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

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 170

Inclusion Criteria

• Hepatitis C genotype 1 or 4
• High viral load (>400,000 IU/ml)
• Indication for antiviral treatment or patient*s desire for antiviral treatment
• Hepatitis C treatment naïve
• Liver biopsy within 3 years of the date of the screening visit or when liver
biopsy is contraindicated e.g. in patients with clotting diseases e.g hemophilia and von Willebrand disease or when a patient refuses to undergo a new liver biopsy in case the liver biopsy is older than 3 years, substitution by fibroscan is allowed.
• Age 18-70 years

Exclusion Criteria

• Signs of progressive liver disease, beyond generally accepted criteria for HCV antiviral therapy:
* serum bilirubin >35 µmol/l, or albumin <36 g/l or prothrombin time >4 sec prolonged or platelets <90x109/l (if normal values are different at the local laboratory, upper and lower limits of the local laboratory should be used)
* 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)
• Thrombocytosis, defined as platelet count >500.000/mm³
• History or evidence of risk of thrombosis
• Poorly controlled hypertension
• Other acquired or inherited causes of liver disease that could explain liver disease activity (if an indicator is present at screening, additional examinations should be done to confirm or rule out the diagnoses)
* 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 >/=1:40)
* 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. decompensatio cordis, myocard infarction, present or history of arrythmia);• Other significant 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);• Creatinine clearance below 50 ml/min (Cockroft/Gault) 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 incl

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>· To study whether 48 weeks of daily high-dose ribavirin in combination with<br /><br>peginterferon alfa-2a will lead to a higher SVR rate (HCV-RNA negativity 24<br /><br>weeks after end of treatment response, ETR) compared with standard-dose<br /><br>weight-based ribavirin</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>· HCV-RNA negativity at week 4 (rapid virologic response, RVR)<br /><br>· HCV-RNA negativity at week 12 (complete early virologic response, cEVR)<br /><br>· HCV-RNA >= 2log10 drop at week 12, but HCV-RNA still detectable (partial early<br /><br>virologic response, pEVR)<br /><br>· HCV-RNA negativity at week 48 (end of treatment response, ETR)<br /><br>· Relapse rate after end of treatment response<br /><br>· Safety (serious adverse events, grade 4 NCI toxicity)<br /><br>· Tolerability of peginterferon alfa-2a and high-dose ribavirin (percentage of<br /><br>patients completing treatment on full or >80% of total intended dose and<br /><br>reasons for dose adjustments)<br /><br>· Normalization of serum ALT at the end of therapy and and at the end of<br /><br>follow-up<br /><br>· Health related quality of life assessment using SF-36 questionnaires</p><br>