Clinical Trial Results:
A phase III, randomised, double-blind and placebo controlled study of once daily BI 201335, 240 mg for 12 or 24 weeks in combination with pegylated interferon- a (PegIFNa) and ribavirin (RBV) in patients with genotype 1 chronic hepatitis C infection who failed a prior PegIFN/RBV treatment

Due to a system error, the data reported in v1 is not correct and has been removed from public view.

Summary
EudraCT number	2010-021715-17
Trial protocol	GB PT BE DE AT ES
Global end of trial date	15 May 2014

Results information
Results version number	v2(current)
This version publication date	23 Jul 2016
First version publication date	26 Jul 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set Data correction due to a system error in EudraCT- Results

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

1220.7

ISRCTN number

US NCT number

NCT01358864

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173 , Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim , +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim , +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.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

13 Jun 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 May 2014

Was the trial ended prematurely?

Main objective of the trial

The aim of this trial is to evaluate the efficacy and the safety of BI 201335 given for 12 or 24 weeks in combination with PegIFN/RBV given for 48 weeks as compared to PegIFN/RBV alone in chronic GT-1 hepatitis C virus infected patients who failed a prior PegIFN/RBV treatment.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. In addition IDMC meetings were held approximately every four months at the project level; trial data were reviewed in open and closed sessions.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Jul 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 39

Country: Number of subjects enrolled

Canada: 74

Country: Number of subjects enrolled

France: 116

Country: Number of subjects enrolled

Germany: 70

Country: Number of subjects enrolled

Austria: 29

Country: Number of subjects enrolled

Japan: 153

Country: Number of subjects enrolled

Portugal: 46

Country: Number of subjects enrolled

Spain: 126

Country: Number of subjects enrolled

Switzerland: 43

Country: Number of subjects enrolled

United Kingdom: 65

Country: Number of subjects enrolled

United States: 103

Worldwide total number of subjects

864

EEA total number of subjects

491

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)

788

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Are arms mutually exclusive

Yes

Relapser:Placebo

Arm description

Patients who had had a prior relapse, received 2 soft gelatin capsules identical to those containing Faldaprevir once daily (orally) and PegIFN/RBV (Pegylated interferon alpha-2a/Ribavirin) administered by injection, for 24 weeks, followed by PegIFN/RBV for 24 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

2 soft gelatin capsules identical to those containing Faldaprevir administered orally for 24 weeks.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1000 (<75 kilograms [kg] body weight) –1200mg (≥75 kg body weight) in 2 divided doses; 600 mg (≤60 kg body weight), 800 mg (>60 AND ≤80 kg body weight), 1000 mg (>80 kg body weight) (only for Japan) in 2 divided doses

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Relapser: Faldaprevir 12 weeks

Arm description

Patients who had had a prior relapse, received Faldaprevir (BI 201335) 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 12 weeks, followed by placebo once daily combined with PegIFN/RBV for 12 weeks. At week 24, if the patients did not achieve early treatment success (ETS) the patients received an additional 24 weeks of PegIFN/RBV alone.

Arm type

Experimental

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

A loading dose of 480 mg of Faldaprevir (FDV) was administered orally on the first day of administration, followed by 240 mg once daily from the second day on.

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

2 soft gelatin capsules identical to those containing Faldaprevir administered orally for last 12 weeks.

Relapser:Faldaprevir 24 weeks

Arm description

Patients who had had a prior relapse, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 24 weeks. At week 24, if the patients did not achieve early treatment success (ETS) the patients received an additional 24 weeks of PegIFN/RBV alone.

Arm type

Experimental

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

A loading dose of 480 mg of Faldaprevir (FDV) was administered orally on the first day of administration, followed by 240 mg once daily from the second day on.

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Partial:Placebo

Arm description

Patients who had had a prior partial response, received 2 soft gelatin capsules identical to those containing Faldaprevir once daily (orally) and PegIFN/RBV (Pegylated interferon alpha-2a/Ribavirin) administered by injection, for 24 weeks, followed by PegIFN/RBV for 24 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

2 soft gelatin capsules identical to those containing Faldaprevir administered orally for 24 weeks.

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Partial:Faldaprevir 12 weeks

Arm description

Patients who had had a prior partial response, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 12 weeks, followed by placebo once daily combined with PegIFN/RBV for 12 weeks. Followed by PegIFN/RBV alone for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

A loading dose of 480 mg of Faldaprevir (FDV) was administered orally on the first day of administration, followed by 240 mg once daily from the second day on.

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

2 soft gelatin capsules identical to those containing Faldaprevir administered orally for last 12 weeks.

Partial:Faldaprevir 24 weeks

Arm description

Patients who had had a prior partial response, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 24 weeks. Followed by PegIFN/RBV alone for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

A loading dose of 480 mg of Faldaprevir (FDV) was administered orally on the first day of administration, followed by 240 mg once daily from the second day on.

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Null:Faldaprevir 12 weeks

Arm description

Patients who had had a prior null response received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 12 weeks, followed by placebo once daily combined with PegIFN/RBV for 12 weeks. Followed by PegIFN/RBV alone for 24 weeks. One patient was randomised to the Null:Faldaprevir 12 weeks arm, however this patient was not treated. Consequently, even though the actual number of subjects that started is 146, only 145 were reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Experimental

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

A loading dose of 480 mg of Faldaprevir (FDV) was administered orally on the first day of administration, followed by 240 mg once daily from the second day on.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

2 soft gelatin capsules identical to those containing Faldaprevir administered orally for last 12 weeks.

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Null:Faldaprevir 24 weeks

Arm description

Arm type

Experimental

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

A loading dose of 480 mg of Faldaprevir (FDV) was administered orally on the first day of administration, followed by 240 mg once daily from the second day on.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Copegus ®

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Pegylated interferon alpha-2a

Investigational medicinal product code

Pegasys ®

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 micrograms (µcg)/0.5 mL pre-filled syringes (except Japan) once weekly 180 µcg/1 mL clear glass vials (only for Japan) once weekly

Number of subjects in period 1 ^[1]	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Started	49	99	103	29	57	55	145	140
Completed	18	86	87	10	46	42	81	85
Not completed	31	13	16	19	11	13	64	55
Other reason not defined above	2	-	-	-	-	-	2	-
Consent withdrawn by subject	3	4	2	-	-	1	1	3
Adverse event, non-fatal	-	6	9	-	4	8	12	7
Lost to follow-up	-	-	1	-	-	-	-	1
Lack of efficacy	26	3	4	19	7	4	49	44

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the study medication.

Baseline characteristics

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Reporting group title

Relapser:Placebo

Reporting group description

Reporting group title

Relapser: Faldaprevir 12 weeks

Reporting group description

Reporting group title

Relapser:Faldaprevir 24 weeks

Reporting group description

Reporting group title

Partial:Placebo

Reporting group description

Reporting group title

Partial:Faldaprevir 12 weeks

Reporting group description

Reporting group title

Partial:Faldaprevir 24 weeks

Reporting group description

Patients who had had a prior partial response, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 24 weeks. Followed by PegIFN/RBV alone for 24 weeks.

Reporting group title

Null:Faldaprevir 12 weeks

Reporting group description

Reporting group title

Null:Faldaprevir 24 weeks

Reporting group description

Reporting group values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks	Total
Number of subjects	49	99	103	29	57	55	145	140	677
Age categorical
Units: Subjects
Age Continuous
Full analysis set (FAS)- included all randomised patients who were dispensed study medication and were documented to have taken at least one dose of study medication.
Units: years
arithmetic mean (standard deviation)	53.4 ± 8.29	53.5 ± 8.57	53.7 ± 8.14	55.7 ± 7.5	52.7 ± 7.9	52 ± 10.32	53.2 ± 8.76	53.6 ± 8.13	-
Gender, Male/Female
Units: participants
Female	20	44	43	10	20	20	54	63	274
Male	29	55	60	19	37	35	91	77	403

End points

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Reporting group title

Relapser:Placebo

Reporting group description

Reporting group title

Relapser: Faldaprevir 12 weeks

Reporting group description

Reporting group title

Relapser:Faldaprevir 24 weeks

Reporting group description

Reporting group title

Partial:Placebo

Reporting group description

Reporting group title

Partial:Faldaprevir 12 weeks

Reporting group description

Reporting group title

Partial:Faldaprevir 24 weeks

Reporting group description

Patients who had had a prior partial response, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 24 weeks. Followed by PegIFN/RBV alone for 24 weeks.

Reporting group title

Null:Faldaprevir 12 weeks

Reporting group description

Reporting group title

Null:Faldaprevir 24 weeks

Reporting group description

Subject analysis set title

Relapser & partial: Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients who had had a prior relapse or prior partial relapse, received 2 soft gelatin capsules identical to those containing Faldaprevir once daily (orally) and PegIFN/RBV administered by injection, for 24 weeks, followed by PegIFN/RBV for 24 weeks.

Subject analysis set title

Relapser & partial: Faldaprevir 12 weeks

Subject analysis set type

Full analysis

Subject analysis set description

Patients who had had a prior partial relapse, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 12 weeks, followed by placebo once daily combined with PegIFN/RBV for 12 weeks. Followed by PegIFN/RBV alone for 24 weeks (for the partial relapsers the last 24 weeks was only if the patient did not achieve early treatment success (ETS)).

Subject analysis set title

Relapser & partial: Faldaprevir 24 weeks

Subject analysis set type

Full analysis

Subject analysis set description

Patients who had had a prior partial relapse, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 24 weeks. Followed by PegIFN/RBV alone for 24 weeks (for the partial relapsers the last 24 weeks was only if the patient did not achieve early treatment success (ETS)).

Primary: Sustained Virological Response 12 weeks post treatment (SVR12)

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End point title

Sustained Virological Response 12 weeks post treatment (SVR12) ^[1]

End point description

Percentage of participants with sustained virological response (SVR12) 12 weeks post treatment defined as plasma Hepatitis C virus Ribonucleic acid (HCV RNA) level <25 IU/mL (undetected) 12 weeks after the originally planned treatment duration.

End point type

Primary

End point timeframe

12 weeks post treatment, up to 60 weeks

Notes
[1] - 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: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks	Relapser & partial: Placebo	Relapser & partial: Faldaprevir 12 weeks	Relapser & partial: Faldaprevir 24 weeks
Number of subjects analysed	145 ^[2]	140 ^[3]	78 ^[4]	156 ^[5]	158 ^[6]
Units: percentage of participants
number (confidence interval 95%)	33.8 (26.1 to 41.5)	32.9 (25.1 to 40.6)	10.3 (3.5 to 17)	65.4 (57.9 to 72.9)	61.4 (53.8 to 69)

Notes
[2] - FAS
[3] - FAS
[4] - FAS
[5] - FAS
[6] - FAS

Statistical Analysis 1

Statistical analysis description

A stratified Cochran-MantelHaenszel test was used, where strata were defined by GT-1a, 1b, other subtype, and previous response to treatment (relapse yes/no). Comparison of active-treatment vs placebo.

Comparison groups

Relapser & partial: Placebo v Relapser & partial: Faldaprevir 12 weeks

Number of subjects included in analysis

234

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[7]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted percent difference

Point estimate

54.7

Confidence interval

level

95%

sides

2-sided

lower limit

44.4

upper limit

Notes
[7] - Adjusted for genotype and previous response to treatment

Statistical Analysis 2

Statistical analysis description

Comparison groups

Relapser & partial: Placebo v Relapser & partial: Faldaprevir 24 weeks

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted percent difference

Point estimate

50.4

Confidence interval

level

95%

sides

2-sided

lower limit

40.1

upper limit

60.8

Notes
[8] - Adjusted for genotype and previous response to treatment

Statistical Analysis 3

Statistical analysis description

A stratified Cochran-MantelHaenszel test was used, where strata were defined by GT-1a, 1b, other subtype, and previous response to treatment (relapse yes/no). Comparison of FDV 24 weeks vs FDV 12 weeks

Comparison groups

Relapser & partial: Faldaprevir 12 weeks v Relapser & partial: Faldaprevir 24 weeks

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Adjusted percent difference

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-5.8

upper limit

14.9

Statistical Analysis 4

Statistical analysis description

Comparison groups

Null:Faldaprevir 12 weeks v Null:Faldaprevir 24 weeks

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Adjusted percent difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-10.9

upper limit

10.7

Secondary: Virological response after 24 weeks of treatment discontinuation (SVR24)

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End point title

Virological response after 24 weeks of treatment discontinuation (SVR24) ^[9]

End point description

Percentage of participants with virological response after 24 weeks of treatment discontinuation (SVR24) defined as plasma Hepatitis C virus Ribonucleic acid (HCV RNA) level <25 IU/mL (undetected) 24 weeks after the originally planned treatment duration.

End point type

Secondary

End point timeframe

24 weeks post treatment, up to 72 weeks

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: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks	Relapser & partial: Placebo	Relapser & partial: Faldaprevir 12 weeks	Relapser & partial: Faldaprevir 24 weeks
Number of subjects analysed	145 ^[10]	140 ^[11]	78 ^[12]	156 ^[13]	158 ^[14]
Units: percentage of participants
number (confidence interval 95%)	33.8 (26.1 to 41.5)	32.9 (25.1 to 40.6)	10.3 (3.5 to 17)	63.5 (55.9 to 71)	59.5 (51.8 to 67.1)

Notes
[10] - FAS
[11] - FAS
[12] - FAS
[13] - FAS
[14] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Relapser & partial: Placebo v Relapser & partial: Faldaprevir 12 weeks

Number of subjects included in analysis

234

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[15]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted percent difference

Point estimate

52.8

Confidence interval

level

95%

sides

2-sided

lower limit

42.4

upper limit

63.2

Notes
[15] - Adjusted for genotype and previous response to treatment

Statistical Analysis 2

Statistical analysis description

Comparison groups

Relapser & partial: Placebo v Relapser & partial: Faldaprevir 24 weeks

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted percent difference

Point estimate

48.5

Confidence interval

level

95%

sides

2-sided

lower limit

38.2

upper limit

58.9

Notes
[16] - Adjusted for genotype and previous response to treatment

Statistical Analysis 3

Statistical analysis description

Comparison groups

Relapser & partial: Faldaprevir 12 weeks v Relapser & partial: Faldaprevir 24 weeks

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Adjusted percent difference

Point estimate

4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

14.9

Statistical Analysis 4

Statistical analysis description

Comparison groups

Null:Faldaprevir 12 weeks v Null:Faldaprevir 24 weeks

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Adjusted percent difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-10.9

upper limit

10.7

Secondary: Early Treatment Success (ETS)

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End point title

Early Treatment Success (ETS)

End point description

Percentage of participants with early Treatment Success (ETS) defined as a plasma HCV RNA level <25 IU/mL (undetected or detected) at Week 4 and <25 IU/mL (undetected) at Week 8.

End point type

Secondary

End point timeframe

Week 4 and Week 8

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[17]	99 ^[18]	103 ^[19]	29 ^[20]	57 ^[21]	55 ^[22]	145 ^[23]	140 ^[24]
Units: percentage of participants
number (not applicable)	4.1	85.9	87.4	3.4	66.7	76.4	58.6	51.4

Notes
[17] - FAS
[18] - FAS
[19] - FAS
[20] - FAS
[21] - FAS
[22] - FAS
[23] - FAS
[24] - FAS

No statistical analyses for this end point

Secondary: ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=NO

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End point title

ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=NO

End point description

The number of participants with alanine aminotransferase (ALT) in normal range at the end of treatment (EoT) when patients do not have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

End of treatment, up to 48 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[25]	99 ^[26]	103 ^[27]	29 ^[28]	57 ^[29]	55 ^[30]	145 ^[31]	140 ^[32]
Units: participants
number (not applicable)
SVR12=NO	42	30	31	28	24	30	96	94
BL normal to EoT normal	9	9	6	3	4	4	15	14
BL elevated to EoT normal	15	10	14	9	14	6	34	38
No EoT data available for ALT	1	0	0	0	0	1	1	0

Notes
[25] - FAS
[26] - FAS
[27] - FAS
[28] - FAS
[29] - FAS
[30] - FAS
[31] - FAS
[32] - FAS

No statistical analyses for this end point

Secondary: ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=YES

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End point title

ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=YES

End point description

The number of participants with alanine aminotransferase (ALT) in normal range at the end of treatment when patients have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

End of treatment, up to 48 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[33]	99 ^[34]	103 ^[35]	29 ^[36]	57 ^[37]	55 ^[38]	145 ^[39]	140 ^[40]
Units: participants
number (not applicable)
SVR12=YES	7	69	72	1	33	25	49	46
BL normal to EoT normal	3	30	30	0	10	8	12	9
BL elevated to EoT normal	4	29	26	1	14	8	23	27

Notes
[33] - FAS
[34] - FAS
[35] - FAS
[36] - FAS
[37] - FAS
[38] - FAS
[39] - FAS
[40] - FAS

No statistical analyses for this end point

Secondary: AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=NO

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End point title

AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=NO

End point description

The number of participants with aspartate aminotransferase (AST) in normal range at the end of treatment when patients do not have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

End of treatment, up to 48 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[41]	99 ^[42]	103 ^[43]	29 ^[44]	57 ^[45]	55 ^[46]	145 ^[47]	140 ^[48]
Units: participants
number (not applicable)
SVR12=NO	42	30	31	28	24	30	96	94
BL normal to EoT normal	19	16	12	4	3	5	18	21
BL elevated to EoT normal	5	5	9	9	14	6	24	28

Notes
[41] - FAS
[42] - FAS
[43] - FAS
[44] - FAS
[45] - FAS
[46] - FAS
[47] - FAS
[48] - FAS

No statistical analyses for this end point

Secondary: AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=YES

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End point title

AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=YES

End point description

The number of participants with aspartate aminotransferase (AST) in normal range at the end of treatment (EoT) when patients have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

End of treatment, up to 48 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[49]	99 ^[50]	103 ^[51]	29 ^[52]	57 ^[53]	55 ^[54]	145 ^[55]	140 ^[56]
Units: participants
number (not applicable)
SVR12=YES	7	69	72	1	33	25	49	46
BL normal to EoT normal	2	35	39	0	13	10	15	16
BL elevated to EoT normal	4	24	22	1	10	9	21	20
No EoT data available for AST	1	0	0	0	0	1	1	0

Notes
[49] - FAS
[50] - FAS
[51] - FAS
[52] - FAS
[53] - FAS
[54] - FAS
[55] - FAS
[56] - FAS

No statistical analyses for this end point

Secondary: ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, When SVR12=NO

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End point title

ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, When SVR12=NO

End point description

The number of participants with alanine aminotransferase (ALT) in normal range post treatment when patients do not have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

12 weeks post treatment, up to 60 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[57]	99 ^[58]	103 ^[59]	29 ^[60]	57 ^[61]	55 ^[62]	145 ^[63]	140 ^[64]
Units: participants
number (not applicable)
SVR12=NO	42	30	31	28	24	30	96	94
BL normal to SVR12 normal	0	9	6	0	2	4	11	6
BL elevated to SVR12 normal	1	6	6	0	4	3	7	9
No ALT data available at SVR12 visit	33	7	3	3	6	5	27	30

Notes
[57] - FAS
[58] - FAS
[59] - FAS
[60] - FAS
[61] - FAS
[62] - FAS
[63] - FAS
[64] - FAS

No statistical analyses for this end point

Secondary: ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, SVR12=YES

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End point title

ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, SVR12=YES

End point description

The number of participants with alanine aminotransferase (ALT) in normal range post treatment when patients have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

12 weeks post treatment, up to 60 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[65]	99 ^[66]	103 ^[67]	29 ^[68]	57 ^[69]	55 ^[70]	145 ^[71]	140 ^[72]
Units: participants
number (not applicable)
SVR12=YES	7	69	72	1	33	25	49	46
BL normal to SVR12 normal	3	31	31	0	13	10	13	10
BL elevated to SVR12 normal	3	35	38	1	20	11	32	35
No ALT data available at SVR12 visit	1	1	0	0	0	0	1	0

Notes
[65] - FAS
[66] - FAS
[67] - FAS
[68] - FAS
[69] - FAS
[70] - FAS
[71] - FAS
[72] - FAS

No statistical analyses for this end point

Secondary: AST Normalisation: AST in Normal Range 12 weeks Post Treatment, When SVR12=NO

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End point title

AST Normalisation: AST in Normal Range 12 weeks Post Treatment, When SVR12=NO

End point description

The number of participants with aspartate aminotransferase (AST) in normal range post treatment when patients do not have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

12 weeks post treatment, up to 60 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[73]	99 ^[74]	103 ^[75]	29 ^[76]	57 ^[77]	55 ^[78]	145 ^[79]	140 ^[80]
Units: participants
number (not applicable)
SVR12=NO	42	30	31	28	24	30	96	94
BL normal to SVR12 normal	0	14	10	0	3	3	13	14
BL elevated to SVR12 normal	2	2	6	0	6	3	6	3
No AST data available at SVR12 visit	33	7	3	23	6	6	27	30

Notes
[73] - FAS
[74] - FAS
[75] - FAS
[76] - FAS
[77] - FAS
[78] - FAS
[79] - FAS
[80] - FAS

No statistical analyses for this end point

Secondary: AST Normalisation: AST in Normal Range 12 weeks Post Treatment, SVR12=YES

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End point title

AST Normalisation: AST in Normal Range 12 weeks Post Treatment, SVR12=YES

End point description

The number of participants with aspartate aminotransferase (AST) in normal range post treatment when patients have sustained virological response 12 weeks post treatment. BL=baseline

End point type

Secondary

End point timeframe

12 weeks post treatment, up to 60 weeks

End point values	Relapser:Placebo	Relapser: Faldaprevir 12 weeks	Relapser:Faldaprevir 24 weeks	Partial:Placebo	Partial:Faldaprevir 12 weeks	Partial:Faldaprevir 24 weeks	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks
Number of subjects analysed	49 ^[81]	99 ^[82]	103 ^[83]	29 ^[84]	57 ^[85]	55 ^[86]	145 ^[87]	140 ^[88]
Units: participants
number (not applicable)
SVR12=YES	7	69	72	1	33	25	49	46
BL normal to SVR12 normal	2	36	41	0	16	13	16	17
BL elevated to SVR12 normal	4	29	28	1	16	8	28	25
No AST data available at SVR12 visit	1	1	0	0	0	0	1	0

Notes
[81] - FAS
[82] - FAS
[83] - FAS
[84] - FAS
[85] - FAS
[86] - FAS
[87] - FAS
[88] - FAS

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

During the course of the study (48 weeks)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Null:Faldaprevir 12 weeks

Reporting group description

Reporting group title

Null:Faldaprevir 24 weeks

Reporting group description

Reporting group title

Relapser & partial:Faldaprevir 24 weeks

Reporting group description

Patients who had had a prior relapse or prior partial response, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 24 weeks. Followed by PegIFN/RBV alone for 24 weeks (for the partial relapsers the last 24 weeks was only if the patient did not achieve early treatment success (ETS)).

Reporting group title

Relapser & partial:Faldaprevir 12 weeks

Reporting group description

Patients who had had a prior relapse or prior partial response, received Faldaprevir 240mg once daily, in the form of 2 soft gelatin capsules administered orally, combined with PegIFN/RBV, administered by injection, for 12 weeks, followed by placebo once daily combined with PegIFN/RBV for 12 weeks. Followed by PegIFN/RBV alone for 24 weeks (for the partial relapsers the last 24 weeks was only if the patient did not achieve early treatment success (ETS)).

Reporting group title

Relapser & partial:Placebo

Reporting group description

Patients who had had a prior relapse or prior partial response, received 2 soft gelatin capsules identical to those containing Faldaprevir once daily (orally) and PegIFN/RBV administered by injection, for 24 weeks, followed by PegIFN/RBV for 24 weeks.

Serious adverse events	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks	Relapser & partial:Faldaprevir 24 weeks	Relapser & partial:Faldaprevir 12 weeks	Relapser & partial:Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 145 (11.03%)	11 / 140 (7.86%)	13 / 158 (8.23%)	14 / 156 (8.97%)	1 / 78 (1.28%)
number of deaths (all causes)	3	0	2	2	0
number of deaths resulting from adverse events	0	0	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 145 (0.69%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 145 (2.07%)	1 / 140 (0.71%)	1 / 158 (0.63%)	3 / 156 (1.92%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	0 / 1	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric decompensation
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio abnormal
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Congenital, familial and genetic disorders
Keratosis follicular
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Nervous system disorders
Coma
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 145 (1.38%)	1 / 140 (0.71%)	1 / 158 (0.63%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	3 / 158 (1.90%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	2 / 145 (1.38%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 145 (1.38%)	2 / 140 (1.43%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	1 / 158 (0.63%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral lichen planus
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Salivary gland calculus
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	2 / 156 (1.28%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatorenal failure
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash erythematous
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fasciitis
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint instability
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal discomfort
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 145 (0.00%)	1 / 140 (0.71%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	0 / 158 (0.00%)	1 / 156 (0.64%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 140 (0.00%)	0 / 158 (0.00%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 145 (0.00%)	0 / 140 (0.00%)	1 / 158 (0.63%)	0 / 156 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0

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

Non-serious adverse events	Null:Faldaprevir 12 weeks	Null:Faldaprevir 24 weeks	Relapser & partial:Faldaprevir 24 weeks	Relapser & partial:Faldaprevir 12 weeks	Relapser & partial:Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	142 / 145 (97.93%)	139 / 140 (99.29%)	156 / 158 (98.73%)	148 / 156 (94.87%)	74 / 78 (94.87%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	24 / 145 (16.55%)	28 / 140 (20.00%)	28 / 158 (17.72%)	28 / 156 (17.95%)	21 / 78 (26.92%)
occurrences all number	24	29	28	28	22
Chills
subjects affected / exposed	1 / 145 (0.69%)	8 / 140 (5.71%)	14 / 158 (8.86%)	9 / 156 (5.77%)	5 / 78 (6.41%)
occurrences all number	1	9	14	9	5
Fatigue
subjects affected / exposed	45 / 145 (31.03%)	47 / 140 (33.57%)	59 / 158 (37.34%)	53 / 156 (33.97%)	16 / 78 (20.51%)
occurrences all number	47	48	62	54	16
Influenza like illness
subjects affected / exposed	27 / 145 (18.62%)	23 / 140 (16.43%)	29 / 158 (18.35%)	28 / 156 (17.95%)	15 / 78 (19.23%)
occurrences all number	30	24	29	29	15
Injection site erythema
subjects affected / exposed	4 / 145 (2.76%)	4 / 140 (2.86%)	3 / 158 (1.90%)	1 / 156 (0.64%)	4 / 78 (5.13%)
occurrences all number	4	4	3	1	4
Malaise
subjects affected / exposed	4 / 145 (2.76%)	11 / 140 (7.86%)	10 / 158 (6.33%)	5 / 156 (3.21%)	4 / 78 (5.13%)
occurrences all number	4	11	10	5	4
Pain
subjects affected / exposed	4 / 145 (2.76%)	4 / 140 (2.86%)	7 / 158 (4.43%)	5 / 156 (3.21%)	4 / 78 (5.13%)
occurrences all number	4	4	7	5	4
Pyrexia
subjects affected / exposed	26 / 145 (17.93%)	38 / 140 (27.14%)	25 / 158 (15.82%)	24 / 156 (15.38%)	14 / 78 (17.95%)
occurrences all number	28	43	26	26	16
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	4 / 145 (2.76%)	3 / 140 (2.14%)	3 / 158 (1.90%)	5 / 156 (3.21%)	4 / 78 (5.13%)
occurrences all number	4	4	3	5	5
Cough
subjects affected / exposed	23 / 145 (15.86%)	24 / 140 (17.14%)	27 / 158 (17.09%)	25 / 156 (16.03%)	16 / 78 (20.51%)
occurrences all number	25	26	27	25	17
Dyspnoea
subjects affected / exposed	8 / 145 (5.52%)	7 / 140 (5.00%)	16 / 158 (10.13%)	16 / 156 (10.26%)	7 / 78 (8.97%)
occurrences all number	8	7	16	16	7
Psychiatric disorders
Depression
subjects affected / exposed	14 / 145 (9.66%)	15 / 140 (10.71%)	12 / 158 (7.59%)	11 / 156 (7.05%)	10 / 78 (12.82%)
occurrences all number	14	15	12	11	10
Anxiety
subjects affected / exposed	5 / 145 (3.45%)	11 / 140 (7.86%)	12 / 158 (7.59%)	9 / 156 (5.77%)	3 / 78 (3.85%)
occurrences all number	5	12	12	9	3
Insomnia
subjects affected / exposed	18 / 145 (12.41%)	29 / 140 (20.71%)	35 / 158 (22.15%)	36 / 156 (23.08%)	13 / 78 (16.67%)
occurrences all number	19	29	35	36	13
Irritability
subjects affected / exposed	10 / 145 (6.90%)	13 / 140 (9.29%)	16 / 158 (10.13%)	10 / 156 (6.41%)	11 / 78 (14.10%)
occurrences all number	10	13	18	10	11
Sleep disorder
subjects affected / exposed	8 / 145 (5.52%)	10 / 140 (7.14%)	5 / 158 (3.16%)	4 / 156 (2.56%)	3 / 78 (3.85%)
occurrences all number	8	10	5	4	3
Investigations
Haemoglobin decreased
subjects affected / exposed	9 / 145 (6.21%)	10 / 140 (7.14%)	4 / 158 (2.53%)	6 / 156 (3.85%)	2 / 78 (2.56%)
occurrences all number	10	10	4	10	2
Weight decreased
subjects affected / exposed	8 / 145 (5.52%)	8 / 140 (5.71%)	2 / 158 (1.27%)	7 / 156 (4.49%)	3 / 78 (3.85%)
occurrences all number	8	8	2	7	3
Nervous system disorders
Disturbance in attention
subjects affected / exposed	2 / 145 (1.38%)	4 / 140 (2.86%)	9 / 158 (5.70%)	4 / 156 (2.56%)	1 / 78 (1.28%)
occurrences all number	2	4	9	4	1
Headache
subjects affected / exposed	52 / 145 (35.86%)	45 / 140 (32.14%)	46 / 158 (29.11%)	39 / 156 (25.00%)	22 / 78 (28.21%)
occurrences all number	55	45	46	39	28
Dizziness
subjects affected / exposed	9 / 145 (6.21%)	5 / 140 (3.57%)	11 / 158 (6.96%)	12 / 156 (7.69%)	6 / 78 (7.69%)
occurrences all number	9	5	11	14	6
Dysgeusia
subjects affected / exposed	7 / 145 (4.83%)	12 / 140 (8.57%)	12 / 158 (7.59%)	8 / 156 (5.13%)	4 / 78 (5.13%)
occurrences all number	7	12	12	8	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	22 / 145 (15.17%)	19 / 140 (13.57%)	27 / 158 (17.09%)	30 / 156 (19.23%)	8 / 78 (10.26%)
occurrences all number	23	22	31	37	9
Neutropenia
subjects affected / exposed	16 / 145 (11.03%)	13 / 140 (9.29%)	18 / 158 (11.39%)	18 / 156 (11.54%)	12 / 78 (15.38%)
occurrences all number	17	17	36	29	19
Thrombocytopenia
subjects affected / exposed	13 / 145 (8.97%)	3 / 140 (2.14%)	6 / 158 (3.80%)	4 / 156 (2.56%)	3 / 78 (3.85%)
occurrences all number	15	3	6	5	3
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	6 / 145 (4.14%)	9 / 140 (6.43%)	4 / 158 (2.53%)	4 / 156 (2.56%)	3 / 78 (3.85%)
occurrences all number	6	10	4	4	3
Eye disorders
Ocular icterus
subjects affected / exposed	6 / 145 (4.14%)	2 / 140 (1.43%)	6 / 158 (3.80%)	8 / 156 (5.13%)	0 / 78 (0.00%)
occurrences all number	6	2	6	8	0
Dry eye
subjects affected / exposed	4 / 145 (2.76%)	5 / 140 (3.57%)	7 / 158 (4.43%)	6 / 156 (3.85%)	5 / 78 (6.41%)
occurrences all number	4	5	7	6	5
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	7 / 145 (4.83%)	13 / 140 (9.29%)	14 / 158 (8.86%)	8 / 156 (5.13%)	2 / 78 (2.56%)
occurrences all number	7	16	15	9	2
Constipation
subjects affected / exposed	7 / 145 (4.83%)	7 / 140 (5.00%)	8 / 158 (5.06%)	14 / 156 (8.97%)	3 / 78 (3.85%)
occurrences all number	7	7	8	16	3
Abdominal pain upper
subjects affected / exposed	11 / 145 (7.59%)	15 / 140 (10.71%)	15 / 158 (9.49%)	16 / 156 (10.26%)	4 / 78 (5.13%)
occurrences all number	11	17	16	16	4
Diarrhoea
subjects affected / exposed	39 / 145 (26.90%)	47 / 140 (33.57%)	59 / 158 (37.34%)	45 / 156 (28.85%)	10 / 78 (12.82%)
occurrences all number	47	58	67	52	11
Dyspepsia
subjects affected / exposed	12 / 145 (8.28%)	9 / 140 (6.43%)	13 / 158 (8.23%)	13 / 156 (8.33%)	6 / 78 (7.69%)
occurrences all number	12	10	15	14	6
Gastrooesophageal reflux disease
subjects affected / exposed	3 / 145 (2.07%)	6 / 140 (4.29%)	0 / 158 (0.00%)	3 / 156 (1.92%)	5 / 78 (6.41%)
occurrences all number	3	6	0	3	5
Nausea
subjects affected / exposed	77 / 145 (53.10%)	75 / 140 (53.57%)	88 / 158 (55.70%)	78 / 156 (50.00%)	18 / 78 (23.08%)
occurrences all number	82	79	93	82	20
Vomiting
subjects affected / exposed	46 / 145 (31.72%)	37 / 140 (26.43%)	47 / 158 (29.75%)	41 / 156 (26.28%)	5 / 78 (6.41%)
occurrences all number	55	68	57	52	6
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	10 / 145 (6.90%)	9 / 140 (6.43%)	11 / 158 (6.96%)	11 / 156 (7.05%)	0 / 78 (0.00%)
occurrences all number	10	9	11	11	0
Jaundice
subjects affected / exposed	16 / 145 (11.03%)	16 / 140 (11.43%)	27 / 158 (17.09%)	29 / 156 (18.59%)	1 / 78 (1.28%)
occurrences all number	17	16	29	29	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	8 / 145 (5.52%)	13 / 140 (9.29%)	16 / 158 (10.13%)	16 / 156 (10.26%)	4 / 78 (5.13%)
occurrences all number	8	13	16	16	4
Dry skin
subjects affected / exposed	19 / 145 (13.10%)	31 / 140 (22.14%)	29 / 158 (18.35%)	29 / 156 (18.59%)	12 / 78 (15.38%)
occurrences all number	19	32	29	29	12
Erythema
subjects affected / exposed	11 / 145 (7.59%)	12 / 140 (8.57%)	9 / 158 (5.70%)	8 / 156 (5.13%)	4 / 78 (5.13%)
occurrences all number	13	15	10	9	5
Pruritus
subjects affected / exposed	47 / 145 (32.41%)	63 / 140 (45.00%)	61 / 158 (38.61%)	54 / 156 (34.62%)	23 / 78 (29.49%)
occurrences all number	52	68	68	58	23
Rash
subjects affected / exposed	38 / 145 (26.21%)	41 / 140 (29.29%)	44 / 158 (27.85%)	37 / 156 (23.72%)	16 / 78 (20.51%)
occurrences all number	42	48	47	39	18
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	5 / 145 (3.45%)	7 / 140 (5.00%)	12 / 158 (7.59%)	14 / 156 (8.97%)	8 / 78 (10.26%)
occurrences all number	5	8	12	15	8
Arthralgia
subjects affected / exposed	10 / 145 (6.90%)	15 / 140 (10.71%)	21 / 158 (13.29%)	14 / 156 (8.97%)	7 / 78 (8.97%)
occurrences all number	11	15	21	14	7
Myalgia
subjects affected / exposed	15 / 145 (10.34%)	18 / 140 (12.86%)	19 / 158 (12.03%)	20 / 156 (12.82%)	8 / 78 (10.26%)
occurrences all number	15	18	19	20	8
Muscle spasms
subjects affected / exposed	4 / 145 (2.76%)	8 / 140 (5.71%)	8 / 158 (5.06%)	7 / 156 (4.49%)	2 / 78 (2.56%)
occurrences all number	4	8	8	9	2
Infections and infestations
Influenza
subjects affected / exposed	4 / 145 (2.76%)	1 / 140 (0.71%)	6 / 158 (3.80%)	4 / 156 (2.56%)	4 / 78 (5.13%)
occurrences all number	4	1	6	5	4
Nasopharyngitis
subjects affected / exposed	6 / 145 (4.14%)	10 / 140 (7.14%)	13 / 158 (8.23%)	14 / 156 (8.97%)	7 / 78 (8.97%)
occurrences all number	7	13	16	16	9
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	27 / 145 (18.62%)	36 / 140 (25.71%)	32 / 158 (20.25%)	33 / 156 (21.15%)	10 / 78 (12.82%)
occurrences all number	29	41	32	34	11

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Were there any global substantial amendments to the protocol? Yes

24 Jun 2011

Revision of Cohort 2 (partial responders) and Cohort 3 (null responders) to contain a maximum of 250 patients each. Several time window changes to offer sites and patients more scheduling flexibility Clarification of definitions for severity of rash and management guidelines for rash/photosensitivity reactions Clarification of genotypic resistance section Clarification of End of Treatment; patients were not stopped early if their viral load was below the limit of quantification. Clarification of inclusion (i.e. liver diseasebiopsies sought but were allowed to be waived if patient would have been put at risk) Clarifications of exclusion criteria for criterion #2, as well as based on CTP classification and updates of the Summary of Product Characteristics (SPC) for ribavirin. Changes included: incidental steatosis diagnosed by biopsy was not an exclusion criterion, decompensated liver disease was based on CTP classification, pre-existing psychiatric conditions, added creatinine clearance ≤50 mL/min) Addition of section on pure red-cell aplasia to facilitate safety reporting Implementation of a revised AE grading system (DAIDS grading) in order to harmonize AE reporting across HCV projects. Adjusted definition and reporting of AEs of special interest Addition of HCRU and work productivity data collection for HEOR evaluation Clarification of management of missed treatment doses Patients that permanently discontinue any study drug were not eligible to stop all treatment at Week 24, but rather followed the 48-week visit schedule.Revision of other endpoints: Extended rapid virological response was removed and progression of liver disease following EOT was added. Clarification that not every severe or serious AE prompted treatment discontinuation.

12 Mar 2012

Modified duration of treatment to SVR12 as primary endpoint and SVR24 as secondary based on regulatory presentations and retrospective analysis of phase II data indicating 98% positive predictive value. Clarification of stopping rule: Viral load results obtained at Visit 2a (Day 2) and Visit 2b (Day 7) were used for correlation with PK levels only. Stopping rule criteria were not considered based on viral load values from Visit 2a and 2b. Clarification of process: Investigators remained blinded to HCV load results during the first 8 weeks of therapy. The Investigator was informed by IVRS when a criteria for treatment discontinuation due to lack of efficacy were met for a given patient during the first 8 weeks of treatment. Once at Week 12 (V6), investigators received HCV RNA results. Clarification of dose modifications: FDV except for the results prior to Week 12 which remained blinded: No dose reductions were permitted for FDV. Interruptions had to be discussed with the clinical monitor. If only FDV was discontinued, patient was continued on PegIFN and RBV if medically appropriate. FDV monotherapy was not allowed. PegIFN: Dose reduction PegIFN (according to ANC or platelets) was initiated as per protocol. If Peg IFN had to be permanently discontinued, RBV and FDV (if applicable) had to also be discontinued within 7 days from the final decision to discontinue PegIFN. PegIFN interruptions had to be discussed with the clinical monitor. RBV: Treatment visit change: Follow Up 2 Visit changed from ±14 days to ±7 days. Revision of EOT process to: The Week 48 visit was also performed for early treatment discontinuation patients as per schedule. Any patient who was virologic failure (lack of efficacy) and was eligible for the rollover trial (PegIFN/RBV failures) but refused participation in 1220.48 was discontinued from the trial. Follow up 2 visit window reduced to encourage more timely visits near database lock. Oral antivirals for herpes simplex were allowed.

21 Mar 2012

Revised approach for implementation of amendment 2 to implement immediately to eliminate hazard and notify IRB/IEC/Competent Authority.

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.

Due to the platform limitations, statistical analysis for null responders compared to historical rates of SVR could not be presented. Results for those can be found on ct.gov, study number NCT01358864.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Sustained Virological Response 12 weeks post treatment (SVR12)

Primary: Sustained Virological Response 12 weeks post treatment (SVR12)

Secondary: Virological response after 24 weeks of treatment discontinuation (SVR24)

Secondary: Virological response after 24 weeks of treatment discontinuation (SVR24)

Secondary: Early Treatment Success (ETS)

Secondary: Early Treatment Success (ETS)

Secondary: ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=NO

Secondary: ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=NO

Secondary: ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=YES

Secondary: ALT Normalisation: ALT in Normal Range at End of Treatment, When SVR12=YES

Secondary: AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=NO

Secondary: AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=NO

Secondary: AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=YES

Secondary: AST Normalisation: AST in Normal Range at End of Treatment, When SVR12=YES

Secondary: ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, When SVR12=NO

Secondary: ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, When SVR12=NO

Secondary: ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, SVR12=YES

Secondary: ALT Normalisation: ALT in Normal Range 12 weeks Post Treatment, SVR12=YES

Secondary: AST Normalisation: AST in Normal Range 12 weeks Post Treatment, When SVR12=NO

Secondary: AST Normalisation: AST in Normal Range 12 weeks Post Treatment, When SVR12=NO

Secondary: AST Normalisation: AST in Normal Range 12 weeks Post Treatment, SVR12=YES

Secondary: AST Normalisation: AST in Normal Range 12 weeks Post Treatment, SVR12=YES

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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