-alpha 2a + RBV (weight based; 1,000 or 1,200 mg/day) | Drug: Standard ribavirin dose<br>* Ribavirin dose started at 1,000mg (body weight <65kg) or 1,200mg (body weight equal or >65kg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virological response |  | 1 Day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | day 1 until 24 weeks after end or treatment | 
| Rapid virological response at 4 weeks of treatment |  | 4 weeks | 
| Early virological response at 12 weeks of treatment |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic hepatitis C, Antiviral treatment, Ribavirin, Sustained virological response, Hemolytic anemia, Erythropoetin