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.

The purpose of this study is to evaluate the affectiveness, safety, tolerability and pharmacokinetics of repeated doses of TMC435350, with or without peginterferon alpha-2a and ribavirin. TMC435350 is a NS3/NS4A viral protease inhibitor used for the treatment of hepatitis C virus (HCV) infection. 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 peginterferon alpha-2a (PegIFNa-2a) and ribavirin (RBV). 96 treatment-naÃ-ve and 24 treatment-experienced patients with chronic genotype 1 HCV infection will be included in this trial. Three blinded placebo-controlled cohorts of treatment-naÃ-ve patients will be sequentially initiated to ensure that higher doses are only administered if previous doses are found safe and tolerable. Similarly, the blinded placebo-controlled cohort in treatment experienced patients will be initiated after an evaluation of the different dose levels in treatment-naÃ-ve patients has been made. In addition, 10 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. After a 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, optionally, until Week 24 for patients with an undetectable HCV viral load at Week 4, who remain undetectable until Week 20). An additional treatment-free follow-up period will be installed until 24 weeks after end of SoC to allow evaluation of sustained virologic response (SVR).

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.

• Lenz O, de Bruijne J, Vijgen L, Verbinnen T, Weegink C, Van Marck H, Vandenbroucke I, Peeters M, Simmen K, Fanning G, Verloes R, Picchio G, Reesink H. Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy. Gastroenterology. 2012 Nov;143(5):1176-8.e1-6. doi: 10.1053/j.gastro.2012.07.117. Epub 2012 Aug 8.
• Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, Marcellin P, Moreno C, Lenz O, Meyvisch P, Peeters M, Sekar V, Simmen K, Verloes R. Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther. 2011;16(7):1021-33.

Inclusion Criteria:

• Documented chronic genotype 1 Hepatitis C infection
• Able to comply with the protocol requirements and having good accessible veins
• Amount of virus in the blood (HCV RNA) >= 10.000 IU/mL, at screening
• Bodyweight as defined by a Quetelet Index (Body Mass Index [BMI]) between 18 and 32 kg/m², extremes included.

Exclusion Criteria:

• Evidence of liver cirrhosis or decompensated liver disease or any other form of non-viral hepatitis
• Patients receiving or having received polymerase inhibitor or protease inhibitor treatment for HCV during the 6 months before screening
• Male patients with female partners of childbearing potential not agreeing to use a reliable birth control method, Female, except if postmenopausal for over 2 years, or posthysterectomy, or post-tubal ligation (without reversal operation)
• History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, which would compromise the patient's safety and/or compliance. A positive urine drug test at screening. Urine will be tested to check the current use of amphetamines, cocaine, and opioids (with the exclusion of methadone)
• Patients having at least one lab toxicity that is found to be clinically significant
• Patients co-infected with HIV, Hepatitis A or B at screening, patients with a pathologically prolonged QTc value or any active clinically significant disease (e.g., tuberculosis, cardiac dysfunction), or medical history or physical examination findings during screening that, in the Investigator's opinion, would compromise the outcome of the trial
• Patients having uncontrolled/unstable diabetes, epilepsy, a manifest psychiatric disease, non-stable methadone use or patients having any other unstable disease, patients enrolled in another clinical trial within 90 days prior to screening