A Phase III Study of TMC435 in Treatment-naive, Genotype 1, Hepatitis C-infected Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of TMC435 compared with placebo in combination with peginterferon alfa-2a (pegIFN alfa-2a) and ribavirin in treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection in Japan.

Detailed Description
-----------------
This is a randomized (study drug assigned by chance), 2-arm, double-blind study to evaluate the efficacy and safety of TMC435 (also referred to as jnj-38733214-aaa) versus placebo in combination with the standard of care (SoC) therapy (peginterferon alfa-2a [pegIFN alfa-2a] and ribavirin) in adult treatment-naïve patients (who never received treatment for HCV) with chronic genotype 1 HCV infection in Japan. The study objective is to evaluate and compare the efficacy of TMC435 vs placebo by the proportion of the patients with undetectable HCV ribonucleic acid (RNA). In the TMC435 treatment group, patients will receive 12 weeks of treatment with TMC435 (100 mg) once daily plus SoC followed by an additional 12 or 36 weeks of treatment with SoC. In the placebo treatment group, patients will receive 12 weeks of treatment with placebo once daily plus SoC followed by an additional 36 weeks of treatment with SoC. TMC435 is a 100-mg capsule and will be taken orally by mouth. The SoC treatment will be given for 24 or 48 weeks. Pegylated interferon is supplied as a vial containing 1.0 mL solution with 180 mcg pegIFN alpha-2a and administered subcutaneously (injected by a syringe under the skin) once weekly. Ribavirin is given as 200-mg tablets (daily dose: 600-1000 mg based on body weight), and taken orally by mouth two times a day after meals.

Official Title
-----------------
A Phase III, Randomized, Double-blind, Placebo-controlled Trial in Japan to Investigate the Efficacy and Safety of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment-Naive, Genotype 1, Hepatitis C-infected Subjects

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient must have chronic genotype 1 HCV infection with HCV RNA level >= 5.0 log10 IU/mL Patient has never received treatment for HCV Patient must be willing to use contraceptive measures from the time of informed consent to 6 months after last dose of study medication Exclusion Criteria: Co-infection with any other HCV genotype or co-infection with the human immunodeficiency virus (HIV) Diagnosed with hepatic cirrhosis or hepatic failure A medical condition which is a contraindication to pegIFN or ribavirin therapy History of, or any current medical condition which could impact the safety of the patient in the study

Ages Eligible for Study
-----------------
Minimum Age: 20 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC435 100 mg 12 Wks + PR 24/48<br>Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 for participants who achieved HCV RNA < 1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48. | Drug: TMC435<br>* 100-mg capsule taken by mouth once daily for 12 weeks<br>Drug: Peginterferon alfa-2a (pegIFN alfa-2a)<br>* PegIFN alfa-2a (PEGASYS) will be administered according to the manufacturer's prescribing information as 180 mcg once weekly injected subcutaneous (under the skin) for up to 24-48 weeks for patients randomized to TMC435 and for up to 48 weeks for patients randomized to placebo.<br>* Other names: PEGASYS;Drug: Ribavirin (RBV)<br>* RBV (COPEGUS) will be administered according to the manufacturer's prescribing information. If body weight is > 80 kg the total daily dose of RBV will be 1000 mg, taken by mouth as 400 mg (2 tablets of 200 mg) after breakfast and 600 mg (3 tablets of 200 mg) after supper. If body weight is > 60 kg to <=80 kg the total daily dose will be 800 mg, taken by mouth as 400 mg (2 tablets of 200 mg per intake) after breakfast and supper. If body weight is <=60 kg the total daily dose of RBV will be 600 mg, taken by mouth as 200 mg (1 tablet of 200 mg) after breakfast and 400 mg (2 tablets of 200 mg) after supper. Total duration of RBV will be 24-48 weeks.<br>* Other names: COPEGUS;|
| Experimental: PBO 12 Wks + PR 48<br>Participants received placebo (PBO) once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 48. | Drug: Placebo<br>* Placebo capsule taken by mouth once daily for 12 weeks<br>Drug: Peginterferon alfa-2a (pegIFN alfa-2a)<br>* PegIFN alfa-2a (PEGASYS) will be administered according to the manufacturer's prescribing information as 180 mcg once weekly injected subcutaneous (under the skin) for up to 24-48 weeks for patients randomized to TMC435 and for up to 48 weeks for patients randomized to placebo.<br>* Other names: PEGASYS;Drug: Ribavirin (RBV)<br>* RBV (COPEGUS) will be administered according to the manufacturer's prescribing information. If body weight is > 80 kg the total daily dose of RBV will be 1000 mg, taken by mouth as 400 mg (2 tablets of 200 mg) after breakfast and 600 mg (3 tablets of 200 mg) after supper. If body weight is > 60 kg to <=80 kg the total daily dose will be 800 mg, taken by mouth as 400 mg (2 tablets of 200 mg per intake) after breakfast and supper. If body weight is <=60 kg the total daily dose of RBV will be 600 mg, taken by mouth as 200 mg (1 tablet of 200 mg) after breakfast and 400 mg (2 tablets of 200 mg) after supper. Total duration of RBV will be 24-48 weeks.<br>* Other names: COPEGUS;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With a Sustained Virologic Response at the End of Treatment (EOT) and 12 Weeks After the Last Dose of Treatment (SVR12) | The table below shows the observed percentage of participants with a SVR12 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) at EOT (Week 24 or 48) and at 12 weeks after the last dose of treatment (Week 36 or 60). | EOT (up to Week 24 or 48) and 12 weeks after the EOT (up to Week 36 or 60) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With a Sustained Virologic Response at the End of Treatment (EOT) and 24 Weeks After the Last Dose of Treatment (SVR24) | The table below shows the observed percentage of participants with a SVR24 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) at the end of treatment (EOT, defined as up to Week 24 or 48) and at 24 weeks after the last dose of treatment (up to Week 48 or 72). | EOT (up to Week 24 or 48) and 24 weeks after the after the last dose of treatment (up to Week 48 or 72) | 
| The Percentage of Participants Who Achieved a Greater Than or Equal to 2 log10 IU/mL Drop From Baseline in Plasma Hepatitis C Virus Ribonucleic Acid (HCV RNA) at Each Time Point During Treatment and Follow-up | The table below shows the percentage of participants with greater than (>) or equal to (=) 2 log10 IU/mL drop from baseline in plasma levels of HCV RNA at each time point during treatment and post-treatment follow-up (FU). | Day 3, Day 7 and Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 36, 42, 48, 52, 60, 72, EOT (up to Week 24 or 48), FU Week 4, 12, and 24 | 
| The Percentage of Participants With Undetectable Plasma Levels of Hepatitis C Virus Ribonucleic Acid (HCV RNA) During Treatment and at the End of Treatment (EOT) | The table below shows the percentage of participants with undetectable plasma levels of HCV RNA <1.2 log10 IU/mL during treatment at Weeks 4, 12, 24, 36, 48, 60, 72, and at the EOT (up to Week 24 or 48). | Weeks 4, 12, 24, 36, 48, 60, 72, and at EOT (up to Week 24 or 48) | 
| The Number of Participants With Viral Breakthrough | Viral breakthrough was defined as a confirmed increase of > 1 log10 IU/mL in plasma levels of hepatitis C virus (HCV) ribonucleic acid (RNA)l from the lowest level reached or a confirmed value of plasma HCV RNA of > 2.0 log10 IU/mL in participants whose plasma HCV RNA level had previously been below 1.2 log10 IU/mL detectable or undetectable during the treatment period (up to the end of treatment [EOT]). | Up to EOT (up to Week 24 or 48) | 
| The Number of Participants Demonstrating Viral Relapse | The table below shows the number of participants who demonstrated viral relapse, defined as undetectable plasma levels of hepatitis C virus (HCV) ribonucleic acid (RNA) at the End of Treatment (EOT) (up to Week 24 or 48) and detectable HCV RNA during follow-up or detectable plasma levels of HCV RNA at the time points of sustained virologic response (SVR) assessment. The incidence of viral relapse was only calculated for participants with undetectable plasma levels of HCV RNA at the EOT and with at least one follow-up HCV RNA. measurement. | Up to Week 72 | 
| The Number of Participants With Abnormal Alanine Aminotransferase (ALT) Levels at Baseline Who Achieved Normal ALT Levels at the End of Treatment (EOT) | The table below shows the number of participants with abnormal ALT levels at Baseline (Day 1) who achieved normal ALT levels at the EOT (up to Week 24 or 48). At Baseline, 61/123 participants in the TMC435 treatment group and 25/60 participants in the Placebo treatment group had abnormal ALT levels. At the EOT, 47 (77.0%) participants in the TMC435 treatment group and 18 (72.0%) participants in the Placebo treatment group had ALT levels that returned to normal (or normalization of ALT levels defined as an ALT value less than or equal to the Upper Limit of Normality [ie, 40 IU/mL] at EOT.). | Baseline (Day 1) to EOT (up to Week 24 or 48) | 
| The Percentage of Participants in the TMC435 Treatment Group Who Met Response Guided Treatment (RGT) Criteria and Completed Treatment With Peginterferon Alpha-2a (PegIFN Alpha-2a) and Ribavirin (RBV) at Week 24 | The table below shows the percentage of participants in the TMC435 treatment group who met RGT criteria (ie, who had plasma levels of hepatitis C virus ribonucleic acid [HCV RNA] <1.2 log10 IU/mL detectable/undetectable at Week 4 and <1.2 log 10 IU/mL undetectable at Week 12) and completed treatment with pegIFN alpha 2a and RBV at Week 24. Participants in the TMC435 treatment group not meeting RGT criteria and participants in the placebo group continued treatment with PegIFN alpha 2a and RBV to Week 48. | Week 24 | 
| Plasma Concentrations of TMC435 | The table below shows median (range) predose plasma concentration (C0h) values and median (range) maximum plasma concentration (Cmax) values for TMC435 for all participants in the TMC435 treatment group. The time frame of Overall (up to Week 12) represents the median exposure estimate using all available data for each participant in the study. | Overall (ie, Up to Week 12) | 
| Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24h) for TMC435 | The table below shows the median (range) AUC24h values for TMC435 for all participants in the TMC435 treatment group who received TMC435 for up to 12 weeks. The time frame of Overall (up to Week 12) represents the median exposure estimate using all available data for each participant in the study. | Overall (Up to Week 12) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ribavirin, Hepatitis C, Chronic, Hepatitis C, Hepatitis C virus, Interferon Alfa-2a, Viral RNA