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Clinical Trial Results:
A Phase IIa, open-label trial to evaluate the safety, tolerability and efficacy of a 12 weeks combination therapy of TMC647055 and TMC435, with and without GSK2336805 (JNJ-569148745), with a pharmacokinetic enhancer with and without ribavirin in chronic genotype 1 hepatitis C infected patients

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2012-002555-42
Trial protocol	BE DE
Global end of trial date	16 Dec 2014

Results information
Results version number	v1(current)
This version publication date	10 Jun 2016
First version publication date	10 Jun 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

TMC647055HPC2001

ISRCTN number

US NCT number

NCT01724086

WHO universal trial number (UTN)

Sponsor organisation name

Janssen Research & Development Ireland

Sponsor organisation address

Eastgate Village, Little Island, Cork, Ireland,

Public contact

Clinical Registry Group, Janssen Research & Development Ireland, clinicaltrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Janssen Research & Development Ireland, clinicaltrialsEU@its.jnj.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Dec 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Dec 2014

Was the trial ended prematurely?

Main objective of the trial

The main objectives of this study were to evaluate the pharmacokinetics, safety and tolerability of a 12 weeks dosing regimen containing TMC647055/simeprevir(SMV)/ritonavir(RTV) and JNJ-56914845 once daily at selected doses with and without ribavirin (RBV) (2 daily doses) in treatment naïve/prior relapser chronic hepatitis C virus (HCV) genotype1 (GT1)-infected subjects and to evaluate the efficacy of a 12 weeks combination therapy of TMC647055/SMV/RTV once daily at selected doses with RBV (2 daily doses) in treatment-naïve/prior relapser chronic HCV GT1-infected subjects and in treatment-naïve/prior relapser chronic HCV GT1b-infected subjects.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included monitoring of adverse events (AEs), clinical laboratory tests (Hematology, Serum chemistry, Urinalysis) vital signs, electrocardiograms (ECG) and physical examination.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Sep 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 81

Country: Number of subjects enrolled

Germany: 9

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

The study was conducted from 12 Sep 2012 to 16 Dec 2014 and included 90 subjects in 4 panels: Panel 1 and 2 included 31 subjects, Panel 3 included 15 subjects and Panel 4 included 44 subjects.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin

Arm description

Subjects (chronic HCV genotype 1a (GT1a) or 1b (GT1b) infected treatment-naive patients/prior relapsers) received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily with ribavirin (RBV) 5 or 6 tablets (depending on body weight) (eq: 200 mg/tablet) per day, divided in 2 doses for 12 weeks

Arm type

Experimental

Investigational medicinal product name

TMC647055

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily for 12 weeks.

Investigational medicinal product name

Simeprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received simeprevir (TMC435) 75 mg capsule (1 x 75 mg) administered once daily for 12 weeks

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects received ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily for 12 weeks.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received ribavirin (RBV) 5 or 6 tablet (depending on body weight) (eq. 200 mg/tablet) per day, divided in 2 doses for 12 weeks.

Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Arm description

Subjects (chronic HCV genotype (GT1b) infected treatment-naive patients/prior relapsers) received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily without RBV for 12 weeks

Arm type

Experimental

Investigational medicinal product name

TMC647055

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily for 12 weeks.

Investigational medicinal product name

Simeprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received simeprevir (TMC435) 75 mg capsule (1 x 75 mg) administered once daily for 12 weeks

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects received ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily for 12 weeks.

Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin

Arm description

Subjects (chronic HCV GT1a infected treatment naïve patients/prior relapsers) received TMC647055 600 milligram (mg) capsules (4 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 50 mg oral solution (0.625 mL oral solution (80 mg/mL) given once daily with ribavirin (RBV) 5 or 6 tablets (depending on body weight) (eq. 200 mg/tablet) per day, divided in 2 doses for 12 weeks

Arm type

Experimental

Investigational medicinal product name

TMC647055

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received TMC647055 600 milligram (mg) capsules (4 X 150 mg) given orally once daily for 12 weeks.

Investigational medicinal product name

Simeprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received simeprevir (TMC435) 75 mg capsule (1 x 75 mg) administered once daily for 12 weeks

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects received ritonavir (RTV) 50 mg oral solution (0.625 mL oral solution (80 mg/mL) given once daily for 12 weeks.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received ribavirin (RBV) 5 or 6 tablet (depending on body weight) (eq. 200 mg/tablet) per day, divided in 2 doses for 12 weeks.

Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Arm description

Subjects (chronic HCV GT1b infected treatment naïve patients/prior relapsers) received TMC647055 600 milligram (mg) capsules (4 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 50 mg oral solution (0.625 mL oral solution (80 mg/mL) given once daily without ribavirin (RBV) for 12 weeks

Arm type

Experimental

Investigational medicinal product name

TMC647055

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received TMC647055 600 milligram (mg) capsules (4 X 150 mg) given orally once daily for 12 weeks.

Investigational medicinal product name

Simeprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received simeprevir (TMC435) 75 mg capsule (1 x 75 mg) adminstered once daily for 12 weeks

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects received ritonavir (RTV) 50 mg oral solution (0.625 mL oral solution (80 mg/mL) given once daily for 12 weeks.

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg

Arm description

Subjects (chronic HCV GT1a or GT1b infected treatment-naive patients/ prior relapsers) received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily and JNJ-56914845 30 mg oral tablet (1 x 30mg) once daily for 12 weeks

Arm type

Experimental

Investigational medicinal product name

TMC647055

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily for 12 weeks.

Investigational medicinal product name

Simeprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received simeprevir (TMC435) 75 mg capsule (1 x 75 mg) administered once daily for 12 weeks

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects received ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily for 12 weeks.

Investigational medicinal product name

JNJ-56914845

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-56914845 30 mg oral tablet (1 x 30mg) given orally once daily for 12 weeks

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

TMC647055

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily for 12 weeks.

Investigational medicinal product name

Simeprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received simeprevir (TMC435) 75 mg capsule (1 x 75 mg) adminstered once daily for 12 weeks

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects received ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily for 12 weeks.

Investigational medicinal product name

JNJ-56914845

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-56914845 60 mg tablet (2 x 30mg) given orally once daily for 12 weeks

Number of subjects in period 1	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg
Started	22	9	7	8	22	22
Completed	21	8	7	7	21	22
Not completed	1	1	0	1	1	0
Consent withdrawn by subject	-	-	-	-	1	-
Lost to follow-up	1	1	-	1	-	-

Baseline characteristics

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Reporting group title

Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin

Reporting group description

Reporting group title

Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Reporting group description

Reporting group title

Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin

Reporting group description

Reporting group title

Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Reporting group description

Reporting group title

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg

Reporting group description

Reporting group title

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg

Reporting group description

Reporting group values	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Total
Number of subjects	22	9	7	8	22	22	90
Title for AgeCategorical
Units: subjects
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	22	9	7	7	21	22	88
From 65 to 84 years	0	0	0	1	1	0	2
85 years and over	0	0	0	0	0	0	0
Title for AgeContinuous
Units: years
median (full range (min-max))	47 (29 to 62)	37 (18 to 64)	44 (28 to 58)	48.5 (43 to 66)	50.5 (24 to 70)	48 (27 to 58)	-
Title for Gender
Units: subjects
Female	10	2	0	5	6	5	28
Male	12	7	7	3	16	17	62

End points

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Reporting group title

Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin

Reporting group description

Reporting group title

Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Reporting group description

Reporting group title

Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin

Reporting group description

Reporting group title

Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Reporting group description

Reporting group title

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg

Reporting group description

Reporting group title

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg

Reporting group description

Subject analysis set title

Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects (chronic HCV genotype 1a (GT1a) infected treatment-naive patients/prior relapsers) received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily with ribavirin (RBV) 5 or 6 tablet (depending on body weight) (eq. 200 mg/tablet) per day, divided in 2 doses for 12 weeks

Subject analysis set title

Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects (chronic HCV genotype 1b (GT1b) infected treatment-naive patients/prior relapsers) received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily with ribavirin (RBV) 5 or 6 tablet (depending on body weight) (eq. 200 mg/tablet) per day, divided in 2 doses for 12 weeks

Primary: Number of Subjects With a Sustained Virologic Response (SVR) 12 Weeks After the Actual end of Treatment

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End point title

Number of Subjects With a Sustained Virologic Response (SVR) 12 Weeks After the Actual end of Treatment ^[1] ^[2]

End point description

SVR12 is defined as undetectable Hepatitis C Virus at the actual end of treatment and HCV RNA less than 25 IU/mL at 12 Weeks after the actual end of treatment. Intent-to-treat (ITT) analysis set included all subjects who received at least one dose of TMC647055, Simeprevir (SMV), Ritonavir (RTV), or JNJ-56914845.

End point type

Primary

End point timeframe

Week 24 (Up to 12 weeks after end-of treatment visit)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistical analysis was performed for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: Proportion
number (confidence interval 95%)	44.4 (17.7 to 74.9)	85.7 (41.9 to 98)	50 (20 to 80)	81.8 (0 to 100)	95.5 (0 to 100)	50 (22.5 to 77.5)	83.3 (52.3 to 95.8)

No statistical analyses for this end point

Primary: Number of Subjects Reporting Adverse Events

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End point title

Number of Subjects Reporting Adverse Events ^[3] ^[4]

End point description

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. ITT analysis set included all subjects who received at least one dose of TMC647055, Simeprevir (SMV), Ritonavir (RTV), or JNJ-56914845.

End point type

Primary

End point timeframe

Up to Week 48 (36 weeks after end of treatment)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: Subjects	7	6	6	20	22	10	12

No statistical analyses for this end point

Primary: Proportion of Subjects With a Sustained Virological Response (SVR 4, SVR 12 and SVR 24)

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End point title

Proportion of Subjects With a Sustained Virological Response (SVR 4, SVR 12 and SVR 24) ^[5] ^[6]

End point description

SVR is defined as hepatitis C virus (HCV) ribonucleic acid (RNA) undetectable at least 12 weeks after the actual end of all HCV treatment. ITT analysis set included all subjects who received at least one dose of TMC647055, SMV, RTV, or JNJ-56914845.

End point type

Primary

End point timeframe

Week 4, 12 and 24

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistical analysis was performed for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: Percentage
number (not applicable)
SVR 4	44.4	85.7	50	81.8	95.5	50	83.3
SVR 12	44.4	85.7	50	81.8	95.5	50	83.3
SVR 24	44.4	85.7	37.5	81.8	95.5	40	83.3

No statistical analyses for this end point

Secondary: Hepatitis C Virus (HCV) RNA levels Over Time

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End point title

Hepatitis C Virus (HCV) RNA levels Over Time ^[7]

End point description

ITT analysis set included all subjects who received at least one dose of TMC647055, SMV, RTV, or JNJ-56914845.

End point type

Secondary

End point timeframe

Up to 36 weeks after end of treatment

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: International Unit per milliliter (IU/mL
arithmetic mean (standard error)
Baseline	6.23 ( 0.25 )	6.504 ( 0.1782 )	6.713 ( 0.1091 )	6.606 ( 0.1129 )	6.437 ( 0.1209 )	6.46 ( 0.14 )	6.46 ( 0.14 )
Day 3	2.49 ( 0.21 )	2.575 ( 0.2068 )	2.633 ( 0.1048 )	2.848 ( 0.1093 )	2.667 ( 0.1296 )	2.34 ( 0.21 )	2.82 ( 0.17 )
Week 1	1.55 ( 0.2 )	1.83 ( 0.2001 )	1.924 ( 0.1179 )	2.186 ( 0.1256 )	1.987 ( 0.122 )	1.56 ( 0.19 )	1.96 ( 0.17 )

No statistical analyses for this end point

Secondary: Number of Subjects With Viral Breakthrough

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End point title

Number of Subjects With Viral Breakthrough ^[8]

End point description

On-treatment virologic failure is defined as an inadequate virologic response (HCV RNA >100 IU/mL confirmed, at Week 4 or afterwards until Week 11) OR with viral breakthrough, 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 had previously been <25 IU/mL. ITT analysis set included all subjects who received at least one dose of TMC647055, SMV, RTV, or JNJ-56914845.

End point type

Secondary

End point timeframe

End of study (Week 48)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: Subjects	1	0	1	0	1	5	1

No statistical analyses for this end point

Secondary: Number of Subjects With Viral Relapse

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End point title

Number of Subjects With Viral Relapse ^[9]

End point description

Viral relapse was defined as HCV RNA <25 IU/mL undetectable at the actual EOT and confirmed HCV RNA ≥25 IU/mL during posttreatment FU

End point type

Secondary

End point timeframe

Up to 36 weeks after end of treatment

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: Subjects	2	0	2	4	0	0	0

No statistical analyses for this end point

Secondary: Minimum Observed Plasma Analyte Concentration of TMC435 (Cmin)

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End point title

Minimum Observed Plasma Analyte Concentration of TMC435 (Cmin) ^[10]

End point description

Cmin is defined as minimum observed plasma concentration of TMC435. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: Nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	1294 ( 1923 )	2545 ( 2922 )	3399 ( 5550 )	1097 ( 1266 )	1962 ( 3170 )	891 ( 1094 )	1566 ( 2178 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Analyte Concentration of TMC435 (Cmax)

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End point title

Maximum Observed Plasma Analyte Concentration of TMC435 (Cmax) ^[11]

End point description

Cmax is defined as maximum observed plasma concentration of TMC435. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	4583 ( 3691 )	5989 ( 4367 )	8966 ( 6509 )	4240 ( 2799 )	5419 ( 6166 )	3043 ( 2509 )	5280 ( 4157 )

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration of TMC435 (Tmax)

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End point title

Time to Reach Maximum Observed Plasma Concentration of TMC435 (Tmax) ^[12]

End point description

Time to Reach Maximum Plasma Concentration (Tmax) is defined as actual sampling time to reach maximum observed analyte concentration Cmax. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: hour (h)
median (full range (min-max))	5.97 (4.93 to 10)	5 (3.07 to 6.07)	5.05 (4.07 to 6.1)	5.64 (3.12 to 12)	5.09 (2.98 to 23.93)	5 (3 to 6.03)	5.95 (4 to 11.93)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC435

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End point title

Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC435 ^[13]

End point description

AUC (0-24) h is defined as area under the plasma concentration-time curve from time 0 up to 24 hours after giving doses. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: nanogram hour per milliliters (ng.h/mL)
arithmetic mean (standard deviation)	67437 ( 76272 )	91627 ( 82074 )	127318 ( 148663 )	59307 ( 48818 )	80893 ( 103010 )	40064 ( 38489 )	67612 ( 67590 )

No statistical analyses for this end point

Secondary: Average Plasma Concentration of TMC435 (Cavg)

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End point title

Average Plasma Concentration of TMC435 (Cavg) ^[14]

End point description

Cavg is defined as average plasma concentration at steady-state over the dose interval calculated by AUC at steady-state. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	2820 ( 3188 )	3829 ( 3426 )	5300 ( 6204 )	2472 ( 2035 )	3368 ( 4298 )	1674 ( 1609 )	2825 ( 2825 )

No statistical analyses for this end point

Secondary: Fluctuation Index of TMC435 (FI)

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End point title

Fluctuation Index of TMC435 (FI) ^[15]

End point description

FI is defined as percentage fluctuation (variation) between maximum and minimum plasma concentration at steady-state, calculated as 100 ([Cmax - Cmin ]/Cavg ). PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Up to week 4

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: Percent
arithmetic mean (standard deviation)	160 ( 71.1 )	136 ( 67.4 )	170 ( 86.5 )	154 ( 58.2 )	134 ( 46.9 )	150 ( 39.6 )	149 ( 48.9 )

No statistical analyses for this end point

Secondary: Minimum Observed Plasma Analyte Concentration of TMC647055 (Cmin)

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End point title

Minimum Observed Plasma Analyte Concentration of TMC647055 (Cmin) ^[16]

End point description

Cmin is defined as minimum observed plasma concentration of TMC647055. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	798 ( 1464 )	2710 ( 3825 )	2591 ( 3594 )	655 ( 826 )	1159 ( 2097 )	670 ( 1071 )	695 ( 1275 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Analyte Concentration of TMC647055 (Cmax)

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End point title

Maximum Observed Plasma Analyte Concentration of TMC647055 (Cmax) ^[17]

End point description

Cmax is defined as maximum observed plasma concentration of TMC647055. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	13936 ( 6228 )	23714 ( 7255 )	36288 ( 15229 )	14189 ( 6686 )	13552 ( 10927 )	14626 ( 6619 )	15029 ( 9034 )

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration of TMC647055 (Tmax)

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End point title

Time to Reach Maximum Observed Plasma Concentration of TMC647055 (Tmax) ^[18]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: hour (h)
median (full range (min-max))	4.93 (3.93 to 5.07)	5 (4 to 6.05)	5 (4 to 6.08)	4.99 (2 to 8)	4.98 (2.98 to 8)	5 (3 to 6)	5 (4 to 9.93)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC647055

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End point title

Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC647055 ^[19]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: nanogram hour per milliliter (ng.h/mL)
arithmetic mean (standard deviation)	112769 ( 84867 )	237623 ( 162469 )	273964 ( 165632 )	115983 ( 76401 )	119731 ( 112601 )	103452 ( 61231 )	109672 ( 77498 )

No statistical analyses for this end point

Secondary: Average Plasma Concentration of TMC647055 (Cavg)

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End point title

Average Plasma Concentration of TMC647055 (Cavg) ^[20]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	4716 ( 3547 )	9933 ( 6784 )	11410 ( 6921 )	4836 ( 3183 )	4984 ( 4695 )	4322 ( 2561 )	4582 ( 3236 )

No statistical analyses for this end point

Secondary: Fluctuation Index of TMC647055 (FI)

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End point title

Fluctuation Index of TMC647055 (FI) ^[21]

End point description

End point type

Secondary

End point timeframe

Up to week 4

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: Percent
arithmetic mean (standard deviation)	329 ( 110 )	284 ( 134 )	340 ( 126 )	310 ( 95.3 )	290 ( 76.6 )	345 ( 78.6 )	322 ( 102 )

No statistical analyses for this end point

Secondary: Minimum Observed Plasma Analyte Concentration of Ritonavir (Cmin)

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End point title

Minimum Observed Plasma Analyte Concentration of Ritonavir (Cmin) ^[22]

End point description

Cmin is defined as minimum observed plasma concentration of Ritonavir. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample. NOTE: The value 99999 indicates no data value or not applicable.

End point type

Secondary

End point timeframe

Week 4

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	9	7	8	22	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	99999 ( 99999 )	19.9 ( 20.3 )	13.5 ( 13.9 )	4.39 ( 3.53 )	5.07 ( 6.26 )	7.15 ( 13.7 )	2.87 ( 1.96 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Analyte Concentration of Ritonavir (Cmax)

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End point title

Maximum Observed Plasma Analyte Concentration of Ritonavir (Cmax) ^[23]

End point description

Cmax is defined as maximum observed plasma concentration of Ritonavir. PK population included all evaluable subjects who received at least 1 dose of study medication and with at least 1 PK blood sample.

End point type

Secondary

End point timeframe

Week 4

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	134 ( 66.8 )	389 ( 268 )	517 ( 184 )	141 ( 75.4 )	146 ( 112 )	148 ( 95.4 )	170 ( 73.2 )

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration of Ritonavir (Tmax)

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End point title

Time to Reach Maximum Observed Plasma Concentration of Ritonavir (Tmax) ^[24]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	22	22	10	12
Units: hour (h)
median (full range (min-max))	4 (2.93 to 5.05)	5 (0 to 5.07)	4.54 (3 to 5.1)	4.08 (0 to 6)	4.05 (3 to 6)	4 (3 to 6)	4.99 (3 to 7.93)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of Ritonavir

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End point title

Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of Ritonavir ^[25]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: nanogram hour per milliliter (ng.h/mL
arithmetic mean (standard deviation)	776 ( 555 )	3054 ( 1951 )	2958 ( 1024 )	852 ( 498 )	902 ( 754 )	1002 ( 919 )	957 ( 392 )

No statistical analyses for this end point

Secondary: Average Plasma Concentration of Ritonavir (Cavg)

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End point title

Average Plasma Concentration of Ritonavir (Cavg) ^[26]

End point description

End point type

Secondary

End point timeframe

Week 4

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: nanogram per Milliliters (ng/mL)
arithmetic mean (standard deviation)	32.5 ( 23.2 )	128 ( 81.6 )	123 ( 42.7 )	35.5 ( 20.7 )	37.5 ( 31.4 )	41.8 ( 38.4 )	40 ( 16.3 )

No statistical analyses for this end point

Secondary: Fluctuation Index of Ritonavir (FI)

Top of page

End point title

Fluctuation Index of Ritonavir (FI) ^[27]

End point description

End point type

Secondary

End point timeframe

Up to week 4

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistical analysis was performed for this endpoint.

End point values	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1a)	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin (GT1b)
Number of subjects analysed	8	7	8	21	22	10	12
Units: Percent
arithmetic mean (standard deviation)	473 ( 230 )	295 ( 71.3 )	421 ( 107 )	397 ( 110 )	399 ( 87.8 )	397 ( 108 )	409 ( 73.5 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Week 48 (24 weeks after end of treatment)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin

Reporting group description

Subjects (chronic HCV genotype 1a (GT1a) or 1b (GT1b) infected treatment-naive patients/prior relapsers) received TMC647055 450 milligram (mg) capsules (3 X 150 mg) given orally once daily, simeprevir (TMC435) 75 mg capsule (1 x 75 mg) given once daily, and ritonavir (RTV) 30 mg oral solution (0.375 mL) given once daily with ribavirin (RBV) 5 or 6 tablets (depending on body weight) (eq; 200 mg/tablet) per day, divided in 2 doses for 12 weeks)

Reporting group title

Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Reporting group description

Reporting group title

Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin

Reporting group description

Reporting group title

Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin

Reporting group description

Reporting group title

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg

Reporting group description

Reporting group title

Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg

Reporting group description

Serious adverse events	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Panel 1: TMC647055 /Simeprevir /Ritonavir w Ribavirin	Panel 2: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 3: TMC647055 /Simeprevir / Ritonavir w Ribavirin	Panel 3: TMC647055 /Simeprevir /Ritonavir w/o Ribavirin	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 30 mg	Panel 4: TMC647055 /Simeprevir /Ritonavir /JNJ-56914845 60 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 22 (100.00%)	7 / 9 (77.78%)	6 / 7 (85.71%)	6 / 8 (75.00%)	19 / 22 (86.36%)	21 / 22 (95.45%)
Vascular disorders
Phlebitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Fatigue
subjects affected / exposed	9 / 22 (40.91%)	0 / 9 (0.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	5 / 22 (22.73%)	8 / 22 (36.36%)
occurrences all number	13	0	1	5	5	10
Influenza like illness
subjects affected / exposed	5 / 22 (22.73%)	2 / 9 (22.22%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	5	3	0	0	1	0
Local swelling
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	1	0	1	0	0	2
Oedema peripheral
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 22 (4.55%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	2	2
Pyrexia
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	2	0	0	0	0	2
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	1	0
Nasal congestion
subjects affected / exposed	0 / 22 (0.00%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 22 (9.09%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	2	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	1	0	0
Depressed mood
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0	0	0
Insomnia
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	2 / 22 (9.09%)	0 / 22 (0.00%)
occurrences all number	2	0	0	2	2	0
Injury, poisoning and procedural complications
Sunburn
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 22 (4.55%)	3 / 22 (13.64%)
occurrences all number	1	0	0	0	1	3
Nervous system disorders
Dysgeusia
subjects affected / exposed	0 / 22 (0.00%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	1	0	0	0	1
Headache
subjects affected / exposed	9 / 22 (40.91%)	5 / 9 (55.56%)	2 / 7 (28.57%)	5 / 8 (62.50%)	8 / 22 (36.36%)	7 / 22 (31.82%)
occurrences all number	11	6	3	8	11	8
Somnolence
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	1	0	0	0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 22 (9.09%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	3 / 22 (13.64%)	0 / 22 (0.00%)
occurrences all number	2	1	0	0	3	0
Eye disorders
Eye irritation
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 22 (0.00%)	1 / 9 (11.11%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	1	0	0	0
Abdominal distension
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Abdominal pain
subjects affected / exposed	3 / 22 (13.64%)	2 / 9 (22.22%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 22 (4.55%)	4 / 22 (18.18%)
occurrences all number	4	2	0	1	1	4
Abdominal pain upper
subjects affected / exposed	3 / 22 (13.64%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	4 / 22 (18.18%)	3 / 22 (13.64%)
occurrences all number	3	1	0	0	4	4
Abdominal rigidity
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Constipation
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	1	0	2
Diarrhoea
subjects affected / exposed	3 / 22 (13.64%)	3 / 9 (33.33%)	1 / 7 (14.29%)	4 / 8 (50.00%)	4 / 22 (18.18%)	10 / 22 (45.45%)
occurrences all number	4	4	2	4	9	18
Diverticulum
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Dyspepsia
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0	0	0
Flatulence
subjects affected / exposed	3 / 22 (13.64%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	3 / 22 (13.64%)	0 / 22 (0.00%)
occurrences all number	3	0	0	0	3	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0	0	0
Lip dry
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	0	2
Nausea
subjects affected / exposed	3 / 22 (13.64%)	1 / 9 (11.11%)	4 / 7 (57.14%)	3 / 8 (37.50%)	2 / 22 (9.09%)	1 / 22 (4.55%)
occurrences all number	3	1	5	3	3	2
Regurgitation
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Toothache
subjects affected / exposed	0 / 22 (0.00%)	2 / 9 (22.22%)	1 / 7 (14.29%)	1 / 8 (12.50%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	0	3	1	1	1	0
Vomiting
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	2 / 22 (9.09%)	0 / 22 (0.00%)
occurrences all number	1	0	0	1	2	0
Hepatobiliary disorders
Jaundice
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	0	0	0	0	1
Dry skin
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	2 / 22 (9.09%)	6 / 22 (27.27%)
occurrences all number	2	0	1	0	2	7
Eczema
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	0	0	0	0	1
Erythema
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 22 (4.55%)	2 / 22 (9.09%)
occurrences all number	2	0	0	0	1	2
Photosensitivity reaction
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 22 (9.09%)	3 / 22 (13.64%)
occurrences all number	1	0	0	0	4	3
Pruritus
subjects affected / exposed	4 / 22 (18.18%)	0 / 9 (0.00%)	2 / 7 (28.57%)	2 / 8 (25.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	4	0	2	3	0	2
Rash
subjects affected / exposed	3 / 22 (13.64%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 22 (4.55%)	1 / 22 (4.55%)
occurrences all number	4	0	1	0	1	1
Skin lesion
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	2	0	1	0	0	2
Back pain
subjects affected / exposed	2 / 22 (9.09%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	1	0	0	0
Bone pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0	0
Muscle spasms
subjects affected / exposed	0 / 22 (0.00%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 22 (9.09%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0	2	0
Myalgia
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	3 / 22 (13.64%)
occurrences all number	2	0	0	0	0	3
Pain in extremity
subjects affected / exposed	1 / 22 (4.55%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	1	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	0	2
Conjunctivitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	1	0	0
Gastroenteritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0
Nail bed infection
subjects affected / exposed	0 / 22 (0.00%)	1 / 9 (11.11%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	4 / 22 (18.18%)	2 / 9 (22.22%)	1 / 7 (14.29%)	1 / 8 (12.50%)	5 / 22 (22.73%)	1 / 22 (4.55%)
occurrences all number	4	2	1	2	5	1
Periodontitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0	0	0
Tooth abscess
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 22 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 22 (9.09%)	1 / 9 (11.11%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	1	1	0	0	1
Hypercholesterolaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0	0
Hyperglycaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 9 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	0	1	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

23 Aug 2012

The sponsor decided to reduce the frequency and maximum duration of the follow up (FU) visits after EOT. This change was also applicable to follow up (FU) visits in case of premature study drug withdrawal. In addition, an SMV 75-mg capsule was added as possible formulation. The posttreatment FU visits were scheduled at Week 4, 8, 12, and 24 after the actual end of treatment (EOT). In case of premature study drug withdrawal, the visit 2 weeks after study drug withdrawal did not change. The posttreatment FU visits at Week 4, 12, and 24 were scheduled for the determination of SVR4, SVR12, and SVR24. The review meetings were updated accordingly. The HCV RNA confirmation test when HCV RNA was detected after previous undetectability was changed from ‘within 3’ to ‘within 4’ weeks. This allowed the retest visit to coincide with one of the next scheduled visits. A minor change was made to the virologic stopping rules: an inadequate virologic response needed to be confirmed.For consistency reasons, the primary endpoint safety was added to the primary endpoints. A time window was added to the blood sampling times. A minor change was made to the criteria of the 36 weeks of PegIFN/RBV FU treatment in Panel 3: the FU treatment was also applicable to subjects with HCV RNA detectable at Week 4. A note was added to the hematology panel and urinalysis, giving extra information about what could or was also reported by the laboratory. Flow cytometry was not done in case of an abnormal urinalysis dipstick test. An SMV 75-mg capsule was added as possible formulation. This allowed more flexibility in the choice of the optimal dose. The Cardiovascular Safety Abnormalities was added and the references regarding cardiovascular abnormalities were updated. Minor inconsistencies and errors was corrected. Some clarifications were added. At implementation of the first general protocol amendment, 29 subjects in Panel 1 and 2 had been screened of whom 17 had started treatment.

05 Dec 2012

The sponsor decided to make the discontinuation of treatment criteria more precise and to streamline the age criteria between 2 of its HCV compounds. The discontinuation of treatment criteria were made more precise to distinguish between treatment-emergent liver-related AEs/abnormalities and abnormal laboratory values that were the consequence of the liver disease. Any related data in other sections were updated for consistency reasons. The age limit was increased up to 70-years-old (in good physical condition) to streamline the age criteria between SMV and TMC647055. If the subject had a positive urine drug test at screening a retesting was allowed after a time interval of minimum 7 days instead of at the same day. This was to exclude one-time and short usage. Minor errors and inconsistencies were corrected and clarifications were made. At implementation of the second general protocol amendment, 45 subjects in Panel 1 and 2 had been screened of whom 31 had started treatment.

24 Apr 2013

This amendment was made to replace Panel 3. Ongoing review of safety, PK, and HCV RNA data obtained from Panel 1 and 2 indicated that the combination treatment TMC647055 + SMV + RTV with and without RBV was generally safe and well tolerated and that exploration of higher dose levels of TMC647055 and RTV could optimize the PK profile and efficacy of the combination treatment. Therefore, the original third panel of 10 null responders described in the original protocol was replaced by a new panel. In order to optimize the PK profile and efficacy of the combination treatment, the original Panel 3 of null responders was replaced by a panel with 2 treatment arms: Arm 1, 8 HCV GT1a and Arm 2, 8 HCV GT1b treatment-naïve subjects or prior relapsers to a previous IFN-based therapy. The subjects in Panel 3 received a 12-week treatment with TMC647055 600 mg qd, SMV 75 mg qd, and RTV 50 mg qd with (Arm 1) or without (Arm 2) RBV 1,000 to 1,200 mg bid. A 36-week IFN/RBV FU treatment was planned for subjects with HCV RNA ≥25 IU/mL at Week 4. The tentative doses of Panel 1 and 2 were updated to the actual doses. The inclusion criteria were updated to reflect the current practice of confirming the HCV GT and subtype at screening. The data analysis and review meeting time points were updated to allow frequent monitoring of safety, PK, and HCV RNA data instead of at predefined time points. The preliminary statistical analysis was made optional and only occurred if deemed necessary. A brief description of the preliminary safety results was added. Additional information was provided regarding the sample size determination. Plasma concentrations of RTV were not incorporated in an existing population model and Cmax was removed from the PK parameters of SMV that were derived in each subject using Bayesian feedback. The text was updated to reflect the completion of study TMC647055HPC1006.

18 Sep 2013

This amendment was created to enable Proof-of-Concept data of the addition of the NS5A inhibitor JNJ-56914845 (at 2 dose levels) onto the currently studied regimen of the PI SMV and the NNI TMC647055, boosted by RTV, against HCV GT1a and GT1b. An additional panel (Panel 4) with 2 arms was included to evaluate the safety, PK, and efficacy of the coadministration of SMV 75 mg qd, TMC647055 450 mg qd, RTV 30 mg qd, and JNJ-56914845 (30 and 60 mg qd) for 12 weeks without RBV, in a population of 40 subjects infected with HCV GT1a or GT1b, with a maximum of 16 subjects infected with GT1b, naive to all hepatitis C treatment or relapsers from previous IFN- and RBV-based treatment. The subjects in this panel did not receive FU treatment. A dose rationale for JNJ-56914845 was added (see Section 3.2). As this study involved SMV, the sun protection measures were updated as recommended by the Food and Drug Administration. At implementation of the forth general protocol amendment, a total of 101 subjects were screened (45 in Panel 1 and 2; 56 in Panel 3 and 4) and a total of 59 had started treatment (31 in Panel 1 and 2; 28 in Panel 3 and 4).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The small sample size only allowed for Proof-of-Concept. No formal hypothesis was made. Statistical analysis for primary endpoint was not performed given the low sample size.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With a Sustained Virologic Response (SVR) 12 Weeks After the Actual end of Treatment

Primary: Number of Subjects With a Sustained Virologic Response (SVR) 12 Weeks After the Actual end of Treatment

Primary: Number of Subjects Reporting Adverse Events

Primary: Number of Subjects Reporting Adverse Events

Primary: Proportion of Subjects With a Sustained Virological Response (SVR 4, SVR 12 and SVR 24)

Primary: Proportion of Subjects With a Sustained Virological Response (SVR 4, SVR 12 and SVR 24)

Secondary: Hepatitis C Virus (HCV) RNA levels Over Time

Secondary: Hepatitis C Virus (HCV) RNA levels Over Time

Secondary: Number of Subjects With Viral Breakthrough

Secondary: Number of Subjects With Viral Breakthrough

Secondary: Number of Subjects With Viral Relapse

Secondary: Number of Subjects With Viral Relapse

Secondary: Minimum Observed Plasma Analyte Concentration of TMC435 (Cmin)

Secondary: Minimum Observed Plasma Analyte Concentration of TMC435 (Cmin)

Secondary: Maximum Observed Plasma Analyte Concentration of TMC435 (Cmax)

Secondary: Maximum Observed Plasma Analyte Concentration of TMC435 (Cmax)

Secondary: Time to Reach Maximum Observed Plasma Concentration of TMC435 (Tmax)

Secondary: Time to Reach Maximum Observed Plasma Concentration of TMC435 (Tmax)

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC435

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC435

Secondary: Average Plasma Concentration of TMC435 (Cavg)

Secondary: Average Plasma Concentration of TMC435 (Cavg)

Secondary: Fluctuation Index of TMC435 (FI)

Secondary: Fluctuation Index of TMC435 (FI)

Secondary: Minimum Observed Plasma Analyte Concentration of TMC647055 (Cmin)

Secondary: Minimum Observed Plasma Analyte Concentration of TMC647055 (Cmin)

Secondary: Maximum Observed Plasma Analyte Concentration of TMC647055 (Cmax)

Secondary: Maximum Observed Plasma Analyte Concentration of TMC647055 (Cmax)

Secondary: Time to Reach Maximum Observed Plasma Concentration of TMC647055 (Tmax)

Secondary: Time to Reach Maximum Observed Plasma Concentration of TMC647055 (Tmax)

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC647055

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of TMC647055

Secondary: Average Plasma Concentration of TMC647055 (Cavg)

Secondary: Average Plasma Concentration of TMC647055 (Cavg)

Secondary: Fluctuation Index of TMC647055 (FI)

Secondary: Fluctuation Index of TMC647055 (FI)

Secondary: Minimum Observed Plasma Analyte Concentration of Ritonavir (Cmin)

Secondary: Minimum Observed Plasma Analyte Concentration of Ritonavir (Cmin)

Secondary: Maximum Observed Plasma Analyte Concentration of Ritonavir (Cmax)

Secondary: Maximum Observed Plasma Analyte Concentration of Ritonavir (Cmax)

Secondary: Time to Reach Maximum Observed Plasma Concentration of Ritonavir (Tmax)

Secondary: Time to Reach Maximum Observed Plasma Concentration of Ritonavir (Tmax)

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of Ritonavir

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24h) of Ritonavir

Secondary: Average Plasma Concentration of Ritonavir (Cavg)

Secondary: Average Plasma Concentration of Ritonavir (Cavg)

Secondary: Fluctuation Index of Ritonavir (FI)

Secondary: Fluctuation Index of Ritonavir (FI)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information