An Efficacy, Pharmacokinetics, Safety and Tolerability Study of TMC435 as Part of a Treatment Regimen for Hepatitis C-Infected Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to provide confirmatory efficacy and safety data of TMC435 as part of a treatment regimen including peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) in patients with genotype 1 Hepatitis C virus (HCV) infection.

Detailed Description
-----------------
This is a multicenter, randomized (study drug is assigned by chance), double-blind (neither sponsor, physician nor patient knows the name of the assigned study drug), Phase III study to compare the efficacy, tolerability and safety of TMC435 (in development for treatment of chronic hepatitis C virus [HCV] infection) versus placebo (a preparation containing no drug used as control) as part of a treatment regimen including peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) (both current therapies for HCV) in adult treatment-naïve patients (patients who have never taken HCV medications) with genotype 1 Hepatitis C virus (HCV) infection. The study will consist of a screening period with a maximum duration of 6 weeks, a response guided 24- or 48-week (TMC435 treatment groups) or 48-week (control group) treatment period, and a post-therapy follow-up period up to 72 weeks after the start of treatment. Patients will be randomly assigned in a 1:1:1 fashion to receive TMC435 or placebo, stratified by HCV genotype 1 subtype and IL28B genotype within each country. In the first 24 weeks, patients will receive 12 weeks TMC435 100 or 150 mg or placebo once-daily (q.d.) plus PegIFNα-2a plus RBV, after which they will continue with PegIFNα-2a and RBV. Response-guided treatment criteria will be used to determine PegIFNα-2a and RBV total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. In the control group, all patients will be required to complete 48 weeks of treatment with PegIFNα-2a and RBV. In all 3 treatment groups, there will be a post-therapy follow-up period up to 72 weeks after the start of treatment. The total study duration for each patient will be a maximum of 78 weeks (including the 6-week screening period).

Official Title
-----------------
A Phase III, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve, Genotype 1 Hepatitis C-Infected Subjects

Conditions
-----------------
Hepatitis C, Chronic

Intervention / Treatment
-----------------
* Drug: TMC435
* Drug: Peginterferon-alpha (PegIFNα-2a)
* Drug: Ribavirin (RBV)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A liver biopsy within 3 years prior to the screening visit (or between screening and day of randomization) with histology consistent with chronic Hepatitis C virus (HCV) infection Presence of contraindications for a liver biopsy in patients who are otherwise deemed eligible for participation does not exclude the patient from participation Genotype 1 HCV infection (confirmed at screening) Plasma HCV RNA of > 10,000 IU/mL at screening Exclusion Criteria: Prior treatment with any approved or investigational drug for the treatment of hepatitis C Co-infection with hepatitis B virus or human immunodeficiency virus (HIV)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC435 150 mg<br>Patients will receive 12 weeks TMC435 150 mg once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV), followed by PegIFNα-2a and RBV alone. Response-guided treatment criteria will be used to determine total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. Patients in the control group will continue to receive treatment with PegIFNα-2a and RBV until Week 48. | Drug: TMC435<br>* TMC435 100 mg or 150 mg capsules taken orally (by mouth) with food once-daily for 12 weeks (Week 12).<br>Drug: Peginterferon-alpha (PegIFNα-2a)<br>* PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.<br>Drug: Ribavirin (RBV)<br>* Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.<br>|
| Experimental: TMC435 100 mg<br>Patients will receive 12 weeks TMC435 100 mg once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV), followed by PegIFNα-2a and RBV alone. Response-guided treatment criteria will be used to determine total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. Patients in the control group will continue PegIFNα-2a and RBV until Week 48. | Drug: TMC435<br>* TMC435 100 mg or 150 mg capsules taken orally (by mouth) with food once-daily for 12 weeks (Week 12).<br>Drug: Peginterferon-alpha (PegIFNα-2a)<br>* PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.<br>Drug: Ribavirin (RBV)<br>* Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.<br>|
| Placebo Comparator: Control<br>Patients will receive placebo once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) for 48 weeks. | Drug: Peginterferon-alpha (PegIFNα-2a)<br>* PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.<br>Drug: Ribavirin (RBV)<br>* Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.<br>Drug: Placebo<br>* Matching placebo capsules taken orally with food once-daily for 48 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12) | Participants considered to have achieved SVR12 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ; 25 international unit per milliliter [IU/mL]) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 12 weeks after the planned end of study drug treatment. | 12 weeks after the end of treatment (EOT: Week 24 or 48) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Study Drug Treatment (SVR24) | Participants considered to have achieved SVR24 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ;25 IU/mL) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 24 weeks after the planned end of study drug treatment. | 24 weeks after the end of treatment (EOT: Week 24 or 48) | 
| Percentage of Participants With Sustained Virologic Response at Week 72 (SVRW72) |  | Week 72 | 
| Percentage of Participants With On-treatment Failure | A participant with on-treatment failure refers to a participant with confirmed detectable HCV RNA at the end of treatment. | End of Treatment (EOT: Week 24 or 48) | 
| Percentage of Participants With Viral Breakthrough | The number of patients who experience viral breakthrough will be determined by measuring Hepatitis C virus (HCV) ribonucleic acid (RNA) levels in plasma. Viral breakthrough was defined as a confirmed increase of >1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of >100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (<25 IU/mL detectable) or undetectable (<25 IU/mL undetectable) while on study treatment. | Week 24 or 48 (End of Treatment) | 
| Percentage of Participants With Viral Relapse | Viral relapse was defined as undetectable HCV RNA at the actual end of treatment and last HCV RNA measurement during follow-up ≥25 IU/mL. | 72 weeks after the EOT (Week 24 or 48) | 
| Percentage of Participants With On-treatment Normalization of Alanine Aminotransferase Level | Percentage of participants with on-treatment normalization of alanine aminotransferase level were assessed. | 72 weeks after the EOT (Week 24 or 48) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis C, Chronic, TMC435, Ribavirin, peginterferon-alpha (PegIFNα-2a)