TMC435350-TiDP16-C201 - OPERA 1: A Study of the Hepatitis C Virus (HCV) Protease Inhibitor TMC435350 or Placebo Administered With or Without the Standard of Care in Treatment Naive and Treatment Experienced Patients Infected With Genotype 1 Hepatitis C Virus.

• Determine the dose dependency of the antiviral effect of TMC435350 during 1 week of monotherapy and during tritherapy with SoC treatment in treatment-naïve HCV-infected patients.
  

• Determine safety and PK profile of TMC435350 during monotherapy and tritherapy with PegIFNa-2a and RBV; Determine incidence and genetics of viral breakthrough and incidence of early and sustained virologic responses; Study interaction of TMC435350 on RBV
  

This is a blinded, randomized, placebo-controlled Phase IIa trial to assess the effectiveness, safety, tolerability, and pharmacokinetics of 4 different dose regimens of TMC435350 (25 mg daily, 75 mg daily, 200 mg daily, and 400 mg daily), given alone or in combination with PegIFNa-2a (weekly 180 µg s.c.) and RBV (bodyweight-based total daily dose of 800/1000/1200 mg, taken as a twice daily regimen). 96 treatment-naïve and 24 treatment-experienced (prior non-responders or relapsers to IFN-based therapy, who did not discontinue anti-HCV therapy for adverse events [AEs]) patients with chronic genotype 1 HCV infection will be included in this trial. In addition, HCV- infected patients having participated in trial TMC435350-TiDP16-C101 will be included in an open-label panel at a dose previously determined safe and efficacious. The trial will consist of a screening period of maximum 6 weeks, a treatment period with TMC435350 or placebo of 4 weeks, a subsequent treatment period of maximum 44 weeks with SoC treatment as provided by the Sponsor (i.e. Pegasys® and Copegus®) and a post-SoC follow-up period of 24 weeks. Panel A : patients will receive either 25, 75, 200 or 400 mg of TMC435350 (n=9) or placebo (n=3) in monotherapy for 7 days, followed by a 21-day combined tritherapy period in which TMC435350 or placebo is coadministered with PegIFNa 2a (Pegasys®) and RBV (Copegus®). Patients in Panel B will receive the same doses of TMC435350 or placebo during 4 weeks of combined tritherapy with PegIFNa 2a an RBV. Stopping rules for dose limiting toxicity have been defined and Data Review Meetings will be organized before each dose escalation. In Panel C, 24 treatment-experienced patients (non-responders/relapsers) will be randomized over 2 TMC435350 dose groups (200 mg or 400 mg, or the final selected dose based on safety, tolerability, and PK data; n = 9 patients each) or placebo (n = 6 patients). These patients will receive 28 day combined tritherapy. Randomization in this cohort will be stratified for relapsers and non-responders. In Panel D, 10 previous non-responder/relapser patients to interferon therapy, having participated in the TMC435350-TiDP16-C101 trial, will be included. These patients will all receive 28 day combined tritherapy including active TMC435350 treatment at a dose of 400 mg (or the final selected dose based on safety, tolerability and PK), in combination with RBV and PegIFNa-2a after safe completion of the 400 mg dose in Panel B. After each 28-day treatment period, patients will be offered free of charge standard of care (SoC) treatment containing PegIFNa-2a (Pegasys®) and RBV (Copegus®) until Week 48 (or Week 24) depending on the virological response during the initial 20 weeks of treatment. The treating Investigator and the patient will be responsible for the final decision. Patients are not allowed to stop SoC treatment at intermediate time points except for reasons of intolerability or adverse events. After EOT (or early discontinuation), a treatment-free follow-up period will be organized with follow-up visits planned during 6 months after the last dose (until Week 72), in order to confirm sustainability of the virological response.

TMC435350 (25 mg daily or 75 mg daily or 200 mg daily or 400 mg daily) or placebo monotherapy for 7 days, followed by 21-day tritherapy period in which TMC435350 or placebo will be coadministered with bodyweight-based RBV (twice daily regimen) for 21 days + PegIFNa-2a 180 µg s.c. on Days 8, 15, and 22 OR TMC435350 (25 mg daily or 75 mg daily or 200 mg daily or 400 mg daily) or placebo with bodyweight-based RBV (twice daily regimen) for 28 days + PegIFNa-2a 180 µg s.c. on Days 1, 8, 15, and 22.