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 alpha-2a and ribavirin as part of their treatment.
This is a randomized, double-blind (neither physician nor participants know the name of the assigned drug), placebo-controlled study of TMC435 in participants who are infected with genotype 1 hepatitis C virus (HCV), who have never received treatment for HCV infection before. Participants in this study will also receive two other drugs for their HCV infection called peginterferon alpha-2a (PegIFN alpha-2a) and ribavirin (RBV). The purpose of the study is to investigate if TMC435 is superior to placebo in reducing plasma levels of HCV ribonucleic acid (RNA) to an undetectable level 12 weeks after the end of treatment. For the first 12 weeks, participants will take either TMC435 or placebo, plus PegIFNα-2a and RBV. For the next 12 weeks, participants will take PegIFN alpha-2a and RBV only. After that, some participants will continue to take PegIFN alpha-2a and RBV for up to 24 additional weeks and some will stop taking PegIFN alpha-2a and RBV depending on response-guided treatment criteria. 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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
395
150 mg capsule once daily for 12 weeks in addition to PegIFN alpha-2a and RBV for 48 weeks
150 mg capsule once daily for 12 weeks in addition to PegIFN alpha-2a and RBV for 24 or 48 weeks
One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFN alpha-2a once weekly for up to 48 weeks.
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.
Time frame: Week 36 or Week 60
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.
Time frame: 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.
Time frame: 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.
Time frame: Week 28 or Week 52
Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA)
The table below shows the change from baseline in log10 HCV RNA levels.
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200-mg tablets of RBV (body-weight adjusted dose) taken orally (by mouth) twice daily for up to 48 weeks.
Unnamed facility
Dothan, Alabama, United States
Unnamed facility
Hoover, Alabama, United States
Unnamed facility
Phoenix, Arizona, United States
Unnamed facility
Bakersfield, California, United States
Unnamed facility
Coronado, California, United States
Unnamed facility
Long Beach, California, United States
Unnamed facility
San Diego, California, United States
Unnamed facility
Aurora, Colorado, United States
Unnamed facility
Englewood, Colorado, United States
Unnamed facility
Miami, Florida, United States
...and 52 more locations
Time frame: 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.
Time frame: 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, \< 25 IU/mL detectable or undetectable), the percentage of participants with plasma levels of HCV RNA \<100 IU/mL, the percentage of participants with virologic responses of a greater than or equal to 2 log10 change from baseline in plasma levels of HCV RNA.
Time frame: 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.
Time frame: 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 greater than or equal to 2 log10 at Week 12.
Time frame: 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.
Time frame: 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.
Time frame: Week 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.
Time frame: 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.
Time frame: 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.
Time frame: Week 12
Percentage of Participants With Partial Response
The table below shows the percentage of participants with partial response, defined as greater than or equal to 2 log10 reduction in Hepatitis C virus ribonucleic acid at Week 12 compared to baseline, but not achieving undetectable HCV RNA while on treatment.
Time frame: 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).
Time frame: 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 (less than 25 IU/mL undetectable) at the end of treatment.
Time frame: 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.
Time frame: 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.
Time frame: Week 48
Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Undetectable or Detectable
The table below shows median time in days to reach HCV RNA levels \<25 IU/mL undetectable or detectable.
Time frame: Up to Week 48
Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Undetectable
The table below shows median time in days to reach HCV RNA levels \<25 IU/mL undetectable.
Time frame: Up to Week 48
Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <100 IU/mL
The table below shows median time in days to reach HCV RNA levels \<100 IU/mL.
Time frame: Up to Week 48
Time to Reach Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <1000 IU/mL
The table below shows median time in days to reach HCV RNA levels \<1000 IU/mL.
Time frame: 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).
Time frame: 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.
Time frame: 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, 158 of 264 participants in the TMC435 treatment group and 89 of 130 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.
Time frame: 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.
Time frame: 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 mean (standard deviation) values of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing for TMC435 for all participants. To calculate the mean AUC 24 for the study, AUC 24 hr values were derived for each participant at each visit and then a median AUC value calcuated across all visits for each participant. The median AUC value across all visits for each participant was used to calculate the mean AUC 24 hr all participants in the study.
Time frame: Fom 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) values for the C0h of TMC435.To calculate the mean C0h for the study, C0h values were derived for each participant at each visit and then a median C0H value calculated across visits for each participant. The median COh value for each participant across all visits was used to calculate the mean C0h for the study.
Time frame: Before administration of TMC435 at Weeks 2, 4, 8, and 12
Plasma Concentration of TMC435: Systemic Clearance (CL)
The table below shows the mean (standard deviation) values for the CL of TMC435.To calculate the mean CL for all participants in the study, CL values were first derived for each participant at each visit and then a median CL value calculated across visits for each participant. The median CL value for each participant was used to calculate the mean CL for all participants in the study.
Time frame: Across 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 began and throughout treatment and follow-up to rate the severity and impact of fatigue they experienced in the preceding 2 weeks on their daily lives. FSS total scores are the average of nine questions with a range from 1 \[no fatigue\] to 7 \[worst possible fatigue\]. An area under the curve (AUC) analysis compared the overall severity of fatigue in each treatment group from baseline to Week 72. The null hypothesis was that there would be no difference between the treatment arms in the amount of fatigue participants experienced throughout the study resulting in equal AUC from baseline to Week 72 (AUC72) for FSS total scores. The Table below shows the lease squares (LS) mean estimates of AUC at Week 72 (as well as at Week 60) and the statistical comparison between treatment groups.
Time frame: 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 Scores 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 during study visits throughout the study. WPAI Overall Productivity Scores ranged from 0% to 100% (higher WPAI scores indicated greater impairment in productivity). An area under the curve (AUC) analysis compared the overall WPAI Overall Work Productivity Scores in each treatment group from Baseline to Week 72. The null hypothesis was that there would be no difference between the treatment arms in the WPAI Overall Work Productivity Scores from Baseline to Week 72. The Table below shows the lease squares (LS) mean estimates of AUC at Week 72 (as well as at Week 60) in WPAI Work Productivity Scores and the statistical comparison between treatment groups.
Time frame: 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 Activity Scores 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. Scores ranged from 0 (no effect on activities) to 10 (completely prevented me from doing my daily activities). An area under the curve (AUC) analysis compared the impairment in daily activity scores in each treatment group from Baseline to Week 72. The null hypothesis was that there would be no difference between the treatment arms in impairment in daily activity scores from Baseline to Week 72. The Table below shows the lease squares (LS) mean estimates of AUC at Week 72 (as well as at Week 60) in the impairment in daily activity scores and the statistical comparison between treatment groups.
Time frame: Baseline to Week 60 and Week 72
Area Under the Curve From Baseline to Week 60 (AUC60) and Week 72 (AUC72) in Work Productivity and Activity (WPAI) Absenteeism Scores Due to Hepatitis C Virus (HCV) Infection and Its Treatment
Time missed from work in hours 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, question #2). The number of hours missed from work because of HCV was divided by the total number of hours supposed to work, and expressed as a percentage. An area under the curve (AUC) analysis compared the WPAI absenteeism scores in each treatment group from Baseline to Week 72. The null hypothesis was that there would be no difference between the treatment arms WPAI absenteeism scores from Baseline to Week 72. The Table below shows the lease squares (LS) mean estimates of AUC at Week 72 (as well as at Week 60) in WPAI absenteeism scores and the statistical comparison between treatment groups.
Time frame: Baseline to Week 60 and Week 72