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

• Sponsor: Janssen Pharmaceutical K.K. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01288209
• Collaborator: (none)
• Enrollment: 106
• Locations: 19
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: TMC435; Drug: Peginterferon alfa-2a (PegIFNα-2a ); Drug: Ribavirin (RBV)	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMC435 100 mg 12 Wks + PR24/48 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; 100-mg capsule taken by mouth once daily for 12 or 24 weeks.; Drug: Peginterferon alfa-2a (PegIFNα-2a ); 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.; Other Names: PEGASYS ; Drug: Ribavirin (RBV); 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.; Other Names: COPEGUS
Experimental: TMC435 100 mg 24 Wks + PR24/48 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; 100-mg capsule taken by mouth once daily for 12 or 24 weeks.; Drug: Peginterferon alfa-2a (PegIFNα-2a ); 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.; Other Names: PEGASYS ; Drug: Ribavirin (RBV); 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.; Other Names: COPEGUS

Outcome Measures

Primary Outcome Measures

1. 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) [EOT (Week 24 or 48) and Week 36 or 60]

   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).

Secondary Outcome Measures

1. 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) [EOT (Week 24 or 48) and Week 48 or 72]

   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).

2. 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 [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 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.

3. The Percentage of Participants With Undetectable Plasma Hepatitis C Virus Ribonucleic Acid (HCV RNA) During Treatment and at the End of Treatment (EOT) [Weeks 4, 12, 24, 36, 48, 60, 72, and at 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).

4. 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 [Weeks 24, 48, EOT (Weeks 24 or 48), SVR12 (Weeks 36 or 60), and SVR24 (Weeks 48 or 72)]

   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.

5. The Number of Participants With Viral Breakthrough During the Study [Up to EOT (Week 24 or 48)]

   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.

6. The Number of Participants Demonstrating Viral Relapse During the Study [Up to 72 weeks]

   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.

7. The Number Participants With Abnormal Alanine Aminotransferase (ALT) Levels at Baseline Who Achieved Normal ALT Levels at the End of Treatment (EOT) [EOT (Week 24 or 48)]

   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.

8. 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 [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.

9. Plasma Concentrations of TMC435 [Week 12, Week 24, and Overall (Weeks 4, 12, and 24)]

   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."

10. Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24h) for TMC435 [Week 12, Week 24, and Overall (Weeks 4, 12, and 24)]

    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."

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Amagasaki		Japan
2		Ichikawa		Japan
3		Kagoshima		Japan
4		Kanazawa		Japan
5		Kawasaki		Japan
6		Kitakyushu		Japan
7		Kumamoto		Japan
8		Kurume		Japan
9		Kyoto		Japan
10		Matsumoto		Japan
11		Musashino		Japan
12		Nishinomiya		Japan
13		Osaka-Sayama		Japan
14		Osaka		Japan
15		Sakai		Japan
16		Sapporo		Japan
17		Suita		Japan
18		Tokyo		Japan
19		Yokohama		Japan

Sponsors and Collaborators

• Janssen Pharmaceutical K.K.

Investigators

• Study Director: Janssen Pharmaceutical K.K. Clinical Trial, Janssen Pharmaceutical K.K.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Pharmaceutical K.K.
• ClinicalTrials.gov Identifier: NCT01288209
• Other Study ID Numbers: CR017689; TMC435HPC3004
• First Posted: Feb 2, 2011
• Last Update Posted: Jan 24, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by Janssen Pharmaceutical K.K.: Hepatitis C, Chronic; Hepatitis C; Hepatitis C virus; Interferon Alfa-2a; Ribavirin; Viral RNA
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Ribavirin; Peginterferon alfa-2a; Simeprevir

Study Results

Participant Flow

Recruitment Details	The study was conducted between 05-Jan-2011 to 05-Sep-2012 and recruited participants with chronic Hepatitis C Virus (HCV) infection from 23 study centers in Japan. A total of 108 participants were randomized, 106 started treatment, and 101 completed the study.
Pre-assignment Detail	Participants with genotype 1 HCV-infection who failed a previous course of interferon (IFN) based therapy received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) until Week 12 (OR Week 24), followed by PR until Week 24/48 based on response-guided treatment (RGT).

Arm/Group Title	TMC435 100 mg 12 Wks + PR 24/48	TMC435 100 mg 24 Wks + PR 24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNa-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels <1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNa-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels <1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48.
Period Title: Overall Study
STARTED	53	53
COMPLETED	51	50
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	TMC435 100 mg 12 Wks + PR 24/48	TMC435 100 mg 24 Wks + PR 24/48	Total
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNa-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels <1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNa-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels <1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48.	Total of all reporting groups
Overall Participants	53	53	106
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	60	60
Sex: Female, Male (Count of Participants)
Female	26 49.1%	27 50.9%	53 50%
Male	27 50.9%	26 49.1%	53 50%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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).
Time Frame	EOT (Week 24 or 48) and Week 36 or 60

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
Number [Percentage of participants]	52.8 99.6%	35.8 67.5%

2. Secondary Outcome

Title	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)
Description	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).
Time Frame	EOT (Week 24 or 48) and Week 48 or 72

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
Number [Percentage of participants]	50.9 96%	35.8 67.5%

3. Secondary Outcome

Title	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
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
Day 3	96.2 181.5%	96.2 181.5%
Day 7	100 188.7%	100 188.7%
Week 2	100 188.7%	96.2 181.5%
Week 3	100 188.7%	94.3 177.9%
Week 4	100 188.7%	90.6 170.9%
Week 8	88.7 167.4%	90.6 170.9%
Week 12	88.7 167.4%	86.8 163.8%
Week 16	84.9 160.2%	83.0 156.6%
Week 20	84.9 160.2%	79.2 149.4%
Week 24	84.9 160.2%	75.5 142.5%
Week 28	75.5 142.5%	69.8 131.7%
week 36	52.8 99.6%	41.5 78.3%
Week 48	50.9 96%	37.7 71.1%
Week 60	50.9 96%	35.8 67.5%
Week 72	50.9 96%	35.8 67.5%
EOT	88.7 167.4%	90.6 170.9%
FU Week 4	77.4 146%	81.1 153%
FU Week 12	52.8 99.6%	39.6 74.7%
FU Week 24	50.9 96%	35.8 67.5%

4. Secondary Outcome

Title	The Percentage of Participants With Undetectable Plasma Hepatitis C Virus Ribonucleic Acid (HCV RNA) During Treatment and at the End of Treatment (EOT)
Description	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).
Time Frame	Weeks 4, 12, 24, 36, 48, 60, 72, and at EOT

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
Week 4	58.5 110.4%	50.9 96%
Week 12	84.9 160.2%	79.2 149.4%
Week 24	79.2 149.4%	71.7 135.3%
Week 36	52.8 99.6%	35.8 67.5%
Week 48	50.9 96%	35.8 67.5%
Week 60	50.9 96%	35.8 67.5%
Week 72	50.9 96%	35.8 67.5%
EOT	83.0 156.6%	84.9 160.2%

5. Secondary Outcome

Title	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
Description	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.
Time Frame	Weeks 24, 48, EOT (Weeks 24 or 48), SVR12 (Weeks 36 or 60), and SVR24 (Weeks 48 or 72)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
SVR12 (Weeks 36 or 60) (n=6; n=8)	0.0 0%	0.0 0%
SVR24 (Weeks 48 or 72) (n=6; n=8)	0.0 0%	0.0 0%
Week 24	NA NaN	NA NaN
Week 48	NA NaN	NA NaN
EOT	NA NaN	NA NaN

6. Secondary Outcome

Title	The Number of Participants With Viral Breakthrough During the Study
Description	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.
Time Frame	Up to EOT (Week 24 or 48)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
Number [Participants]	7 13.2%	6 11.3%

7. Secondary Outcome

Title	The Number of Participants Demonstrating Viral Relapse During the Study
Description	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.
Time Frame	Up to 72 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	44	45
Number [Participants]	17 32.1%	23 43.4%

8. Secondary Outcome

Title	The Number Participants With Abnormal Alanine Aminotransferase (ALT) Levels at Baseline Who Achieved Normal ALT Levels at the End of Treatment (EOT)
Description	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.
Time Frame	EOT (Week 24 or 48)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	34	35
Number [Participants]	20 37.7%	28 52.8%

9. Secondary Outcome

Title	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
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all randomized participants who received at least one dose of study drug during the study except for those who did not meet the major eligibility criteria for the study and participants who did not have efficacy data available after treatment with study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
Number [Percentage of participants]	81.1 153%	73.6 138.9%

10. Secondary Outcome

Title	Plasma Concentrations of TMC435
Description	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."
Time Frame	Week 12, Week 24, and Overall (Weeks 4, 12, and 24)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis was performed in the pharmacokinetic (PK) population, defined as all participants from whom sparse blood samples were drawn and who received at least 1 dose of study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
C0h (Week 12) (n=47; n=44)	1844	910
C0h (Week 24) (n=0; n=40)	NA	866
C0h (Overall) (n=53; n=53)	1784	906
Cmax (Week 12) (n=47; n=44)	3408	2476
Cmax (Week 24) (n=0; n=40)	NA	2443
Cmax (Overall) (n=53; n=53)	3401	2488

11. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24h) for TMC435
Description	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."
Time Frame	Week 12, Week 24, and Overall (Weeks 4, 12, and 24)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis was performed in the pharmacokinetic (PK) population, defined as all participants from whom sparse blood samples were drawn and who received at least 1 dose of study medication.

Arm/Group Title	TMC435 100 mg 12 Wks + PR24/48	TMC435 100 mg 24 Wks + PR24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.	Participants received TMC435 100 mg once daily with PegIFNα-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved 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 continued PR until Week 48.
Measure Participants	53	53
AUC24h (Week 12) (n=47; n=44)	62993	39867
AUC24h (Week 24) (n=0; n=40)	NA	38931
Overall (n=53; n=53)	62313	40014

Adverse Events

Time Frame	Up to approximately 52 weeks (includes all serious and other adverse events that newly occurred or worsened after treatment with TMC435, PegIFNα-2b or ribavirin, until the end date of the last study medication intake + 28 days).
Arm/Group Title	TMC435 100 mg 12 Wks + PR 24/48		TMC435 100 mg 24 Wks + PR 24/48
Arm/Group Description	Participants received TMC435 100 mg once daily with PegIFNa-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 24. Treatment was stopped at Week 24 if participants achieved plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels <1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48.		Participants received TMC435 100 mg once daily with PegIFNa-2a and ribavirin ( PR) for 24 weeks (Wks). Treatment was stopped at Week 24 if participants achieved plasma hepatitis C virus (HCV) ribonucleic acid (RNA) levels <1.2 log10 IU/mL detectable or undetectable at Week 4, and undetectable HCV RNA at Week 12. All other participants continued PR until Week 48.
All Cause Mortality
	TMC435 100 mg 12 Wks + PR 24/48		TMC435 100 mg 24 Wks + PR 24/48
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TMC435 100 mg 12 Wks + PR 24/48		TMC435 100 mg 24 Wks + PR 24/48
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/53 (3.8%)		3/53 (5.7%)
Blood and lymphatic system disorders
Anaemia	0/53 (0%)		1/53 (1.9%)
Infections and infestations
Pyelonephritis acute	0/53 (0%)		1/53 (1.9%)
Injury, poisoning and procedural complications
Laceration	1/53 (1.9%)		0/53 (0%)
Nervous system disorders
Hypoaesthesia	0/53 (0%)		1/53 (1.9%)
Renal and urinary disorders
Calculus ureteric	0/53 (0%)		1/53 (1.9%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/53 (1.9%)		0/53 (0%)
Other (Not Including Serious) Adverse Events
	TMC435 100 mg 12 Wks + PR 24/48		TMC435 100 mg 24 Wks + PR 24/48
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/53 (100%)		52/53 (98.1%)
Blood and lymphatic system disorders
Anaemia	28/53 (52.8%)		30/53 (56.6%)
Leukopenia	2/53 (3.8%)		8/53 (15.1%)
Thrombocytopenia	2/53 (3.8%)		6/53 (11.3%)
Neutropenia	1/53 (1.9%)		4/53 (7.5%)
Eye disorders
Retinopathy	2/53 (3.8%)		3/53 (5.7%)
Dry eye	1/53 (1.9%)		3/53 (5.7%)
Gastrointestinal disorders
Stomatitis	11/53 (20.8%)		10/53 (18.9%)
Diarrhoea	6/53 (11.3%)		7/53 (13.2%)
Nausea	6/53 (11.3%)		9/53 (17%)
Abdominal discomfort	5/53 (9.4%)		9/53 (17%)
Constipation	4/53 (7.5%)		4/53 (7.5%)
Dental caries	3/53 (5.7%)		0/53 (0%)
Vomiting	3/53 (5.7%)		2/53 (3.8%)
Cheilitis	2/53 (3.8%)		3/53 (5.7%)
General disorders
Pyrexia	33/53 (62.3%)		31/53 (58.5%)
Malaise	30/53 (56.6%)		24/53 (45.3%)
Fatigue	9/53 (17%)		11/53 (20.8%)
Injection site reaction	6/53 (11.3%)		12/53 (22.6%)
Injection site erythema	5/53 (9.4%)		3/53 (5.7%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/53 (3.8%)		3/53 (5.7%)
Infections and infestations
Nasopharyngitis	10/53 (18.9%)		16/53 (30.2%)
Cystitis	1/53 (1.9%)		3/53 (5.7%)
Pharyngitis	0/53 (0%)		4/53 (7.5%)
Injury, poisoning and procedural complications
Contusion	3/53 (5.7%)		3/53 (5.7%)
Investigations
White blood cell count decreased	33/53 (62.3%)		31/53 (58.5%)
Neutrophil count decreased	28/53 (52.8%)		28/53 (52.8%)
Platelet count decreased	27/53 (50.9%)		21/53 (39.6%)
Haemoglobin decreased	13/53 (24.5%)		12/53 (22.6%)
Blood bilirubin increased	9/53 (17%)		11/53 (20.8%)
Haematocrit decreased	8/53 (15.1%)		8/53 (15.1%)
Red blood cell count decreased	8/53 (15.1%)		5/53 (9.4%)
Blood cholesterol decreased	7/53 (13.2%)		5/53 (9.4%)
Blood triglycerides increased	7/53 (13.2%)		7/53 (13.2%)
High density lipoprotein decreased	7/53 (13.2%)		1/53 (1.9%)
Alanine aminotransferase increased	6/53 (11.3%)		1/53 (1.9%)
Aspartate aminotransferase increased	6/53 (11.3%)		1/53 (1.9%)
Blood calcium decreased	6/53 (11.3%)		4/53 (7.5%)
Blood thyroid stimulating hormone increased	4/53 (7.5%)		1/53 (1.9%)
Bilirubin conjugated increased	3/53 (5.7%)		4/53 (7.5%)
Blood alkaline phosphatase increased	3/53 (5.7%)		0/53 (0%)
Lipase increased	3/53 (5.7%)		2/53 (3.8%)
Low density lipoprotein decreased	3/53 (5.7%)		1/53 (1.9%)
Weight decreased	3/53 (5.7%)		5/53 (9.4%)
Metabolism and nutrition disorders
Decreased appetite	12/53 (22.6%)		15/53 (28.3%)
Hypocalcaemia	3/53 (5.7%)		1/53 (1.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/53 (24.5%)		13/53 (24.5%)
Myalgia	7/53 (13.2%)		6/53 (11.3%)
Back pain	2/53 (3.8%)		6/53 (11.3%)
Musculoskeletal stiffness	0/53 (0%)		3/53 (5.7%)
Nervous system disorders
Headache	23/53 (43.4%)		23/53 (43.4%)
Dysgeusia	4/53 (7.5%)		6/53 (11.3%)
Dizziness	3/53 (5.7%)		1/53 (1.9%)
Psychiatric disorders
Insomnia	5/53 (9.4%)		10/53 (18.9%)
Respiratory, thoracic and mediastinal disorders
Cough	11/53 (20.8%)		4/53 (7.5%)
Oropharyngeal pain	4/53 (7.5%)		2/53 (3.8%)
Skin and subcutaneous tissue disorders
Alopecia	21/53 (39.6%)		15/53 (28.3%)
Rash	20/53 (37.7%)		23/53 (43.4%)
Pruritus	16/53 (30.2%)		12/53 (22.6%)
Dry skin	6/53 (11.3%)		4/53 (7.5%)
Erythema	2/53 (3.8%)		3/53 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days to allow for filing of a patent application.