An Efficacy, Safety, and Tolerability Study of TMC435 in Treatment-naive, Genotype 1 Hepatitis C-infected Participants

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effectiveness and safety of TMC435 compared with placebo in participants who are infected with genotype 1 hepatitis C virus who have never received treatment before. Participants will also receive peginterferon alfa-2a or peginterferon alfa-2b and ribavirin as part of their treatment.

Detailed Description
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This is a randomized, double-blind (neither physician or participant knows the name of the assigned drug), placebo-controlled study of TMC435 in participants who are infected with genotype 1 hepatitis C virus who have never received treatment for this before. Participants in this study will also receive two other drugs for their infection (either peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®) or peginterferon alfa-2b (PegIntron®) and ribavirin (Rebetol®). The purpose of the study is to investigate if TMC435 is superior to placebo in reducing hepatitis C virus to an undetectable level 24 weeks after the end of treatment. For the first 12 weeks, participants will take TMC435 or placebo, plus peginterferon and ribavirin. For the next 12 weeks, participants will take peginterferon and ribavirin only. After that, some participants will continue to take peginterferon and ribavirin for up to 24 additional weeks. Other participants will stop taking peginterferon and ribavirin. The study doctor will inform each participant about how to take their study medication and when they should stop taking it. After a participant stops taking study medication, they will continue to come to the doctor's office for study visits until a total of 72 weeks after they enroll in the study. The total duration of the study is 78 weeks (including screening). Participants will be monitored for safety throughout the study. Study assessments at each study visit may include but are not limited to: blood and urine collection for testing, electrocardiogram (ECG) assessments (a measurement of the electrical activity of your heart), participant questionnaires, and physical examinations. TMC435 will be taken as an oral capsule of 150 mg once per day. Peginterferon (Pegasys ®) will be given as an injection of 180 µg once each week. Peginterferon (PegIntron®) will be given as an injection once each week and the dose will depend on your body weight. Ribavirin will be taken as a tablet (Copegus ®) or a capsule (Rebetol ®) twice each day and the dose will depend on your body weight.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety and Tolerability of TMC435 Versus Placebo as Part of a Treatment Regimen Including Peginterferon α-2a (Pegasys®) and Ribavirin (Copegus®) or Peginterferon α-2b (PegIntron®) and Ribavirin (Rebetol®) in Treatment-naïve, Genotype 1, Hepatitis C-infected Subjects

Conditions
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Hepatitis C

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genotype 1 hepatitis C infection (confirmed at screening) Participant has not received any prior treatment for hepatitis C Participant must have had a liver biopsy within 3 years before screening (or between the screening and baseline visit) showing chronic hepatitis C infection Must agree to use 2 forms of effective contraception throughout study (both males and females) Exclusion Criteria: Infection with HIV or non genotype 1 hepatitis C Liver disease not related to hepatitic C infection Hepatic decompensation Significant laboratory abnormalities or other active diseases Pregnant or planning to become pregnant

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC435<br>TMC435 150 mg capsule once daily for 12 weeks in addition to peginterferon alfa-2a (Pegasys) or peginterferon alfa-2b (PegIntron) (PegIFN alpha-2a/b) and ribavirin (Copegus or Rebetol) for 24 or 48 weeks | Drug: TMC435<br>* 150 mg capsule once daily for 12 weeks in addition to peginterferon alfa-2a or peginterferon alfa-2b and ribavirin for 24 or 48 weeks<br>Drug: Peginterferon alpha-2a or Peginterferon alpha-2b (PegIFNα-2a/b)<br>* One subcutaneous (under the skin) injection of PegIFNα-2a (containing 0.5 mL solution with 180 mcg PegIFNα-2a) OR PegIFNα-2b (0.5 mL from a pre-filled pen) once weekly for up to 48 weeks.<br>* Other names: PegIFNα-2b (PegIntron);Drug: Ribavirin (RBV)<br>* 200-mg tablets of ribavirin (Copegus or Rebetol) (body-weight adjusted dose) taken orally (by mouth) twice daily for up to 48 weeks.<br>* Other names: Rebetol;|
| Placebo Comparator: Placebo<br>Placebo 150 mg capsule once daily for 12 weeks in addition peginterferon alfa-2a (Pegasys) or peginterferon alfa-2b (PegIntron) (PegIFN alpha-2a/b) and ribavirin (Copegus or Rebetol) for 48 weeks | Drug: Placebo<br>* 150 mg capsule once daily for 12 weeks in addition to peginterferon alfa-2a or peginterferon alfa-2b and ribavirin for 48 weeks<br>Drug: Peginterferon alpha-2a or Peginterferon alpha-2b (PegIFNα-2a/b)<br>* One subcutaneous (under the skin) injection of PegIFNα-2a (containing 0.5 mL solution with 180 mcg PegIFNα-2a) OR PegIFNα-2b (0.5 mL from a pre-filled pen) once weekly for up to 48 weeks.<br>* Other names: PegIFNα-2b (PegIntron);Drug: Ribavirin (RBV)<br>* 200-mg tablets of ribavirin (Copegus or Rebetol) (body-weight adjusted dose) taken orally (by mouth) twice daily for up to 48 weeks.<br>* Other names: Rebetol;|

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 12 Weeks After the Planned End of Treatment (SVR12) | The table below shows the percentage of participants in each treatment group who achieved a SVR12, defined as the percentage of participants with undetectable plasma Hepatitis C virus ribonucleic acid 12 weeks after planned end of treatment. | Week 36 or Week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants Achieving a Sustained Virologic Response at Week 72 (SVRW72) | The table below shows the percentage of participants in each treatment group who achieved a SVRW72, defined as the percentage of participants with undetectable plasma Hepatitis C virus ribonucleic acid levels at end of treatment (EOT) and at Week 72. | Week 72 | 
| The Percentage of Participants Who Achieved a Sustained Virologic Response 24 Weeks After the Planned End of Treatment (SVR24) | The table below shows the percentage of participants in each treatment group who achieved a SVR24, defined as the percentage of participants with undetectable plasma Hepatitis C virus ribonucleic acid levels 24 weeks after planned end of treatment. | Week 48 or Week 72 | 
| The Percentage of Participants Who Achieved a Sustained Virologic Response 4 Weeks After the Planned End of Treatment (SVR4) | The table below shows the percentage of participants in each treatment group who achieved a SVR4, defined as the percentage of participants with undetectable plasma Hepatitis C virus ribonucleic acid levels 4 weeks after planned end of treatment. | Week 28 or Week 52 | 
| Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | The table below shows changes from baseline in log10 HCV RNA. | Day 3, Week 1, Week 4, Week 12, Week 24, and Week 48 | 
| Actual Values of log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | The table below shows actual values of log10 HCV RNA levels. | Day 3, Week 1, Week 4, Week 12, Week 24, and Week 48 | 
| Percentage of Participants With On-treatment Virologic Response at All Time Points | The table below shows the percentage of participants with Hepatitis C Virus (HCV) ribonucleic acid (RNA) plasma levels below the limit of detection (ie, <25 IU/mL undetectable), the percentage of participants with a HCV RNA plasma level below the limit of quantification (ie, less than [<] 25 IU/mL detectable or undetectable), the percentage of participants with plasma levels of HCV RNA <100 IU/mL, the percentage of HCV-Infected participants with virologic responses of a greater than or equal to 2 log10 change from baseline in plasma levels of HCV RNA. | Day 3, Week 1, Week 2, Week 8, Week 16, Week 20, Week 28, Week 36, and Week 42 | 
| 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 undetectable plasma Hepatitis C virus ribonucleic acid levels after receiving 4 weeks of treatment. | Week 4 | 
| The Percentage of Participants Achieving a Early Virologic Response (EVR) | The table below shows the percentage of participants who achieved an EVR, defined as having a change from baseline in plasma Hepatitis C virus ribonucleic acid of 2 log10 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 Hepatitis C Virus ribonucleic acid levels at Week 12. | Week 12 | 
| The Percentage of Participants Achieving a Extended Rapid Virologic Response (eRVR) | The table below shows the percentage of participants in each treatment group who had a eRVR, defined as having undetectable plasma Hepatitis C Virus ribonucleic acid levels at Week 4 and 12. | Weeks 4 and 12 | 
| The Percentage of Participants With <1 log10 Decrease in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) From Baseline at Week 4 | The table below shows the percentage of participants in each treatment group with <1 log10 HCV RNA decrease at Week 4. | Week 4 | 
| Percentage of Participants With in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels >1000 IU/mL at Week 4 | The table below shows the percentage of participants in each treatment group with HCV RNA levels >1000 IU/mL at Week 4. | Week 4 | 
| Percentage of Participants With Null Response | The table below shows the percentage of participants with null response, defined as <2 log10 reduction in Hepatitis C virus ribonucleic acid at Week 12 compared to baseline. | Week 12 | 
| Percentage of Participants With Partial Response | The table below shows the percentage of participants with partial response, defined as =>2 log10 reduction in Hepatitis C virus (HCV) ribonucleic acid (RNA) at Week 12 compared to baseline, but not achieving undetectable HCV RNA while on treatment. | Week 12 | 
| Percentage of Participants With Viral Breakthrough | The table below shows the percentage of participants with viral breakthrough, 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 (ie, lowest value measured in between baseline and current value), or a confirmed plasma HCV RNA level of greater than 100 IU/mL in participants whose plasma HCV RNA had previously been below the limit of quantification (25 IU/mL detectable) or undetectable (<25 IU/mL undetectable). | Up to Week 48 | 
| Percentage of Participants With Viral Relapse | The table below shows the percentage of participants with viral relapse, defined as having confirmed detectable plasma level of Hepatitis C virus (HCV) ribonucleic acid (RNA) during the follow-up period in participants with undetectable plasma HCV RNA (<25 IU/mL undetectable) at the end of treatment. | Up to Week 72 | 
| Percentage of Participants Who Completed All Study Treatment at Week 24 Because of the Treatment Duration Rule | The table below shows the percentage of participants in the TMC435 treatment group who met the treatment duration rule (ie, having hepatitis C virus [HCV] ribonucleic acid [RNA] levels <25 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA levels at Week 12) and completed treatment with PegIFNα-2a and RBV for 24 weeks. Participants in the TMC435 treatment group not meeting RGT criteria and participants in the placebo group were treated with PegIFNα-2a and RBV treatment for 48 weeks. | Week 24 | 
| Percentage of Participants With On-treatment Failure | The table below shows percentage of participants with on-treatment failure defined as confirmed detectable Hepatitis C virus ribonucleic acid levels at actual end of treatment. | Week 48 | 
| Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Undetectable or Detectable | The table below shows the median time in days to reach HCV RNA levels <25 IU/mL undetectable or detectable. | Up to Week 48 | 
| Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Undetectable | The table below shows the median time in days to reach HCV RNA levels <25 IU/mL undetectable. | Up to Week 48 | 
| Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <100 IU/mL | The table below shows the median time in days to reach HCV RNA levels <100 IU/mL. | Up to Week 48 | 
| Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <1000 IU/mL | The table below shows the median time in days to reach HCV RNA levels <1000 IU/mL. | Up to Week 48 | 
| The Percentage of Participants With Viral Breakthrough at Different Time Points | The table below shows the percentage of participants at different time points with viral breakthrough, defined as a confirmed increase of greater than 1 log10 IU/mL in plasma HCV ribonucleic acid (RNA) level from the lowest level reached (ie, lowest value measured in between baseline and current value), or a confirmed plasma HCV RNA level of greater than 100 IU/mL in participants whose plasma HCV RNA had previously been below the limit of quantification (25 IU/mL detectable) or undetectable (<25 IU/mL undetectable). | Up to Week 48 | 
| Time From End-of-treatment to Viral Relapse | The table below shows the mean number of days to viral relapse, defined as participants having confirmed detectable plasma level of Hepatitis C Virus (HCV) ribonucleic acid (RNA) during the follow-up period in participants with undetectable plasma HCV RNA (<25 IU/mL undetectable) at the end of treatment. | Up to Week 72 | 
| The Percentage of Participants With Normalization of Alanine Aminotransferase (ALT) | The percentage of participants analyzed were those with baseline ALT values out of the normal range (ie, 164 of 257 participants in the TMC435 treatment group and 79 of 134 participants in the Placebo group had ALT values at baseline that were out of the normal range.). Normalization of ALT values means that ALT values out of the normal range returned to within the normal range. | Up to Week 48 | 
| Median Time to Normalization of Alanine Aminotransferase (ALT) Levels | The table below shows the median time in weeks to normalization of ALT levels. | Up to Week 48 | 
| Plasma Concentration of TMC435: Area Under the Plasma Concentration-time Curve From the Time of Administration to 24 Hours After Dosing (AUC24h) | The table below shows the mean (standard deviation) values of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing for TMC435. | At protocol-specified time points from the time of administration up to 24 hours after dosing at Weeks 2, 4, 8, and 12 | 
| Plasma Concentration of TMC435: Predose Plasma Concentration (C0h) | The table below shows the mean (standard deviation) of C0h values of TMC435. NOTE: the timing of collection of blood samples post-dose for analysis at Week 2, 4, 8, and 12 was not specifed; only the interval was between blood samples was specified (ie, 2 samples collected 2 hours apart at Week 2, 4, 8, and 12). | Blood samples tested were taken before administration of TMC435 and at 2 random time points after dosing (taken atleast 2 hours apart from each other) at Week 2, 4, 8, and 12 | 
| Plasma Concentration of TMC435: Systemic Clearance (CL) | The table below shows the mean (standard deviation) of CL values of TMC435. NOTE: the pre-dose CL values taken at Weeks, 2, 4, 8, and 12 were averaged and then the mean values from all participants were averaged to provide the final value reported below. | At protocol-specified time points at Weeks 2, 4, 8, and 12 | 
| Area Under the Curve From Baseline to Week 60 (AUC60) and Week 72 (AUC72) for the Fatigue Severity Scale (FSS) Total Scores | Study participants completed FSS questionnaires during study visits before treatment and throughout follow-up to rate the severity and impact of fatigue experienced in the preceding 2 weeks. FSS total scores are the average of nine questions with a range from 1 [no fatigue] to 7 [worst fatigue]; the possible score range from baseline to Week 60 would be 60-420 and to Week 72 would be 72-504. The average FSS total score from baseline to Week 60 and to Week 72 was calculated for each participant and then the average of those values were calculated to show the average FSS total score for each treatment group. The null hypothesis was that there would be no difference between the treatment arms in the FSS total score. The Table below shows the lease squares (LS) mean estimates of the area under the curve (AUC) at Week 72 (as well as at Week 60) and the statistical comparison between treatment groups. | Baseline to Week 60 and Week 72 | 
| Area Under the Curve From Baseline to Week 60 (AUC60) and Week 72 (AUC72) for Impairment in Overall Work Productivity Due to Hepatitis C Virus (HCV) Infection and Its Treatment | Impairment in overall work productivity was measured using the Work Productivity and Activity Impairment (WPAI): Hepatitis C questionnaire completed by participants throughout the study. WPAI Overall Productivity Scores ranged from 0% to 100% (higher WPAI scores indicated greater impairment in productivity). The average WPAI score from baseline to Week 72 was calculated for each participant and then the average of those values were calculated to show the average WPAI score for each treatment group. The null hypothesis was there is no statistically significant difference between the treatment groups in the AUC for the change from baseline to Week 72 (AUC72) in WPAI Productivity Scores. The Table below shows WPAI Productivity Scores at Week 72 (as well as at Week 60) from the model used to calculate the AUC and the statistical comparison between treatment groups. | Baseline to Week 60 and Week 72 | 
| Area Under the Curve From Baseline to Week 60 (AUC60) and Week 72 (AUC72) for Impairment in Daily Activities Due to Hepatitis C Virus (HCV) Infection and Its Treatment | Impairment in daily activity was measured using the Work Productivity and Activity Impairment (WPAI): Hepatitis C questionnaire, Question 6. The possible impairment in WPAI daily activity score range from baseline to Week 60 was 0-6000 and to Week 72 was 0-7200, with the higher scores indicating more impairment in daily activities. The average WPAI impairment in daily activity score from baseline to Week 72 was calculated for each participant and then the average of those values were calculated to show the average WPAI impairment in daily activity score for each treatment group. The null hypothesis was there is no statistically significant difference between the treatment arms in the AUC for the change from baseline to Week 72 (AUC72) in WPAI impairment in daily activity scores. The Table below shows the WPAI Impairment in daily activity scores at Week 72 (as well as at Week 60) and the statistical analysis between treatment groups. | Baseline to Week 60 and Week 72 | 
| Area Under the Curve From Baseline to Week 60 (AUC60) and Week 72 (AUC72) for Time Missed From Work Due to Hepatitis C Virus (HCV) Infection and Its Treatment | Hours missed from work because of HCV infection or its treatment was assessed by measuring the change from baseline in the Work Productivity and Activity Impairment (WPAI): Hepatitis C questionnaire Absenteeism score (time missed from work). The possible WPAI WPAI absenteeism score range from baseline to Week 60 was 0-6000 and to Week 72 was 0-7200, with the higher scores indicating more impairment in WPAI absenteeism. The average WPAI absenteeism score from baseline to Week 60/72 was calculated for each participant and then the average of those values calculated for each treatment group. The area under the curve (AUC60/AUC72) over time from baseline to Week 60/72 was derived from a piecewise-linear model allowing the slopes to change at Week 4, 12, 24, 36, 48 and 60. The null hypothesis was there is no statistically significant difference between the treatment arms in the area under the curve (AUC) from baseline to Week 72 (AUC72) in WPAI absenteeism score. | Baseline to Week 60 and Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C, TMC435, HCV, Hep C, genotype 1