A Phase III Study of TMC435 in Treatment-naive, Genotype 1, Hepatitis C-infected Patients

• Sponsor: Janssen Pharmaceutical K.K. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01292239
• Collaborator: (none)
• Enrollment: 183
• Locations: 28
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 6.5
• 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 compared with placebo in combination with peginterferon alfa-2a (pegIFN alfa-2a) and ribavirin in treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection in Japan.

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

Detailed Description

This is a randomized (study drug assigned by chance), 2-arm, double-blind study to evaluate the efficacy and safety of TMC435 (also referred to as jnj-38733214-aaa) versus placebo in combination with the standard of care (SoC) therapy (peginterferon alfa-2a [pegIFN alfa-2a] and ribavirin) in adult treatment-naïve patients (who never received treatment for HCV) with chronic genotype 1 HCV infection in Japan. The study objective is to evaluate and compare the efficacy of TMC435 vs placebo by the proportion of the patients with undetectable HCV ribonucleic acid (RNA). In the TMC435 treatment group, patients will receive 12 weeks of treatment with TMC435 (100 mg) once daily plus SoC followed by an additional 12 or 36 weeks of treatment with SoC. In the placebo treatment group, patients will receive 12 weeks of treatment with placebo once daily plus SoC followed by an additional 36 weeks of treatment with SoC. TMC435 is a 100-mg capsule and will be taken orally by mouth. The SoC treatment will be given for 24 or 48 weeks. Pegylated interferon is supplied as a vial containing 1.0 mL solution with 180 mcg pegIFN alpha-2a and administered subcutaneously (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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 183 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-blind, Placebo-controlled Trial in Japan to Investigate the Efficacy and Safety of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment-Naive, Genotype 1, Hepatitis C-infected Subjects
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMC435 100 mg 12 Wks + PR 24/48 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 for participants who achieved HCV RNA < 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.	Drug: TMC435; 100-mg capsule taken by mouth once daily for 12 weeks; Drug: Peginterferon alfa-2a (pegIFN alfa-2a); PegIFN alfa-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 for patients randomized to TMC435 and for up to 48 weeks for patients randomized to placebo.; 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: PBO 12 Wks + PR 48 Participants received placebo (PBO) once daily with PegIFNα-2a and ribavirin (PR) for 12 weeks (Wks) followed by PR until Week 48.	Drug: Placebo; Placebo capsule taken by mouth once daily for 12 weeks; Drug: Peginterferon alfa-2a (pegIFN alfa-2a); PegIFN alfa-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 for patients randomized to TMC435 and for up to 48 weeks for patients randomized to placebo.; 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 (up to Week 24 or 48) and 12 weeks after the EOT (up to Week 36 or 60)]

   The table below shows the observed percentage of participants with a SVR12 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) at 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 at the End of Treatment (EOT) and 24 Weeks After the Last Dose of Treatment (SVR24) [EOT (up to Week 24 or 48) and 24 weeks after the after the last dose of treatment (up to Week 48 or 72)]

   The table below shows the observed percentage of participants with a SVR24 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) at the end of treatment (EOT, defined as up to Week 24 or 48) and at 24 weeks after the last dose of treatment (up to 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, 42, 48, 52, 60, 72, EOT (up to Week 24 or 48), FU Week 4, 12, and 24]

   The table below shows the percentage of participants with greater than (>) or equal to (=) 2 log10 IU/mL drop from baseline in plasma levels of HCV RNA at each time point during treatment and post-treatment follow-up (FU).

3. The Percentage of Participants With Undetectable Plasma Levels of 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 (up to Week 24 or 48)]

   The table below shows the percentage of participants with undetectable plasma levels of HCV RNA <1.2 log10 IU/mL during treatment at Weeks 4, 12, 24, 36, 48, 60, 72, and at the EOT (up to Week 24 or 48).

4. The Number of Participants With Viral Breakthrough [Up to EOT (up to Week 24 or 48)]

   Viral breakthrough was defined as a confirmed increase of > 1 log10 IU/mL in plasma levels of hepatitis C virus (HCV) ribonucleic acid (RNA)l from the lowest level reached or a confirmed value of plasma HCV RNA of > 2.0 log10 IU/mL in participants whose plasma HCV RNA level had previously been below 1.2 log10 IU/mL detectable or undetectable during the treatment period (up to the end of treatment [EOT]).

5. The Number of Participants Demonstrating Viral Relapse [Up to Week 72]

   The table below shows the number of participants who demonstrated viral relapse, defined as undetectable plasma levels of hepatitis C virus (HCV) ribonucleic acid (RNA) at the End of Treatment (EOT) (up to Week 24 or 48) and detectable HCV RNA during follow-up or detectable plasma levels of HCV RNA at the time points of sustained virologic response (SVR) assessment. The incidence of viral relapse was only calculated for participants with undetectable plasma levels of HCV RNA at the EOT and with at least one follow-up HCV RNA. measurement.

6. The Number of Participants With Abnormal Alanine Aminotransferase (ALT) Levels at Baseline Who Achieved Normal ALT Levels at the End of Treatment (EOT) [Baseline (Day 1) to EOT (up to Week 24 or 48)]

   The table below shows the number of participants with abnormal ALT levels at Baseline (Day 1) who achieved normal ALT levels at the EOT (up to Week 24 or 48). At Baseline, 61/123 participants in the TMC435 treatment group and 25/60 participants in the Placebo treatment group had abnormal ALT levels. At the EOT, 47 (77.0%) participants in the TMC435 treatment group and 18 (72.0%) participants in the Placebo treatment group had ALT levels that returned to normal (or normalization of ALT levels defined as an ALT value less than or equal to the Upper Limit of Normality [ie, 40 IU/mL] at EOT.).

7. The Percentage of Participants in the TMC435 Treatment Group Who Met Response Guided Treatment (RGT) Criteria and Completed Treatment With Peginterferon Alpha-2a (PegIFN Alpha-2a) and Ribavirin (RBV) at Week 24 [Week 24]

   The table below shows the percentage of participants in the TMC435 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 pegIFN alpha 2a and RBV at Week 24. Participants in the TMC435 treatment group not meeting RGT criteria and participants in the placebo group continued treatment with PegIFN alpha 2a and RBV to Week 48.

8. Plasma Concentrations of TMC435 [Overall (ie, Up to Week 12)]

   The table below shows median (range) predose plasma concentration (C0h) values and median (range) maximum plasma concentration (Cmax) values for TMC435 for all participants in the TMC435 treatment group. The time frame of "Overall" (up to Week 12) represents the median exposure estimate using all available data for each participant in the study.

9. Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24h) for TMC435 [Overall (Up to Week 12)]

   The table below shows the median (range) AUC24h values for TMC435 for all participants in the TMC435 treatment group who received TMC435 for up to 12 weeks. The time frame of "Overall" (up to Week 12) represents the median exposure estimate using all available data for each participant in the study.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patient must have chronic genotype 1 HCV infection with HCV RNA level >= 5.0 log10 IU/mL

• Patient has never received treatment for HCV

• Patient 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 pegIFN 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		Chiba		Japan
3		Chuo		Japan
4		Hiroshima		Japan
5		Ichikawa		Japan
6		Ikeda		Japan
7		Inashiki		Japan
8		Iruma		Japan
9		Kagoshima		Japan
10		Kanazawa		Japan
11		Kitakyushu		Japan
12		Kumamoto		Japan
13		Kurume		Japan
14		Kyoto		Japan
15		Matsumoto		Japan
16		Musashino		Japan
17		Nagoya		Japan
18		Niigata		Japan
19		Nishinomiya		Japan
20		Ohmura		Japan
21		Osaka-Sayama		Japan
22		Osaka		Japan
23		Sakai		Japan
24		Sapporo		Japan
25		Sendai		Japan
26		Tokyo		Japan
27		Touon		Japan
28		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: NCT01292239
• Other Study ID Numbers: CR017686; TMC435HPC3003
• First Posted: Feb 9, 2011
• Last Update Posted: Jan 17, 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 17-January-2011 and 22-October-2012 and recruited participants with chronic genotype 1 Hepatitis C Virus (HCV) infection who were treatment-naïve from 37 study centers in Japan. A total 183 participants were randomized and started treatment; 172 completed the study.
Pre-assignment Detail	Treatment-naïve HCV-infected participants were assigned to 1 of 2 groups to receive TMC435 100 mg once daily with PegIFN alpha-2a and ribavirin (PR) until Week 12, followed by PR until Week 24 or 48 OR placebo with PR until Week 12, followed by PR until Week 48.

Arm/Group Title	TMC435 100 mg 12 Wks + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Period Title: Overall Study
STARTED	123	60
COMPLETED	119	53
NOT COMPLETED	4	7

Baseline Characteristics

Arm/Group Title	TMC435 100 mg 12 Wks + PR 24/48	PBO 12 Wks + PR 48	Total
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).	Total of all reporting groups
Overall Participants	123	60	183
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56	54.5	55
Sex: Female, Male (Count of Participants)
Female	84 68.3%	36 60%	120 65.6%
Male	39 31.7%	24 40%	63 34.4%

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 with a SVR12 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) at EOT (Week 24 or 48) and at 12 weeks after the last dose of treatment (Week 36 or 60).
Time Frame	EOT (up to Week 24 or 48) and 12 weeks after the EOT (up to 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	123	60
Number [Percentage of participants]	88.6 72%	61.7 102.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMC435 100 mg 12 Wks + PR 24/48, PBO 12 Wks + PR 48
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The p-value was based on the asymptomatic distribution of the generalized Cochran-Mantel-Haenszel (CMH) statistic controlling for stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments	The Cochran-Mantel-Haenszel test was adjusted for stratification factors (age and IL28B genotype).
Method of Estimation	Estimation Parameter	(see comment)
	Estimated Value	27.5
	Confidence Interval	(2-Sided) 95%; 14.38 to 40.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	The parameter estimated was the difference of stratum adjusted proportion between groups.

2. Secondary Outcome

Title	The Percentage of Participants With a Sustained Virologic Response at 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 with a SVR24 defined as undetectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) at the end of treatment (EOT, defined as up to Week 24 or 48) and at 24 weeks after the last dose of treatment (up to Week 48 or 72).
Time Frame	EOT (up to Week 24 or 48) and 24 weeks after the after the last dose of treatment (up to 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	123	60
Number [Percentage of participants]	88.6 72%	56.7 94.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMC435 100 mg 12 Wks + PR 24/48, PBO 12 Wks + PR 48
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The p-value was based on the asymptomatic distribution of the generalized Cochran-Mantel-Haenszel (CMH) statistic controlling for stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments	The Cochran-Mantel-Haenszel test was adjusted for stratification factors (age and IL28B genotype).
Method of Estimation	Estimation Parameter	(see comment)
	Estimated Value	32.6
	Confidence Interval	(2-Sided) 95%; 19.75 to 45.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	The parameter estimated was the difference of stratum adjusted proportion between groups.

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 with greater than (>) or equal to (=) 2 log10 IU/mL drop from baseline in plasma levels of HCV RNA at each time point during treatment and post-treatment follow-up (FU).
Time Frame	Day 3, Day 7 and Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 36, 42, 48, 52, 60, 72, EOT (up to Week 24 or 48), FU Week 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	123	60
Day 3	98.4 80%	26.7 44.5%
Day 7	99.2 80.7%	46.7 77.8%
Week 2	100.0 81.3%	58.3 97.2%
Week 3	100.0 81.3%	71.7 119.5%
Week 4	99.2 80.7%	76.7 127.8%
Week 8	100.0 81.3%	88.3 147.2%
Week 12	97.6 79.3%	88.3 147.2%
Week 16	95.1 77.3%	88.3 147.2%
Week 20	95.9 78%	86.7 144.5%
Week 24	92.7 75.4%	83.3 138.8%
Week 28	94.3 76.7%	80.0 133.3%
Week 36	87.8 71.4%	80.0 133.3%
Week 42	2.4 2%	76.7 127.8%
Week 48	86.2 70.1%	75.0 125%
Week 52	0.0 0%	71.7 119.5%
Week 60	88.6 72%	65.0 108.3%
Week 72	88.6 72%	58.3 97.2%
EOT (up to Week 24 or 48)	99.2 80.7%	96.7 161.2%
FU Week 4	96.7 78.6%	83.3 138.8%
FU Week 12	89.4 72.7%	65.0 108.3%
FU Week 24	88.6 72%	58.3 97.2%

4. Secondary Outcome

Title	The Percentage of Participants With Undetectable Plasma Levels of 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 plasma levels of HCV RNA <1.2 log10 IU/mL during treatment at Weeks 4, 12, 24, 36, 48, 60, 72, and at the EOT (up to Week 24 or 48).
Time Frame	Weeks 4, 12, 24, 36, 48, 60, 72, and at EOT (up to 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	123	60
Week 4	83.7 68%	13.3 22.2%
Week 12	96.7 78.6%	63.3 105.5%
Week 24	91.9 74.7%	73.3 122.2%
Week 36	87.0 70.7%	71.7 119.5%
Week 48	86.2 70.1%	75.0 125%
Week 60	88.6 72%	61.7 102.8%
Week 72	88.6 72%	56.7 94.5%
EOT (up to Week 24 or 48)	99.2 80.7%	88.3 147.2%

5. Secondary Outcome

Title	The Number of Participants With Viral Breakthrough
Description	Viral breakthrough was defined as a confirmed increase of > 1 log10 IU/mL in plasma levels of hepatitis C virus (HCV) ribonucleic acid (RNA)l from the lowest level reached or a confirmed value of plasma HCV RNA of > 2.0 log10 IU/mL in participants whose plasma HCV RNA level had previously been below 1.2 log10 IU/mL detectable or undetectable during the treatment period (up to the end of treatment [EOT]).
Time Frame	Up to EOT (up to 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	123	60
Number [Participants]	1 0.8%	2 3.3%

6. Secondary Outcome

Title	The Number of Participants Demonstrating Viral Relapse
Description	The table below shows the number of participants who demonstrated viral relapse, defined as undetectable plasma levels of hepatitis C virus (HCV) ribonucleic acid (RNA) at the End of Treatment (EOT) (up to Week 24 or 48) and detectable HCV RNA during follow-up or detectable plasma levels of HCV RNA at the time points of sustained virologic response (SVR) assessment. The incidence of viral relapse was only calculated for participants with undetectable plasma levels of HCV RNA at the EOT and with at least one follow-up HCV RNA. measurement.
Time Frame	Up to Week 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	118	49
Number [Participants]	9 7.3%	15 25%

7. Secondary Outcome

Title	The Number of 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 with abnormal ALT levels at Baseline (Day 1) who achieved normal ALT levels at the EOT (up to Week 24 or 48). At Baseline, 61/123 participants in the TMC435 treatment group and 25/60 participants in the Placebo treatment group had abnormal ALT levels. At the EOT, 47 (77.0%) participants in the TMC435 treatment group and 18 (72.0%) participants in the Placebo treatment group had ALT levels that returned to normal (or normalization of ALT levels defined as an ALT value less than or equal to the Upper Limit of Normality [ie, 40 IU/mL] at EOT.).
Time Frame	Baseline (Day 1) to EOT (up to 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 + PR 24/48	PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).	Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
Measure Participants	61	25
Number [Participants]	47 38.2%	18 30%

8. Secondary Outcome

Title	The Percentage of Participants in the TMC435 Treatment Group Who Met Response Guided Treatment (RGT) Criteria and Completed Treatment With Peginterferon Alpha-2a (PegIFN Alpha-2a) and Ribavirin (RBV) at Week 24
Description	The table below shows the percentage of participants in the TMC435 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 pegIFN alpha 2a and RBV at Week 24. Participants in the TMC435 treatment group not meeting RGT criteria and participants in the placebo group continued treatment with PegIFN alpha 2a and RBV to Week 48.
Time Frame	Week 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 + PR 24/48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).
Measure Participants	123
Number [Percentage of participants]	91.9 74.7%

9. Secondary Outcome

Title	Plasma Concentrations of TMC435
Description	The table below shows median (range) predose plasma concentration (C0h) values and median (range) maximum plasma concentration (Cmax) values for TMC435 for all participants in the TMC435 treatment group. The time frame of "Overall" (up to Week 12) represents the median exposure estimate using all available data for each participant in the study.
Time Frame	Overall (ie, Up to Week 12)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis was performed in the 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 + PR 24/48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).
Measure Participants	123
C0h	1005
Cmax	2601

10. 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 TMC435 for all participants in the TMC435 treatment group who received TMC435 for up to 12 weeks. The time frame of "Overall" (up to Week 12) represents the median exposure estimate using all available data for each participant in the study.
Time Frame	Overall (Up to Week 12)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis was performed in the 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 + PR 24/48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).
Measure Participants	123
Median (Full Range) [ng.h/mL]	42721

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		PBO 12 Wks + PR 48
Arm/Group Description	Participants were given TMC435 100 mg once daily plus peginterferon alpha-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 24 (PR24). Treatment was to be stopped at Week 24 for participants who achieved plasma levels of Hepatitis C virus ribonucleic acid (HCV RNA) < 1.2 log10 IU/mL detectable or undetectable at Week 4 and undetectable HCV RNA at Week 12. Other participants continued PR until Week 48 (PR48).		Participants were given placebo (PBO) once daily plus peginterferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFNα-2a (P) and RBV (R) until Week 48 (PR 48).
All Cause Mortality
	TMC435 100 mg 12 Wks + PR 24/48		PBO 12 Wks + PR 48
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TMC435 100 mg 12 Wks + PR 24/48		PBO 12 Wks + PR 48
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/123 (3.3%)		6/60 (10%)
Cardiac disorders
Cardiac failure	1/123 (0.8%)		0/60 (0%)
Ear and labyrinth disorders
Vertigo positional	0/123 (0%)		1/60 (1.7%)
General disorders
Malaise	0/123 (0%)		1/60 (1.7%)
Hepatobiliary disorders
Hepatic mass	0/123 (0%)		1/60 (1.7%)
Infections and infestations
Peritonitis	1/123 (0.8%)		0/60 (0%)
Musculoskeletal and connective tissue disorders
Inclusion body myositis	0/123 (0%)		1/60 (1.7%)
Intervertebral disc protrusion	0/123 (0%)		1/60 (1.7%)
Nervous system disorders
Dizziness	0/123 (0%)		1/60 (1.7%)
Headache	0/123 (0%)		1/60 (1.7%)
Renal and urinary disorders
Glomerulonephritis membranous	1/123 (0.8%)		0/60 (0%)
Skin and subcutaneous tissue disorders
Erythema	2/123 (1.6%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	TMC435 100 mg 12 Wks + PR 24/48		PBO 12 Wks + PR 48
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	123/123 (100%)		60/60 (100%)
Blood and lymphatic system disorders
Anaemia	70/123 (56.9%)		36/60 (60%)
Neutropenia	8/123 (6.5%)		1/60 (1.7%)
Leukopenia	7/123 (5.7%)		3/60 (5%)
Thrombocytopenia	5/123 (4.1%)		3/60 (5%)
Ear and labyrinth disorders
Vertigo	8/123 (6.5%)		0/60 (0%)
Eye disorders
Retinal exudates	7/123 (5.7%)		2/60 (3.3%)
Retinal haemorrhage	7/123 (5.7%)		1/60 (1.7%)
Retinopathy	7/123 (5.7%)		5/60 (8.3%)
Dry eye	1/123 (0.8%)		3/60 (5%)
Gastrointestinal disorders
Stomatitis	28/123 (22.8%)		12/60 (20%)
Diarrhoea	20/123 (16.3%)		17/60 (28.3%)
Abdominal discomfort	16/123 (13%)		5/60 (8.3%)
Nausea	16/123 (13%)		12/60 (20%)
Constipation	9/123 (7.3%)		5/60 (8.3%)
Vomiting	6/123 (4.9%)		5/60 (8.3%)
Abdominal pain upper	5/123 (4.1%)		6/60 (10%)
Cheilitis	4/123 (3.3%)		3/60 (5%)
Abdominal pain	2/123 (1.6%)		5/60 (8.3%)
Gingivitis	2/123 (1.6%)		3/60 (5%)
Toothache	1/123 (0.8%)		3/60 (5%)
General disorders
Pyrexia	75/123 (61%)		31/60 (51.7%)
Malaise	52/123 (42.3%)		27/60 (45%)
Injection site reaction	22/123 (17.9%)		9/60 (15%)
Fatigue	13/123 (10.6%)		7/60 (11.7%)
Injection site erythema	4/123 (3.3%)		6/60 (10%)
Administration site reaction	3/123 (2.4%)		3/60 (5%)
Hepatobiliary disorders
Hyperbilirubinaemia	8/123 (6.5%)		2/60 (3.3%)
Infections and infestations
Nasopharyngitis	21/123 (17.1%)		17/60 (28.3%)
Gastroenteritis	1/123 (0.8%)		3/60 (5%)
Investigations
White blood cell count decreased	78/123 (63.4%)		41/60 (68.3%)
Neutrophil count decreased	69/123 (56.1%)		37/60 (61.7%)
Platelet count decreased	60/123 (48.8%)		23/60 (38.3%)
Haemoglobin decreased	27/123 (22%)		9/60 (15%)
Blood bilirubin increased	20/123 (16.3%)		4/60 (6.7%)
Blood triglycerides increased	17/123 (13.8%)		5/60 (8.3%)
Haematocrit decreased	16/123 (13%)		8/60 (13.3%)
Red blood cell count decreased	13/123 (10.6%)		6/60 (10%)
Lipase increased	9/123 (7.3%)		1/60 (1.7%)
Weight decreased	9/123 (7.3%)		8/60 (13.3%)
Metabolism and nutrition disorders
Decreased appetite	28/123 (22.8%)		20/60 (33.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	30/123 (24.4%)		14/60 (23.3%)
Back pain	9/123 (7.3%)		9/60 (15%)
Myalgia	9/123 (7.3%)		11/60 (18.3%)
Arthritis	0/123 (0%)		3/60 (5%)
Nervous system disorders
Headache	54/123 (43.9%)		26/60 (43.3%)
Dysgeusia	20/123 (16.3%)		8/60 (13.3%)
Dizziness	4/123 (3.3%)		4/60 (6.7%)
Psychiatric disorders
Insomnia	27/123 (22%)		25/60 (41.7%)
Depression	0/123 (0%)		3/60 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	11/123 (8.9%)		8/60 (13.3%)
Oropharyngeal pain	6/123 (4.9%)		5/60 (8.3%)
Skin and subcutaneous tissue disorders
Rash	57/123 (46.3%)		37/60 (61.7%)
Alopecia	44/123 (35.8%)		28/60 (46.7%)
Pruritus	35/123 (28.5%)		18/60 (30%)
Erythema	17/123 (13.8%)		4/60 (6.7%)
Eczema	10/123 (8.1%)		4/60 (6.7%)
Dry skin	8/123 (6.5%)		9/60 (15%)
Seborrhoeic dermatitis	2/123 (1.6%)		5/60 (8.3%)

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.