Trial Outcomes & Findings for An Efficacy, Pharmacokinetics, Safety and Tolerability Study of TMC435 as Part of a Treatment Regimen for Hepatitis C-Infected Patients (NCT NCT01725529)

Last Updated: 2015-08-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

457 participants

Primary outcome timeframe

12 weeks after the end of treatment (EOT: Week 24 or 48)

Results posted on

2015-08-13

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo 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.	Simeprevir (TMC435) 100mg 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.	Simeprevir (TMC435) 150mg 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.
Overall Study STARTED	152	153	152
Overall Study COMPLETED	137	137	142
Overall Study NOT COMPLETED	15	16	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 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.	Simeprevir (TMC435) 100mg 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.	Simeprevir (TMC435) 150mg 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.
Overall Study Adverse Event	1	0	0
Overall Study Lost to Follow-up	2	1	1
Overall Study Protocol Violation	0	1	1
Overall Study Withdrawal by Subject	12	14	8

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=152 Participants 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.	Simeprevir (TMC435) 100mg n=153 Participants 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.	Simeprevir (TMC435) 150mg n=152 Participants 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 n=457 Participants Total of all reporting groups
Age, Continuous	45 years n=5 Participants	45 years n=7 Participants	44 years n=5 Participants	45 years n=4 Participants
Sex: Female, Male Female	79 Participants n=5 Participants	67 Participants n=7 Participants	75 Participants n=5 Participants	221 Participants n=4 Participants
Sex: Female, Male Male	73 Participants n=5 Participants	86 Participants n=7 Participants	77 Participants n=5 Participants	236 Participants n=4 Participants

PRIMARY outcome

Timeframe: 12 weeks after the end of treatment (EOT: Week 24 or 48)

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

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants 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.	Simeprevir (TMC435) 100mg n=153 Participants 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.	Simeprevir (TMC435) 150mg n=152 Participants 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.
Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12)	75.7 Percentage of participants	88.9 Percentage of participants	90.8 Percentage of participants

SECONDARY outcome

Timeframe: 24 weeks after the end of treatment (EOT: Week 24 or 48)

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants 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.	Simeprevir (TMC435) 100mg n=153 Participants 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.	Simeprevir (TMC435) 150mg n=152 Participants 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.
Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Study Drug Treatment (SVR24)	75.0 percentage of participants	88.9 percentage of participants	90.8 percentage of participants

SECONDARY outcome

Timeframe: Week 72

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants 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.	Simeprevir (TMC435) 100mg n=153 Participants 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.	Simeprevir (TMC435) 150mg n=152 Participants 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.
Percentage of Participants With Sustained Virologic Response at Week 72 (SVRW72)	75.0 percentage of participants	87.6 percentage of participants	90.1 percentage of participants

SECONDARY outcome

Timeframe: End of Treatment (EOT: Week 24 or 48)

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

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

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants 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.	Simeprevir (TMC435) 100mg n=153 Participants 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.	Simeprevir (TMC435) 150mg n=152 Participants 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.
Percentage of Participants With On-treatment Failure	12.5 percentage of participants	3.3 percentage of participants	3.3 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants 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.	Simeprevir (TMC435) 100mg n=153 Participants 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.	Simeprevir (TMC435) 150mg n=151 Participants 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.
Percentage of Participants With Viral Breakthrough	2.0 percentage of participants	2.6 percentage of participants	2.6 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=131 Participants 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.	Simeprevir (TMC435) 100mg n=142 Participants 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.	Simeprevir (TMC435) 150mg n=141 Participants 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.
Percentage of Participants With Viral Relapse	11.5 percentage of participants	1.4 percentage of participants	2.8 percentage of participants

SECONDARY outcome

Timeframe: 72 weeks after the EOT (Week 24 or 48)

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

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants 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.	Simeprevir (TMC435) 100mg n=79 Participants 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.	Simeprevir (TMC435) 150mg n=89 Participants 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.
Percentage of Participants With On-treatment Normalization of Alanine Aminotransferase Level	85.7 percentage of participants	86.1 percentage of participants	89.9 percentage of participants

Adverse Events

Placebo

Serious events: 9 serious events

Other events: 149 other events

Deaths: 0 deaths

Simeprevir (TMC435) 100mg

Serious events: 5 serious events

Other events: 149 other events

Deaths: 0 deaths

Simeprevir (TMC435) 150mg

Serious events: 5 serious events

Other events: 149 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

ASSOCIATE DIRECTOR, MEDICAL DEPARTMENT

Janssen R&D US

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=152 participants at risk 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.	Simeprevir (TMC435) 100mg n=153 participants at risk 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.	Simeprevir (TMC435) 150mg n=152 participants at risk 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.
Injury, poisoning and procedural complications Craniocerebral injury	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Foot fracture	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Meniscus lesion	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Multiple injuries	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Rib fracture	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Tibia fracture	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Traumatic lung injury	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Wound	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Contusion	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Injury, poisoning and procedural complications Ligament sprain	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Metabolism and nutrition disorders Cholesterosis	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Metabolism and nutrition disorders Type 2 diabetes mellitus	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Metabolism and nutrition disorders Decreased appetite	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Renal and urinary disorders Nephrolithiasis	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Renal and urinary disorders Ureteric stenosis	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Cardiac disorders Angina unstable	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Cardiac disorders Supraventricular tachycardia	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Gastrointestinal disorders Colitis ischaemic	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
General disorders Non-cardiac chest pain	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
General disorders Pain	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Hepatobiliary disorders Cholelithiasis	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Infections and infestations Incision site infection	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Infections and infestations Atypical pneumonia	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Infections and infestations Chronic hepatitis C	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Infections and infestations Pulmonary tuberculosis	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Psychiatric disorders Depression	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Vascular disorders Shock haemorrhagic	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Blood and lymphatic system disorders Anaemia	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Musculoskeletal and connective tissue disorders Undifferentiated connective tissue disease	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain neoplasm	0.66% 1/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.00% 0/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)

Measure	Placebo n=152 participants at risk 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.	Simeprevir (TMC435) 100mg n=153 participants at risk 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.	Simeprevir (TMC435) 150mg n=152 participants at risk 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.
Investigations Neutrophil count decreased	61.8% 94/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	56.9% 87/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	55.3% 84/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations White blood cell count decreased	53.3% 81/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	50.3% 77/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	52.6% 80/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Platelet count decreased	41.4% 63/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	37.3% 57/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	48.0% 73/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Haemoglobin decreased	37.5% 57/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	30.1% 46/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	30.9% 47/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Blood bilirubin increased	17.8% 27/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	20.3% 31/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	35.5% 54/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Bilirubin conjugated increased	3.3% 5/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	6.5% 10/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	21.7% 33/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Red blood cell count decreased	16.4% 25/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	15.0% 23/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	13.2% 20/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Lymphocyte count decreased	13.2% 20/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	12.4% 19/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	11.8% 18/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Haematocrit decreased	12.5% 19/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	11.1% 17/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	11.2% 17/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Alanine aminotransferase increased	17.8% 27/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	9.2% 14/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	12.5% 19/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Blood bilirubin unconjugated increased	5.3% 8/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	7.2% 11/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	13.8% 21/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Aspartate aminotransferase increased	15.8% 24/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	7.8% 12/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	9.9% 15/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Monocyte count decreased	7.2% 11/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	7.8% 12/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	8.6% 13/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Blood calcium decreased	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.9% 9/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Neutrophil percentage decreased	3.3% 5/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	6.5% 10/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.3% 8/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Low density lipoprotein decreased	3.3% 5/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	3.9% 6/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	7.2% 11/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Mean cell haemoglobin concentration decreased	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.9% 9/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.3% 8/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Mean cell volume increased	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	6.5% 10/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	4.6% 7/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Blood cholesterol decreased	3.9% 6/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	3.9% 6/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Blood lactate dehydrogenase increased	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.6% 4/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	3.9% 6/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Gamma-glutamyltransferase increased	9.2% 14/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	1.3% 2/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.0% 3/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Investigations Blood potassium decreased	5.3% 8/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.0% 3/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
General disorders Pyrexia	30.3% 46/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	19.0% 29/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	25.0% 38/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
General disorders Fatigue	23.7% 36/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	22.9% 35/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	18.4% 28/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
General disorders Influenza like illness	12.5% 19/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	13.1% 20/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	12.5% 19/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
General disorders Asthenia	4.6% 7/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.2% 8/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	4.6% 7/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Blood and lymphatic system disorders Anaemia	34.9% 53/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	24.8% 38/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	28.9% 44/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Blood and lymphatic system disorders Neutropenia	21.1% 32/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	18.3% 28/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	20.4% 31/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Blood and lymphatic system disorders Thrombocytopenia	14.5% 22/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	13.1% 20/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	9.9% 15/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Blood and lymphatic system disorders Leukopenia	10.5% 16/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	8.5% 13/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	10.5% 16/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Skin and subcutaneous tissue disorders Rash	17.8% 27/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	17.6% 27/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	19.7% 30/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Skin and subcutaneous tissue disorders Alopecia	17.1% 26/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	13.7% 21/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	17.1% 26/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Skin and subcutaneous tissue disorders Pruritus	11.2% 17/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	15.0% 23/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	11.2% 17/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Musculoskeletal and connective tissue disorders Myalgia	14.5% 22/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	13.7% 21/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	9.9% 15/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Musculoskeletal and connective tissue disorders Arthralgia	2.6% 4/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.2% 8/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	3.3% 5/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Nervous system disorders Headache	18.4% 28/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	15.0% 23/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	10.5% 16/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Gastrointestinal disorders Nausea	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.2% 8/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.3% 8/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Gastrointestinal disorders Diarrhoea	4.6% 7/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.6% 4/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Gastrointestinal disorders Abdominal pain upper	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.6% 4/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Metabolism and nutrition disorders Decreased appetite	10.5% 16/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	11.1% 17/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	7.2% 11/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Hepatobiliary disorders Hyperbilirubinaemia	2.6% 4/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	9.2% 14/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Infections and infestations Upper respiratory tract infection	7.9% 12/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.6% 4/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	8.6% 13/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Infections and infestations Nasopharyngitis	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	1.3% 2/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	3.3% 5/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Psychiatric disorders Insomnia	11.8% 18/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.2% 8/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Respiratory, thoracic and mediastinal disorders Cough	11.2% 17/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.2% 8/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	5.3% 8/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Endocrine disorders Hypothyroidism	5.9% 9/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	2.0% 3/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	3.9% 6/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)
Ear and labyrinth disorders Vertigo	6.6% 10/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	0.65% 1/153 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)	4.6% 7/152 • up to 4 weeks after End of treatment (EOT: Week 24 or Week 48)