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

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Baseline to Week 60 and Week 72

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Baseline to Week 60 and Week 72

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Baseline to Week 60 and Week 72

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Baseline to Week 60 and Week 72

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

The table below shows changes from baseline in log10 HCV RNA.

Time frame: Day 3, Week 1, Week 4, Week 12, Week 24, and Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

The table below shows the median time in weeks to normalization of ALT levels.

Time frame: Up to Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Day 3, Week 1, Week 2, Week 8, Week 16, Week 20, Week 28, Week 36, and Week 42

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Week 12

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Up to Week 72

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: At protocol-specified time points from the time of administration up to 24 hours after dosing at Weeks 2, 4, 8, and 12

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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).

Time frame: 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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: At protocol-specified time points at Weeks 2, 4, 8, and 12

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Week 12

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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: Weeks 4 and 12

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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.

Time frame: Up to Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

The table below shows the median time in days to reach HCV RNA levels \<1000 IU/mL.

Time frame: Up to Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

The table below shows the median time in days to reach HCV RNA levels \<100 IU/mL.

Time frame: Up to Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

The table below shows the median time in days to reach HCV RNA levels \<25 IU/mL undetectable.

Time frame: Up to Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

The table below shows the median time in days to reach HCV RNA levels \<25 IU/mL undetectable or detectable.

Time frame: Up to Week 48

Population: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.