Randomized Controlled Open Label Trial of Peg Alpha 2a Interferon and Adjusted-dose of Ribavirin vs. Standard Therapy in the Treatment of Naive Chronic Hepatitis C Patients Infected With Genotype 4
Condition: Chronic Hepatitis C Virus
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic
Study type: Interventional
Phase: Phase 4

Summary: 
      The study aims to study the outcome of pharmacokinetics-adjusted dose ribavirin (plus pegIFN)
      on the SVR in chronic HCV patients.
    

Detailed description: 
      Background: The introduction of Peg interferon and Ribavirin (an oral nucleoside analogue)
      for chronic Hepatitis C has led to the concept that chronic hepatitis C (HCV) is a curable
      disease. Improvement of treatment efficacy is still a major challenge. Optimal Ribavirin
      doses are essential to achieve SVR (sustained virological response). A recent trial showed
      significantly higher sustained virological response (SVR) in patients receiving 15.2
      mg/kg/day of Ribavirin compared with 13.3 mg/kg/day. Ribavirin was given in combination with
      Peg interferon alpha-2b (1). A small pilot study, in which 10 patients with Chronic Hepatitis
      C genotype 1 were treated with Ribavirin dosage up to 3600 mg/day- mean of 2540 mg/day- plus
      Peg-interferon alpha-2a, achieving a target concentration of Ribavirin >15 micromol before W
      12, led to 90% of SVR(2). All patients managed to complete the one year treatment period but
      all needed EPO and two were transfused.

      Patient's global exposure to Ribavirin as evaluated by the area under the curve (AUC) seems
      more pertinent in terms of exposure-effect relationship than measuring Ribavirin level at any
      single time point. A recent study showed in HCV patients infected with genotype 1 that
      Ribavirin plasma exposure after the first dose (i.e., interdose AUC0-12h or abbreviated
      AUC0-4h) was significantly and strongly linked with SVR, whereas AUCs determined at W12 and
      W24 and trough concentrations at Day 0 and W12 were not (3).

      Therefore, we propose a randomized controlled trial to investigate whether adjusted Ribavirin
      doses based on AUC0-4h obtained at D-7 after 600mg dose of Ribavirin versus fixed standard
      doses can improve outcome in treatment of chronic hepatitis C naïve patients infected with
      genotype 4.

      Methodology: After AUC0-4h has been determined at D-7 (7 days before randomization) for 190
      genotype 4 patients recruited into the trial, the patients are randomized into two groups:
      Group A: to receive standard dose of Ribavirin 1000-1200 mg/day) and Group B: to receive
      adjusted-dose of Ribavirin according to AUC0-4h. The individual calculated dose should be
      administered for each patient beginning on the first day of treatment. Both groups will
      receive combination treatment with peginterferon alpha 2a 180 mcg/week for a total of 48
      weeks.

      Both treatment groups will receive Darbepoetin if subsequent Hb is < 11 g/dl for males and
      females. Our main inclusion criteria will be: patients 18-70 years old with serological
      evidence of chronic hepatitis C and positive HCV RNA of genotype 4, with a liver biopsy
      within 3 years prior to recruitment. Our main exclusion criteria will be: decompensated
      cirrhotic patients, HBV/HIV co-infection, evidence of hepatocellular carcinoma (HCC),
      significant evolutive cardiovascular, pulmonary, renal or psychiatric disease,
      pregnancy/breast feeding or patients post liver transplantation and anemia.

      Our primary outcome will be: HCV-RNA negativity 24 weeks after the end of treatment (SVR)
      (input adjusted dose on SVR). Our secondary outcome will be: rapid virological response
      (RVR), early virological response (EVR), partial early virological response (pEVR), end of
      treatment response (ETR), relapse after (ETR), biochemical response and safety and
      tolerability of high doses of Ribavirin.
    

Intervention name(s): Pegylated interferon alpha-2a
Intervention type(s): Drug
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment