An Efficacy, Pharmacokinetics, Safety and Tolerability Study of TMC435 as Part of a Treatment Regimen for Hepatitis C-Infected Patients

• Sponsor: Janssen R&D Ireland (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01725529
• Collaborator: (none)
• Enrollment: 457
• Locations: 21
• Arms: 3
• Duration (Months): 24
• Patients Per Site: 21.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to provide confirmatory efficacy and safety data of TMC435 as part of a treatment regimen including peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) in patients with genotype 1 Hepatitis C virus (HCV) infection.

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

Detailed Description

This is a multicenter, randomized (study drug is assigned by chance), double-blind (neither sponsor, physician nor patient knows the name of the assigned study drug), Phase III study to compare the efficacy, tolerability and safety of TMC435 (in development for treatment of chronic hepatitis C virus [HCV] infection) versus placebo (a preparation containing no drug used as control) as part of a treatment regimen including peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) (both current therapies for HCV) in adult treatment-naïve patients (patients who have never taken HCV medications) with genotype 1 Hepatitis C virus (HCV) infection. The study will consist of a screening period with a maximum duration of 6 weeks, a response guided 24- or 48-week (TMC435 treatment groups) or 48-week (control group) treatment period, and a post-therapy follow-up period up to 72 weeks after the start of treatment. Patients will be randomly assigned in a 1:1:1 fashion to receive TMC435 or placebo, stratified by HCV genotype 1 subtype and IL28B genotype within each country. In the first 24 weeks, patients will receive 12 weeks TMC435 100 or 150 mg or placebo once-daily (q.d.) plus PegIFNα-2a plus RBV, after which they will continue with PegIFNα-2a and RBV. Response-guided treatment criteria will be used to determine PegIFNα-2a and RBV total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. In the control group, all patients will be required to complete 48 weeks of treatment with PegIFNα-2a and RBV. In all 3 treatment groups, there will be a post-therapy follow-up period up to 72 weeks after the start of treatment. The total study duration for each patient will be a maximum of 78 weeks (including the 6-week screening period).

Study Design

• Study Type: Interventional
• Actual Enrollment: 457 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve, Genotype 1 Hepatitis C-Infected Subjects
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMC435 150 mg Patients will receive 12 weeks TMC435 150 mg once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV), followed by PegIFNα-2a and RBV alone. Response-guided treatment criteria will be used to determine total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. Patients in the control group will continue to receive treatment with PegIFNα-2a and RBV until Week 48.	Drug: TMC435; TMC435 100 mg or 150 mg capsules taken orally (by mouth) with food once-daily for 12 weeks (Week 12).; Drug: Peginterferon-alpha (PegIFNα-2a); PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.; Drug: Ribavirin (RBV); Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.
Experimental: TMC435 100 mg Patients will receive 12 weeks TMC435 100 mg once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV), followed by PegIFNα-2a and RBV alone. Response-guided treatment criteria will be used to determine total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. Patients in the control group will continue PegIFNα-2a and RBV until Week 48.	Drug: TMC435; TMC435 100 mg or 150 mg capsules taken orally (by mouth) with food once-daily for 12 weeks (Week 12).; Drug: Peginterferon-alpha (PegIFNα-2a); PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.; Drug: Ribavirin (RBV); Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.
Placebo Comparator: Control Patients will receive placebo once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) for 48 weeks.	Drug: Peginterferon-alpha (PegIFNα-2a); PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.; Drug: Ribavirin (RBV); Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.; Drug: Placebo; Matching placebo capsules taken orally with food once-daily for 48 weeks.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12) [12 weeks after the end of treatment (EOT: Week 24 or 48)]

   Participants considered to have achieved SVR12 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ; 25 international unit per milliliter [IU/mL]) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 12 weeks after the planned end of study drug treatment.

Secondary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Study Drug Treatment (SVR24) [24 weeks after the end of treatment (EOT: Week 24 or 48)]

   Participants considered to have achieved SVR24 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ;25 IU/mL) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 24 weeks after the planned end of study drug treatment.

2. Percentage of Participants With Sustained Virologic Response at Week 72 (SVRW72) [Week 72]

3. Percentage of Participants With On-treatment Failure [End of Treatment (EOT: Week 24 or 48)]

   A participant with on-treatment failure refers to a participant with confirmed detectable HCV RNA at the end of treatment.

4. Percentage of Participants With Viral Breakthrough [Week 24 or 48 (End of Treatment)]

   The number of patients who experience viral breakthrough will be determined by measuring Hepatitis C virus (HCV) ribonucleic acid (RNA) levels in plasma. Viral breakthrough was defined as a confirmed increase of >1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of >100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (<25 IU/mL detectable) or undetectable (<25 IU/mL undetectable) while on study treatment.

5. Percentage of Participants With Viral Relapse [72 weeks after the EOT (Week 24 or 48)]

   Viral relapse was defined as undetectable HCV RNA at the actual end of treatment and last HCV RNA measurement during follow-up ≥25 IU/mL.

6. Percentage of Participants With On-treatment Normalization of Alanine Aminotransferase Level [72 weeks after the EOT (Week 24 or 48)]

   Percentage of participants with on-treatment normalization of alanine aminotransferase level were assessed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A liver biopsy within 3 years prior to the screening visit (or between screening and day of randomization) with histology consistent with chronic Hepatitis C virus (HCV) infection

• Presence of contraindications for a liver biopsy in patients who are otherwise deemed eligible for participation does not exclude the patient from participation

• Genotype 1 HCV infection (confirmed at screening)

• Plasma HCV RNA of > 10,000 IU/mL at screening

Exclusion Criteria:

• Prior treatment with any approved or investigational drug for the treatment of hepatitis C

• Co-infection with hepatitis B virus or human immunodeficiency virus (HIV)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Beijing		China
2		Changchun		China
3		Changsha		China
4		Chengdu		China
5		Chongqing		China
6		Guangzhou		China
7		Hangzhou		China
8		Harbin		China
9		Jinan		China
10		Lanzhou		China
11		Nanjing		China
12		Shanghai		China
13		Shenyang		China
14		Tianjin		China
15		Wuhan		China
16		Zhengzhou		China
17		Busan		Korea, Republic of
18		Chuncheon, Gangwon-Do		Korea, Republic of
19		Gyeongsangnam-Do		Korea, Republic of
20		Incheon		Korea, Republic of
21		Seoul		Korea, Republic of

Sponsors and Collaborators

• Janssen R&D Ireland

Investigators

• Study Director: Janssen R&D Ireland Clinical Trial, Janssen R&D Ireland

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen R&D Ireland
• ClinicalTrials.gov Identifier: NCT01725529
• Other Study ID Numbers: CR017962; TMC435HPC3005
• First Posted: Nov 14, 2012
• Last Update Posted: Aug 13, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by Janssen R&D Ireland: Hepatitis C, Chronic; TMC435; Ribavirin; peginterferon-alpha (PegIFNα-2a)
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Ribavirin; Simeprevir

Study Results

Participant Flow

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Period Title: Overall Study
STARTED	152	153	152
COMPLETED	137	137	142
NOT COMPLETED	15	16	10

Baseline Characteristics

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg	Total
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Total of all reporting groups
Overall Participants	152	153	152	457
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	45	45	44	45
Sex: Female, Male (Count of Participants)
Female	79 52%	67 43.8%	75 49.3%	221 48.4%
Male	73 48%	86 56.2%	77 50.7%	236 51.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12)
Description	Participants considered to have achieved SVR12 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ; 25 international unit per milliliter [IU/mL]) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 12 weeks after the planned end of study drug treatment.
Time Frame	12 weeks after the end of treatment (EOT: Week 24 or 48)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all the randomized participants who took at least 1 dose of study drug.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	152	153	152
Number [Percentage of participants]	75.7 49.8%	88.9 58.1%	90.8 59.7%

2. Secondary Outcome

Title	Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Study Drug Treatment (SVR24)
Description	Participants considered to have achieved SVR24 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ;25 IU/mL) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 24 weeks after the planned end of study drug treatment.
Time Frame	24 weeks after the end of treatment (EOT: Week 24 or 48)

Outcome Measure Data

Analysis Population Description

ITT population included all the randomized participants who took at least 1 dose of study drug.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	152	153	152
Number [percentage of participants]	75.0 49.3%	88.9 58.1%	90.8 59.7%

3. Secondary Outcome

Title	Percentage of Participants With Sustained Virologic Response at Week 72 (SVRW72)
Time Frame	Week 72

Outcome Measure Data

Analysis Population Description

ITT population included all the randomized participants who took at least 1 dose of study drug. 'N' (number of participants analyzed) signifies those participants who were analyzed for this measure.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	152	153	152
Number [percentage of participants]	75.0 49.3%	87.6 57.3%	90.1 59.3%

4. Secondary Outcome

Title	Percentage of Participants With On-treatment Failure
Description	A participant with on-treatment failure refers to a participant with confirmed detectable HCV RNA at the end of treatment.
Time Frame	End of Treatment (EOT: Week 24 or 48)

Outcome Measure Data

Analysis Population Description

ITT population included all the randomized participants who took at least 1 dose of study drug.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	152	153	152
Number [percentage of participants]	12.5 8.2%	3.3 2.2%	3.3 2.2%

5. Secondary Outcome

Title	Percentage of Participants With Viral Breakthrough
Description	The number of patients who experience viral breakthrough will be determined by measuring Hepatitis C virus (HCV) ribonucleic acid (RNA) levels in plasma. Viral breakthrough was defined as a confirmed increase of >1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of >100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (<25 IU/mL detectable) or undetectable (<25 IU/mL undetectable) while on study treatment.
Time Frame	Week 24 or 48 (End of Treatment)

Outcome Measure Data

Analysis Population Description

ITT population included all the randomized participants who took at least 1 dose of study drug. 'N' (number of participants analyzed) signifies those participants who were analyzed for this measure.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	152	153	151
Number [percentage of participants]	2.0 1.3%	2.6 1.7%	2.6 1.7%

6. Secondary Outcome

Title	Percentage of Participants With Viral Relapse
Description	Viral relapse was defined as undetectable HCV RNA at the actual end of treatment and last HCV RNA measurement during follow-up ≥25 IU/mL.
Time Frame	72 weeks after the EOT (Week 24 or 48)

Outcome Measure Data

Analysis Population Description

ITT population included all the randomized participants who took at least 1 dose of study drug. 'N' (number of participants analyzed) signifies those participants who were analyzed for this measure.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	131	142	141
Number [percentage of participants]	11.5 7.6%	1.4 0.9%	2.8 1.8%

7. Secondary Outcome

Title	Percentage of Participants With On-treatment Normalization of Alanine Aminotransferase Level
Description	Percentage of participants with on-treatment normalization of alanine aminotransferase level were assessed.
Time Frame	72 weeks after the EOT (Week 24 or 48)

Outcome Measure Data

Analysis Population Description

ITT population included all the randomized participants who took at least 1 dose of study drug. 'N' (number of participants analyzed) signifies those participants who were analyzed for this measure.

Arm/Group Title	Placebo	Simeprevir (TMC435) 100mg	Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.	Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.	Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
Measure Participants	91	79	89
Number [percentage of participants]	85.7 56.4%	86.1 56.3%	89.9 59.1%

Adverse Events

Time Frame	up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Arm/Group Title	Placebo		Simeprevir (TMC435) 100mg		Simeprevir (TMC435) 150mg
Arm/Group Description	Participants received placebo matching to TMC435 100 milligram (mg) and TMC435 150 mg for 12 weeks once daily (q.d.) plus peginterferon-alpha (PegIFNa-2a) and ribavirin (RBV) for 48 weeks.		Participants received TMC435 100 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 150 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.		Participants received TMC435 150 mg once daily (q.d.) for 12 weeks plus peginterferon-alpha (PegIFNα-2a), ribavirin (RBV) and Placebo matching to TMC435 100 mg, followed by PegIFNα-2a and RBV alone. Response-guided treatment criterion was used to determine total treatment duration of 24 or 48 weeks for participants in the TMC435 treatment groups.
All Cause Mortality
	Placebo		Simeprevir (TMC435) 100mg		Simeprevir (TMC435) 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Simeprevir (TMC435) 100mg		Simeprevir (TMC435) 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/152 (5.9%)		5/153 (3.3%)		5/152 (3.3%)
Blood and lymphatic system disorders
Anaemia	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Cardiac disorders
Angina unstable	0/152 (0%)		1/153 (0.7%)		0/152 (0%)
Supraventricular tachycardia	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Gastrointestinal disorders
Colitis ischaemic	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
General disorders
Non-cardiac chest pain	0/152 (0%)		1/153 (0.7%)		0/152 (0%)
Pain	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Hepatobiliary disorders
Cholelithiasis	1/152 (0.7%)		0/153 (0%)		1/152 (0.7%)
Infections and infestations
Incision site infection	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Atypical pneumonia	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Chronic hepatitis C	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Pulmonary tuberculosis	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Foot fracture	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Meniscus lesion	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Multiple injuries	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Rib fracture	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Tibia fracture	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Traumatic lung injury	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Wound	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Contusion	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Ligament sprain	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Metabolism and nutrition disorders
Cholesterosis	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Type 2 diabetes mellitus	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Decreased appetite	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Musculoskeletal and connective tissue disorders
Undifferentiated connective tissue disease	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	1/152 (0.7%)		0/153 (0%)		0/152 (0%)
Psychiatric disorders
Depression	0/152 (0%)		1/153 (0.7%)		0/152 (0%)
Renal and urinary disorders
Nephrolithiasis	0/152 (0%)		1/153 (0.7%)		0/152 (0%)
Ureteric stenosis	0/152 (0%)		1/153 (0.7%)		0/152 (0%)
Vascular disorders
Shock haemorrhagic	0/152 (0%)		0/153 (0%)		1/152 (0.7%)
Other (Not Including Serious) Adverse Events
	Placebo		Simeprevir (TMC435) 100mg		Simeprevir (TMC435) 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	149/152 (98%)		149/153 (97.4%)		149/152 (98%)
Blood and lymphatic system disorders
Anaemia	53/152 (34.9%)		38/153 (24.8%)		44/152 (28.9%)
Neutropenia	32/152 (21.1%)		28/153 (18.3%)		31/152 (20.4%)
Thrombocytopenia	22/152 (14.5%)		20/153 (13.1%)		15/152 (9.9%)
Leukopenia	16/152 (10.5%)		13/153 (8.5%)		16/152 (10.5%)
Ear and labyrinth disorders
Vertigo	10/152 (6.6%)		1/153 (0.7%)		7/152 (4.6%)
Endocrine disorders
Hypothyroidism	9/152 (5.9%)		3/153 (2%)		6/152 (3.9%)
Gastrointestinal disorders
Nausea	10/152 (6.6%)		8/153 (5.2%)		8/152 (5.3%)
Diarrhoea	7/152 (4.6%)		4/153 (2.6%)		10/152 (6.6%)
Abdominal pain upper	10/152 (6.6%)		4/153 (2.6%)		9/152 (5.9%)
General disorders
Pyrexia	46/152 (30.3%)		29/153 (19%)		38/152 (25%)
Fatigue	36/152 (23.7%)		35/153 (22.9%)		28/152 (18.4%)
Influenza like illness	19/152 (12.5%)		20/153 (13.1%)		19/152 (12.5%)
Asthenia	7/152 (4.6%)		8/153 (5.2%)		7/152 (4.6%)
Hepatobiliary disorders
Hyperbilirubinaemia	4/152 (2.6%)		14/153 (9.2%)		10/152 (6.6%)
Infections and infestations
Upper respiratory tract infection	12/152 (7.9%)		4/153 (2.6%)		13/152 (8.6%)
Nasopharyngitis	10/152 (6.6%)		2/153 (1.3%)		5/152 (3.3%)
Investigations
Neutrophil count decreased	94/152 (61.8%)		87/153 (56.9%)		84/152 (55.3%)
White blood cell count decreased	81/152 (53.3%)		77/153 (50.3%)		80/152 (52.6%)
Platelet count decreased	63/152 (41.4%)		57/153 (37.3%)		73/152 (48%)
Haemoglobin decreased	57/152 (37.5%)		46/153 (30.1%)		47/152 (30.9%)
Blood bilirubin increased	27/152 (17.8%)		31/153 (20.3%)		54/152 (35.5%)
Bilirubin conjugated increased	5/152 (3.3%)		10/153 (6.5%)		33/152 (21.7%)
Red blood cell count decreased	25/152 (16.4%)		23/153 (15%)		20/152 (13.2%)
Lymphocyte count decreased	20/152 (13.2%)		19/153 (12.4%)		18/152 (11.8%)
Haematocrit decreased	19/152 (12.5%)		17/153 (11.1%)		17/152 (11.2%)
Alanine aminotransferase increased	27/152 (17.8%)		14/153 (9.2%)		19/152 (12.5%)
Blood bilirubin unconjugated increased	8/152 (5.3%)		11/153 (7.2%)		21/152 (13.8%)
Aspartate aminotransferase increased	24/152 (15.8%)		12/153 (7.8%)		15/152 (9.9%)
Monocyte count decreased	11/152 (7.2%)		12/153 (7.8%)		13/152 (8.6%)
Blood calcium decreased	9/152 (5.9%)		9/153 (5.9%)		9/152 (5.9%)
Neutrophil percentage decreased	5/152 (3.3%)		10/153 (6.5%)		8/152 (5.3%)
Low density lipoprotein decreased	5/152 (3.3%)		6/153 (3.9%)		11/152 (7.2%)
Mean cell haemoglobin concentration decreased	9/152 (5.9%)		9/153 (5.9%)		8/152 (5.3%)
Mean cell volume increased	9/152 (5.9%)		10/153 (6.5%)		7/152 (4.6%)
Blood cholesterol decreased	6/152 (3.9%)		6/153 (3.9%)		9/152 (5.9%)
Blood lactate dehydrogenase increased	10/152 (6.6%)		4/153 (2.6%)		6/152 (3.9%)
Gamma-glutamyltransferase increased	14/152 (9.2%)		2/153 (1.3%)		3/152 (2%)
Blood potassium decreased	8/152 (5.3%)		1/153 (0.7%)		3/152 (2%)
Metabolism and nutrition disorders
Decreased appetite	16/152 (10.5%)		17/153 (11.1%)		11/152 (7.2%)
Musculoskeletal and connective tissue disorders
Myalgia	22/152 (14.5%)		21/153 (13.7%)		15/152 (9.9%)
Arthralgia	4/152 (2.6%)		8/153 (5.2%)		5/152 (3.3%)
Nervous system disorders
Headache	28/152 (18.4%)		23/153 (15%)		16/152 (10.5%)
Psychiatric disorders
Insomnia	18/152 (11.8%)		8/153 (5.2%)		9/152 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	17/152 (11.2%)		8/153 (5.2%)		8/152 (5.3%)
Skin and subcutaneous tissue disorders
Rash	27/152 (17.8%)		27/153 (17.6%)		30/152 (19.7%)
Alopecia	26/152 (17.1%)		21/153 (13.7%)		26/152 (17.1%)
Pruritus	17/152 (11.2%)		23/153 (15%)		17/152 (11.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring 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 in writing, such publication will be withheld for up to an additional 60 days.