High-dose Ribavirin in Treatment of Chronic Hepatitis C Genotype 1 or 4

Study Overview
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Brief Summary
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Optimal ribavirin dosages are essential in achieving SVR (sustained virological response). Several studies have shown higher SVR rates in patients receiving higher doses of ribavirin. Therefore we propose a randomized controlled open label multicenter trial to investigate wether high (25-29mg/kg) dose ribavirin can improve outcome in patients in infected with hepatitis C virus genotype 1 or 4 compared to standard dose (12-15mg/kg).

Detailed Description
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Optimal ribavirin dosages are essential in achieving SVR. The initial evidence supporting higher doses of ribavirin for peginterferon alfa-2b comes from a secondary analysis of the pivotal multicenter trial of peginterferon alfa-2b and ribavirin. Patients receiving more than 10.6 mg/kg/day ribavirin experienced significantly higher SVR rates (48% vs. 38%). A large multicenter trial designed to test standard dose ribavirin (1000-1200 mg/day) versus low-dose ribavirin (800 mg/day) in combination with peginterferon alfa-2a, showed 52% SVR in the standard dose group versus 41% in the low-dose group for genotype 1 infected patients. In the pooled data from two pivotal studies with peginterferon alfa-2a and ribavirin, the probability of achieving an SVR for genotype 1 patients was influenced by the ribavirin dose per kg body weight. A 40-50% increase in the probability of SVR was found for a 12-16 mg/kg dose increase of ribavirin. For peginterferon alfa-2b it was also shown among genotype 1 patients, that weight-based ribavirin (800-1400 mg/day) leads to higher SVR rates compared to fixed dose ribavirin (800 mg/day) (34% vs. 29%). Moreover, ribavirin dosing up to 1400 mg/day was safe and the rate of treatment discontinuation was the same for both treatment groups. In a small pilot study, 10 genotype 1 patients with a high baseline load were treated with peginterferon alfa-2a and individualized high-dose ribavirin in order to achieve a ribavirin target concentration in serum of 15 μmol/l. The mean ribavirin dose of 2540 mg/day (range 1600-3600 mg/day) was high, but resulted in 90% SVR. All patients experienced severe anemia, which was treated with concomitant epoetin beta and blood transfusion. As mentioned before, the main concern of high-dose ribavirin will be a dose-dependent hemolytic anemia and the addition of epoetin alfa has shown significant increase of haemoglobin during (peg)interferon/ribavirin therapy. Erythropoietin doses from 9,000 to 60,000 IU/week have been used in order keep the highest possible ribavirin doses. A recent trial showed a significant higher SVR rate in genotype 1 patients treated with peginterferon alfa-2b, increased dose ribavirin (15.2 mg/kg/day) and epoetin alfa than in patients treated with peginterferon alfa-2b and standard dose ribavirin (13.3 mg/kg/day) with or without epoetin alfa. Using the standard ribavirin dose, routine use of erythropoietin significantly decreased the frequency of anemia and the mean ribavirin dose reduction. Moreover, with the addition of erythropoietin, a significant higher mean dose could be given to patients in the increased ribavirin dose arm.

Official Title
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High-dose Versus Standard-dose Weight-based Ribavirin in Combination With Peginterferon Alfa-2a for Patients Infected With Hepatitis C Virus Genotype 1 or 4

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: ribavirin
* Drug: ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: hepatitis C genotype 1 or 4 high viral load (>400000 IU/ml) indication for antiviral treatment or patient's desire for antiviral treatment hepatitis C treatment naive liver biopsy within 3 years of screening visit or when biopsy is contraindicated e.g in patients with clotting diseases or when a patient refuses to undergo a new biopsy in case the liver biopsy is older than 3 years, substitution by fibroscan is allowed. age 18-70 years Exclusion Criteria: serum bilirubin >35 μmol/l albumin <36 g/l prothrombin time >4 sec prolonged platelets <90x109/l decompensated cirrhosis (Child-Pugh Grade B or C) hepatic imaging (ultrasound, CT or MRI) with the evidence of hepatocellular carcinoma (hepatic imaging should be performed within 3 months prior to screening for cirrhotic patients and within 6 months prior to screening for non-cirrhotic patients) alcoholic liver disease (indicator: MCV>100) obesity induced liver disease (indicators: steatosis proven by biopsy or ultrasound in association with a body mass index >30) drug related liver disease (indicator: positive history of hepatic toxic drug intake with a causal relation) auto-immune hepatitis (indicators: IgG >30g/l, anti smooth-muscle or antinuclear antibodies titer ³1:40) hemochromatosis (indicator: ferritin >1000 μg/l) Wilson's disease (indicator: ceruloplasmin (<0.2 g/l) alpha-1 antitrypsin deficiency (indicator alpha-1 antitrypsin <0.8 g/L) co-infection with hepatitis B virus or human immunodeficiency virus (HIV) any cardiovascular dysfunction (e.g. cardiac decompensation, myocardial infarction, present or history of arrythmia) other medical illness that might interfere with this study: significant pulmonary or renal dysfunction, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g.: steroid therapy, organ transplants other than cornea and hair transplant) contra-indications for peginterferon and/or ribavirin: severe psychiatric disorder, such as major psychoses, suicidal ideation, suicidal attempt and/or manifest depression. Severe depression would include the following: (a) subjects who have been hospitalized for depression, (b) subjects who have received electroconvulsive therapy for depression, or (c) subjects whose depression has resulted in a prolonged absence of work and/or significant disruption of daily functions. Subjects with a history of mild depression may be considered for entry into the protocol provided that a pretreatment assessment of the subject's mental status supports that the subject is clinically stable and that there is ongoing evaluation of the patient's mental status during the study visual symptoms related to retinal abnormalities pregnancy, breast-feeding or inadequate contraception thalassemia, spherocytosis females who are pregnant or intending to become pregnant or male partners of females who are pregnant or intending to become pregnant absolute neutrophil count (ANC) <1.40x109/l hemoglobin (Hb) <7.5 mmol/l (female) or <8.1 mmol/l (male) serum creatinine concentration >1.5 times the upper limit of normal at screening substance abuse, such as I.V. drugs or alcohol (indicator: >28 drinks/week). If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 1 year any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Active Comparator: Standard dose<br>Standard-dose ribavirin (12-15 mg/kg/day) in combination with peginterferon 180µg QW | Drug: ribavirin<br>* 12-15 mg/kg/day<br>* Other names: NeoRecormon;|
| Experimental: High dose<br>High-dose ribavirin (25-29 mg/kg/day) in combination with peginterferon 180µg QW | Drug: ribavirin<br>* 25-29 mg/kg/day<br>* Other names: NeoRecormon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR) |  | 72 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCV-RNA negativity at week 4 (rapid virological response, RVR) |  | 4 weeks | 
| HCV-RNA negativity at week 12 (complete early virological response, cEVR) |  | 12 weeks | 
| HCV-RNA ≥ 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR) |  | 12 weeks | 
| HCV- RNA negativity at week 48 (end of treatment response, ETR) |  | 48 weeks | 
| Relapse rate after ETR |  | 48 weeks - end of follow up | 
| Safety and tolerability of high-dose daily ribavirin (serious adverse events, grade 4 NCI toxicity, percentage of patients completing treatment on full or >80% of total intended dose and reasons for dose adjustments) |  | week 0 till end of follow up | 
| Biochemical response (normalization of serum ALT at the end of therapy and at the end of follow-up) |  | week 0 - end of follow up | 
| Health related quality of life and psychopathology before, during and after treatment by SF-36 and SCL-90 questionnaires |  | week 0 - week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic, hepatitis C, ribavirin, SVR, genotype one, genotype four