A Phase III Study of TMC435 in Genotype 1, Hepatitis C-infected Participants Who Failed to Respond to Previous IFN-based Therapy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of TMC435 in combination with peginterferon alfa-2a (PegIFNα-2a) and ribavirin in genotype 1 hepatitis C virus (HCV)-infected participants who failed to respond to previous interferon (IFN)-based therapy in Japan.

Detailed Description
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This is a randomized (study drug assigned by chance), 2-arm, open-label study to evaluate the efficacy and safety of TMC435 (also referred to as jnj-38733214-aaa) in combination with the standard of care (SoC) therapy consisting of peginterferon alfa-2a (PegIFNα-2a ) and ribavirin (RBV) administered according to the manufacturer's prescribing information in adult, genotype 1 hepatitis C virus (HCV)-infected participants who failed to respond to previous interferon (IFN)-based therapy in Japan. The study objective is to evaluate the efficacy of TMC435 by the proportion of participants with undetectable HCV ribonucleic acid (RNA). Participants will receive 12 weeks of treatment with TMC435 (100 mg) once daily plus PegIFNα-2a (P) and RBV P) followed by 12 or 36 weeks of treatment with PR OR participants will receive 24 weeks of treatment with TMC435 (100 mg) once daily plus PR followed by 24 weeks of treatment with PR. TMC435 is a 100-mg capsule and will be taken orally (via the mouth). Treatment with PR will last 24 or 48 weeks: Pegylated interferon is supplied as a vial containing 1.0 mL solution with 180 mcg PegIFNα-2a and will be 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. Participants will receive oral capsules of TMC435 (100 mg) once daily up to Week 12 or 24.

Official Title
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A Phase III, Randomized, Open-label, Two-arm Trial in Japan to Investigate the Efficacy and Safety of TMC435 as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Hepatitis C, Genotype 1-Infected Subjects Who Failed to Respond to Previous IFN-based Therapy

Conditions
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Hepatitis C, Chronic

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have chronic genotype 1 HCV infection with HCV RNA level >= 5.0 log10 IU/mL Participant failed to respond to previous IFN-based therapy Participant 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 PegIFNα-2a 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
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Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC435 100 mg 12 Wks + PR24/48<br>Participants will receive TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment will be stopped at Week 24 if participants achieve plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels < 1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable plasma HCV RNA levels at Week 12. All other participants will continue PR until Week 48. | Drug: TMC435<br>* 100-mg capsule taken by mouth once daily for 12 or 24 weeks.<br>Drug: Peginterferon alfa-2a (PegIFNα-2a )<br>* PegIFNα-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.<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: TMC435 100 mg 24 Wks + PR24/48<br>Participants will receive TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment will be stopped at Week 24 if participants achieve plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels < 1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable plasma HCV RNA levels at Week 12. All other participants will continue PR until Week 48. | Drug: TMC435<br>* 100-mg capsule taken by mouth once daily for 12 or 24 weeks.<br>Drug: Peginterferon alfa-2a (PegIFNα-2a )<br>* PegIFNα-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.<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?
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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 in each treatment group with a SVR12 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels at the EOT (Week 24 or 48) and at 12 weeks after the last dose of treatment (Week 36 or 60). | EOT (Week 24 or 48) and Week 36 or 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With a Sustained Virologic Response 24 Weeks After the End of Treatment (EOT) and 24 Weeks After the Last Dose of Treatment (SVR24) | The table below shows the observed percentage of participants in each treatment group with a SVR24 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels at the EOT (Week 24 or 48) and at 24 weeks after the last dose of treatment (Week 48 or 72). | EOT (Week 24 or 48) and 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 in each treatment group with a greater than (>) or equal to (=) 2 log10 IU/mL drop from baseline in HCV RNA at each time point during treatment and post-treatment follow-up. | Day 3, Day 7, and Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 36, 48, 60, 72, EOT, and Follow-up (FU) Weeks 4, 12, and 24 | 
| The Percentage of Participants With Undetectable Plasma 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 HCV RNA (<1.2 log10 IU/mL) during treatment at Weeks 4, 12, 24, 36, 48, 60, 72, and at EOT (Week 24 or 48). | Weeks 4, 12, 24, 36, 48, 60, 72, and at EOT | 
| The Percentage of Participants With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels During Treatment for Participants Who Did Not Achieve Undetectable Plasma HCV RNA Levels at Week 12 | The table below shows the percentage of participants with undetectable HCV RNA at Weeks 24, 48, end of treatment (EOT), at the time of assessment for a sustained virologic response (SVR) 12 weeks after the last planned dose (SVR12) (Week 36 or 60), and SVR24 (Week 48 or 72) who did not achieve undetectable HCV RNA levels at Week 12. The number of participants analyzed is listed at each time point in order of the treatment groups from left to right in the table (ie, Week x, n=x, x) if different from the Number of Participants Analyzed. Results are not available for Weeks 24, 48, and EOT because there were no participants who met the criteria for a SVR at those time points. | Weeks 24, 48, EOT (Weeks 24 or 48), SVR12 (Weeks 36 or 60), and SVR24 (Weeks 48 or 72) | 
| The Number of Participants With Viral Breakthrough During the Study | The table below shows the number of all participants in each treatment group who experienced viral breakthrough during the treatment period in the study (Baseline to end of treatment [EOT], ie, Week 24 or 48). Viral breakthrough is defined as a confirmed increase of greater than (>) 1 log10 IU/mL in plasma hepatitis C virus (HCV) ribonucleic acid (RNA) level from the lowest level reached or a confirmed value of plasma HCV RNA of > 2.0 log10 IU/mL in all participants whose plasma HCV RNA level had previously been below 1.2 log10 IU/mL detectable or undetectable. | Up to EOT (Week 24 or 48) | 
| The Number of Participants Demonstrating Viral Relapse During the Study | The table below shows the number of participants in each treatment group who demonstrated viral relapse during the study. Viral relapse is defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels at EOT and detectable HCV RNA during follow-up or detectable HCV RNA at the time points for a sustained viral response (SVR) assessment. The incidence of viral relapse was only calculated for participants with undetectable HCV RNA levels at EOT and with at least one follow-up HCV RNA measurement. | Up to 72 weeks | 
| The Number 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 in each treatment group with abnormal ALT levels at baseline (Day 1) who achieved normalization of ALT levels defined as having an ALT value less than or equal to the Upper Limit of Normality (ie, 40 IU/mL) at the EOT. At Baseline, 34/53 participants in the TMC435 100 mg 12 Wks PR 24/48 treatment group and 35/53 participants in the TMC435 100 mg 24 Wks PR 24/48 treatment group had abnormal ALT levels. | EOT (Week 24 or 48) | 
| The Percentage of Participants Who Met Response Guided Treatment (RGT) Criteria and Completed Treatment With Peginterferon Alpha-2a (PegIFNα-2a) and Ribavirin (RBV) at Week 24 | The table below shows the percentage of participants in each 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 PegIFNα-2a and RBV at Week 24. Participants in the TMC435 treatment groups not meeting RGT criteria continued treatment with PegIFNα-2a and RBV to Week 48. | Week 24 | 
| Plasma Concentrations of TMC435 | The table below shows median (range) TMC435 predose plasma concentration (C0h) values and TMC435 maximum plasma concentration (Cmax) values for participants in each treatment group at Week 12, Week 24, and Overall (Weeks 4, 12, and 24). The time frame of Overall representes the median exposure estimate using all available data collected at Weeks 4, 12, and 24 for each participant in the study. The number of participants analyzed is listed at each time point in order of the treatment groups from left to right in the table (ie, Week x, n=x, x) if different from the Number of Participants Analyzed. | Week 12, Week 24, and Overall (Weeks 4, 12, and 24) | 
| 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 participants in each treatment group at Week 12, Week 24, and Overall (Weeks 4, 12, and 24). The time frame of Overall represents the median exposure estimate using all available data collected at Weeks 4, 12, and 24 for each participant in the study. The number of participants analyzed is listed at each time point in order of the treatment groups from left to right in the table (ie, Week x, n=x, x) if different from the Number of Participants Analyzed. | Week 12, Week 24, and Overall (Weeks 4, 12, and 24) | 

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