A Safety and Effectiveness Study of TMC435 in Chronic, Genotype 1, Hepatitis C Patients Who Failed to Previous Standard Treatment

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy, safety and tolerability of different regimens of TMC435 with standard treatment compared to standard treatment alone in participants with chronic, genotype 1, hepatitis C virus (HCV) infection who has failed previous treatment with pegylated interferon (Peg-INF-alfa-2a) and ribavirin (RBV).

Detailed Description
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The study is a randomized (study drug assigned by chance), double-blind (neither physician nor participant knows the name of the assigned drug), placebo-controlled Phase IIb trial with TMC435 in participants with chronic, genotype 1, hepatitis C virus (HCV) infection who have failed standard treatment with pegylated interferon (Peg-INF-alfa-2a) and ribavirin (RBV). The study will compare the efficacy, tolerability and safety of different regimens with TMC435 combined with standard treatment (Peg-INF-alfa-2a and RBV) versus standard treatment alone. The trial will consist of a screening period of maximum 6 weeks, a 48-week treatment period, and a 24-week follow-up period. Participants will be eligible to enroll in the trial if they failed to respond to a prior course of standard treatment or relapsed following standard treatment. Participants will be randomly assigned to receive TMC435 with standard treatment for 12 weeks followed by standard treatment (plus placebo) for 36 weeks, TMC435 (100 mg or 150 mg once a day) with standard treatment for 24 weeks followed by standard treatment (plus placebo) for 24 weeks, TMC435 (100 mg or 150 mg once a day) with standard treatment for 48 weeks, or a placebo with standard treatment for 48 weeks.

Official Title
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A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Trial to Investigate the Efficacy, Tolerability, Safety and Pharmacokinetics of TMC435 as Part of a Treatment Regimen Including PegIFNa-2a and Ribavirin in HCV Genotype 1 Infected Subjects Who Failed Previous Standard Therapy

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: TMC435
* Drug: Placebo
* Drug: Peg-IFN-alfa-2a (P)
* Drug: Ribavirin (R)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have chronic hepatitis C infection as evidenced by liver biopsy, anti-hepatitis C virus (HCV) and HCV RNA positive Must have chronic hepatitis C infection (genotype 1) with HCV RNA level greater than10000 IU/mL Patient must have failed at least 1 prior course of peg interferon (Peg-IFN-alfa-2a)/ribavirin (RBV) therapy (standard treatment) Must be willing to use 2 effective methods of birth control for up to 7 months after last dose of study medication Exclusion Criteria: Has an evidence of decompensated liver disease Co-infection with any other Hepatitis C virus genotype or co-infection with the human immunodeficiency virus (HIV) Has a medical condition which is a contraindication to Peg-INF or RBV therapy Have had 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: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC435 100 mg 12 Wks + PR48<br>Participants will receive TMC435 100 mg once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 12 weeks followed by Placebo with PR for 36 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Placebo<br>* One or 2 capsules of placebo identical in appearance to TMC435 taken orally once daily for 24, 36, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 48 weeks.<br>* Other names: COPEGUS;|
| Experimental: TMC435 100 mg 24 Wks + PR48<br>Participants willl receive TMC435 100 mg once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 24 weeks followed by Placebo with PR for 24 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Placebo<br>* One or 2 capsules of placebo identical in appearance to TMC435 taken orally once daily for 24, 36, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 48 weeks.<br>* Other names: COPEGUS;|
| Experimental: TMC435 100 mg 48 Wks + PR48<br>Participants will receive TMC435 100 mg once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 48 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Placebo<br>* One or 2 capsules of placebo identical in appearance to TMC435 taken orally once daily for 24, 36, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 48 weeks.<br>* Other names: COPEGUS;|
| Experimental: TMC435 150 mg 12 Wks + PR48<br>Participants will receive TMC435 150 mg once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 12 weeks followed by Placebo and PR for 36 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Placebo<br>* One or 2 capsules of placebo identical in appearance to TMC435 taken orally once daily for 24, 36, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 48 weeks.<br>* Other names: COPEGUS;|
| Experimental: TMC435 150 mg 24 Wks + PR48<br>Participants will receive TMC435 150 mg once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 24 weeks followed Placebo and PR for 24 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Placebo<br>* One or 2 capsules of placebo identical in appearance to TMC435 taken orally once daily for 24, 36, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 48 weeks.<br>* Other names: COPEGUS;|
| Experimental: TMC435 150 mg 48 Wks + PR48<br>Participants will receive TMC435 150 mg once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 48 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 48 weeks.<br>* Other names: COPEGUS;|
| Placebo Comparator: Placebo 48 Wks + PR48<br>Participants will receive Placebo once daily with Peg-IFN-alfa-2a (P) once weekly and ribavirin (R) twice daily for 48 weeks. | Drug: TMC435<br>* One TMC435 100-mg capsule or two 75-mg capsules orally (by mouth) once daily for 12, 24, or 48 weeks.<br>Drug: Peg-IFN-alfa-2a (P)<br>* 180 micrograms taken as one 0.5 mL subcutaneous injection once weekly for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin (R)<br>* 1000 or 1200 mg/day (5 or 6 tablets) taken orally as a twice daily regimen taken for 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 Achieving a Sustained Virologic Response at the End of Treatment (EOT) and 24 Weeks After the EOT (SVR24) | The table below shows the percentage of participants in the overall population with an SVR24, defined as having plasma levels of Hepatitis C Virus ribonucleic acid less than 25 IU/mL undetectable at the EOT and 24 weeks after the EOT. | Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With a Greater Than 2 log10 Drop in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Time Points During Treatment | The table below shows the percentage of participants in each treatment group who achieved a greater than 2 log10 drop in plasma levels of HCV RNA at selected time points during treatment. | Weeks, 2, 4, 8, and 12 | 
| The Percentage of Participants Achieving Plasma Levels of Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Undetectable During Treatment and Follow-up | The table below shows the percentage of participants in each treatment who achieved plasma HCV RNA levels of <25 IU/mL undetectable at selected time points during treatment and follow-up and at the end of treatment (EOT). | Weeks, 2, 4, 8, 12, 24, 36, 48, 60, 72 and EOT (up to Week 48) | 
| The Percentage of Participants Achieving Plasma Levels of Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Detectable or Undetectable During Treatment and Follow-up | The table below shows the percentage of participants in each treatment group who achieved plasma HCV RNA levels below the limit of quantification defined as less than 25 IU/mL (detectable or undetectable) at selected time points during treatment, follow-up, and at the end of treatment (EOT). | Weeks, 2, 4, 8, 12, 24, 36, 48, 60, 72, and EOT (up to Week 48) | 
| The Percentage of Participants Achieving a Rapid Virologic Response (RVR) | The table below shows the percentage of participants in each treatment group who achieved a RVR, defined as having an undetectable plasma Hepatitis C virus ribonucleic acid level after receiving 4 weeks of treatment. | Week 4 | 
| The Percentage of Participants Achieving an Early Virologic Response (EVR) | The table below shows the percentage of participants who achieved an EVR, defined as having a greater than or equal to 2 log10 reduction in plasma Hepatitis C virus ribonucleic acid from baseline at Week 12. | Week 12 | 
| The Percentage of Participants Achieving a Complete Early Virologic Response (cEVR) | The table below shows the percentage of participants in each treatment group who had a cEVR, defined as having undetectable plasma levels of Hepatitis C virus ribonucleic acid at Week 12. | Week 12 | 
| The Percentage of Participants Achieving a Sustained Virologic Response 12 Weeks After the Planned End of Treatment (SVR12) | The table below shows the percentage of participants in the overall population who achieved undetectable plasma Hepatitis C virus ribonucleic acid levels at the end of treatment (EOT) and 12 Weeks after the planned EOT. | Week 60 | 
| The Percentage of Participants With Viral Breakthrough | The table below shows the percentage of participants in the overall population in each treatment group during the treatment period who experienced viral breakthrough, defined as a confirmed increase of greater than 1 log10 IU/mL in Hepatitis C virus (HCV) ribonucleic acid (RNA) from the lowest level reached or a confirmed HCV RNA of > 100 IU/mL in participants whose HCV RNA had previously been below the lower limit of quantification (i.e., less than 25 IU/mL detectable or undetectable). | EOT (up to Week 48) | 
| The Percentage of Participants With Viral Relapse | The table below shows the percentage of participants in the overall population who had viral relapse, defined as confirmed detectable Hepatitis C virus (HCV) ribonucleic acid (RNA) during the follow-up period in participants with HCV RNA less than 25 IU/mL undetectable at end of treatment. | Up to Week 72 | 
| The Number of Participants Who Achieved Normalized Alanine Aminotransferase (ALT) Levels at the End of Treatment (EOT) | The table below shows the number of participants with abnormal ALT levels at Baseline who achieved the normal ALT levels at the EOT (up to Week 48). | EOT (up to Week 48) | 
| Plasma Concentrations of TMC435 | The table below shows median (range) predose plasma concentration (C0h) values and median (range) average steady-state plasma concentration (Css,av) values for TMC435 for participants in each of the 6 TMC435 treatment groups. | 0 (predose, baseline) and 4, 8, 12, and 24 hours post-dose at Weeks 2, 4, 8, 12, 16, 24, and 48 | 
| 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 participants in each TMC435 treatment group. | 0 (predose, baseline) and 4, 8, 12, and 24 hours post-dose at Weeks 2, 4, 8, 12, 16, 24, and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C, Peginterferon alpha-2a, PegIFNalpha-2a, RBV, Ribavirin, Placebo, TMC435-TIDP16-C206, TMC435-C206, TMC435, HCV