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Clinical Trial Results:
A Randomized, Open-Label, Multicenter Study to Evaluate the Antiviral Activity, Safety, and Pharmacokinetics, of ABT-450 with Ritonavir (ABT-450/r) in Combination with ABT-267 and/or ABT-333 With and Without Ribavirin (RBV) for 8, 12 or 24 Weeks in Treatment-Naïve and Null Responder Subjects with Genotype 1 Chronic Hepatitis C Virus Infection

Summary
EudraCT number	2010-022455-31
Trial protocol	GB ES
Global end of trial date	19 Sep 2013

Results information
Results version number	v1(current)
This version publication date	20 Apr 2016
First version publication date	13 Jun 2015
Other versions

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

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Trial information

Top of page

Sponsor protocol code

M11-652

ISRCTN number

US NCT number

NCT01464827

WHO universal trial number (UTN)

Sponsor organisation name

Abbvie Deutschland GmbH & Co.KG

Sponsor organisation address

Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4XE

Public contact

Global Medical Information, AbbVie, 011 800-633-9110,

Scientific contact

Daniel Cohen, MD, AbbVie , daniel.cohen@abbvie.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

19 Sep 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

Assess the safety of all treatment regimens and the percentage of subjects achieving 24-week sustained virologic response (SVR24; hepatitis C virus [HCV] ribonucleic acid [RNA] less than the lower limit of quantitation [LLOQ] at post-treatment Week 24) following treatment for 8 weeks versus 12 weeks with 3 direct-acting antiviral agents (DAA) and ribavirin (RBV) in HCV genotype 1-infected treatment-naïve adults.

Protection of trial subjects

The study was conducted in accordance with the protocol, ICH guidelines, applicable regulations and guidelines governing clinical study conduct, and the ethical principles that have their origin in the Declaration of Helsinki. All subjects entering the study had to sign an informed consent that was explained to them and questions encouraged.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Oct 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 36

Country: Number of subjects enrolled

United Kingdom: 33

Country: Number of subjects enrolled

United States: 400

Country: Number of subjects enrolled

Australia: 8

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

France: 58

Country: Number of subjects enrolled

Germany: 39

Country: Number of subjects enrolled

New Zealand: 1

Worldwide total number of subjects

580

EEA total number of subjects

166

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)

548

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Subjects underwent screening procedures within 35 days prior to enrollment. HCV genotype 1-infected adult male and female subjects who were either treatment-naïve or previous null responders to pegylated interferon (pegIFN) and RBV were eligible to participate.

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

Group A

Arm description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 8 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Group B

Arm description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group C

Arm description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group D

Arm description

Treatment-naïve participants received ABT-450 200 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Group E

Arm description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ABT-333 400 mg twice daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Group F

Arm description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group G

Arm description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group H

Arm description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group I

Arm description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group J

Arm description

Participants who were null-responders to previous HCV treatment received ABT-450 200 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group K

Arm description

Participants who were null-responders to previous HCV treatment received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group L

Arm description

Participants who were null-responders to previous HCV treatment received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group M

Arm description

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Group N

Arm description

Arm type

Experimental

Investigational medicinal product name

ABT-450

Investigational medicinal product code

Other name

Paritaprevir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg tablets

Investigational medicinal product name

ABT-333

Investigational medicinal product code

Other name

Dasabuvir

Pharmaceutical forms

Tablet

Routes of administration

Other use

Dosage and administration details

400 mg tablets

Investigational medicinal product name

ABT-267

Investigational medicinal product code

Other name

Ombitasvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablets

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg capsules

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).

Number of subjects in period 1	Group A	Group B	Group C	Group D	Group E	Group F	Group G	Group H	Group I	Group J	Group K	Group L	Group M	Group N
Started	80	43	39	40	80	39	41	40	40	47	23	23	23	22
Treated	80	41	39	40	79	39	40	40	40	45	23	22	23	20
Completed	77	36	39	36	72	38	37	37	37	44	21	21	21	19
Not completed	3	7	0	4	8	1	4	3	3	3	2	2	2	3
Consent withdrawn by subject	1	-	-	-	1	-	-	1	-	-	-	-	-	-
Adverse event, non-fatal	-	-	-	-	-	-	-	-	-	-	-	-	1	-
Other	2	3	-	2	3	-	1	-	3	1	2	-	1	-
Lost to follow-up	-	2	-	2	3	1	2	2	-	-	-	1	-	1
Not treated	-	2	-	-	1	-	1	-	-	2	-	1	-	2

Baseline characteristics

Top of page

Reporting group title

Group A

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 8 weeks.

Reporting group title

Group B

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group C

Reporting group description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group D

Reporting group description

Treatment-naïve participants received ABT-450 200 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group E

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ABT-333 400 mg twice daily for 12 weeks.

Reporting group title

Group F

Reporting group description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group G

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Reporting group title

Group H

Reporting group description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks.

Reporting group title

Group I

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks.

Reporting group title

Group J

Reporting group description

Reporting group title

Group K

Reporting group description

Reporting group title

Group L

Reporting group description

Reporting group title

Group M

Reporting group description

Reporting group title

Group N

Reporting group description

Reporting group values	Group A	Group B	Group C	Group D	Group E	Group F	Group G	Group H	Group I	Group J	Group K	Group L	Group M	Group N	Total
Number of subjects	80	43	39	40	80	39	41	40	40	47	23	23	23	22	580
Age categorical
Units: Subjects
Age continuous
Data are provided for the safety population (participants who received at least 1 dose of direct-acting antiviral agent).
Units: years
arithmetic mean (standard deviation)	50.1 ( 9.99 )	50.8 ( 9.84 )	51.1 ( 8.07 )	49 ( 10.59 )	48.3 ( 10.53 )	49.4 ( 9.72 )	51 ( 11.08 )	51.5 ( 11.95 )	51.5 ( 9.78 )	50.6 ( 11.19 )	48.5 ( 12.91 )	51.2 ( 12.07 )	51.5 ( 9.06 )	54.6 ( 11.78 )	-
Gender categorical
Units: Subjects
Female	34	24	14	20	34	19	16	22	24	19	7	10	8	9	260
Male	46	19	25	20	46	20	25	18	16	28	16	13	15	13	320

End points

Top of page

Reporting group title

Group A

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 8 weeks.

Reporting group title

Group B

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group C

Reporting group description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group D

Reporting group description

Treatment-naïve participants received ABT-450 200 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group E

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ABT-333 400 mg twice daily for 12 weeks.

Reporting group title

Group F

Reporting group description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group G

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Reporting group title

Group H

Reporting group description

Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks.

Reporting group title

Group I

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks.

Reporting group title

Group J

Reporting group description

Reporting group title

Group K

Reporting group description

Reporting group title

Group L

Reporting group description

Reporting group title

Group M

Reporting group description

Reporting group title

Group N

Reporting group description

Subject analysis set title

Group A

Subject analysis set type

Safety analysis

Subject analysis set description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 8 weeks.

Subject analysis set title

Group B

Subject analysis set type

Safety analysis

Subject analysis set description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Subject analysis set title

Group C + D

Subject analysis set type

Safety analysis

Subject analysis set description

Treatment-naïve participants received ABT-450 (100 mg or 200 mg) and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Subject analysis set title

Group E

Subject analysis set type

Safety analysis

Subject analysis set description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ABT-333 400 mg twice daily for 12 weeks.

Subject analysis set title

Group F + G

Subject analysis set type

Safety analysis

Subject analysis set description

Treatment-naïve participants received ABT-450 (100 mg or 150 mg) and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Subject analysis set title

Group H + I

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Group J

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Group K + L

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who were null-responders to previous HCV treatment received ABT-450 (100 mg or 150 mg) and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Subject analysis set title

Group M + N

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Groups F + G + K + L

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants (treatment-naïve and null-responders) received ABT-450 (100 mg or 150 mg) and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Subject analysis set title

Groups H + I + M + N

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Groups C + D + J

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants (treatment-naïve and null-responders) received ABT-450 (100 mg or 200 mg) and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Subject analysis set title

Groups F + G + H + I

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Groups K + L + M + N

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Number of Participants With Adverse Events (AEs)

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End point title

Number of Participants With Adverse Events (AEs) ^[1]

End point description

An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each AE to the use of direct-acting antiviral agents (DAAs) and to ribavirin, and rated the severity of each event as either: Mild: The AE was transient and easily tolerated by the participant; Moderate: The AE caused the participant discomfort and interrupted usual activities; Severe: The AE caused considerable interference with the participant's usual activities and could have been incapacitating or life-threatening. A serious adverse event was any event that resulted in death, was life-threatening, resulted in or prolonged hospitalization, resulted in a congenital anomaly or persistent or significant disability or was any other important medical event requiring medical or surgical intervention.

End point type

Primary

End point timeframe

From the time of study drug administration until 30 days following discontinuation of study drug administration (up to 28 weeks).

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: Safety was assessed by summarizing the incidence of adverse events.

End point values	Group A	Group B	Group C + D	Group E	Group F + G	Group H + I	Group J	Group K + L	Group M + N
Number of subjects analysed	80	41	79	79	79	80	45	45	45
Units: participants
Any adverse event	67	36	71	68	71	77	42	39	37
Any adverse event at least possibly DAArelated	58	29	53	51	57	68	35	30	28
Any severe adverse event	3	0	3	5	3	3	1	1	1
Any serious adverse event	0	0	2	2	1	1	0	0	2
Any AE leading to discontinuation of study drug	1	0	0	0	3	3	1	0	1
Any AE leading to interruption of study drug	0	1	2	1	0	1	0	0	0
Any AE leading to ribavirin dose modification	2	2	4	0	9	10	3	1	3
Any fatal adverse events	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose for 8 Weeks Versus 12 Weeks of Treatment With 3 DAAs and Ribavirin

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End point title

Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose for 8 Weeks Versus 12 Weeks of Treatment With 3 DAAs and Ribavirin

End point description

The percentage of participants achieving sustained virologic response 24 weeks after the last dose of study drug (SVR24), defined as hepatitis C virus (HCV) ribonucleic acid (RNA) less than the lower limit of quantitation (LLOQ), without any confirmed quantifiable (≥ LLOQ) post-treatment value before that time point. HCV RNA levels were measured from plasma by a central laboratory. The LLOQ for the assay was 25 IU/mL. The primary efficacy endpoint was the comparison between treatment-naïve participants following 8 weeks of treatment with 3 DAAs and ribavirin and those with 12 weeks of treatment with 3 DAAs and ribavirin (Group A versus Group G). Participants with missing data were counted as non-responders.

End point type

Primary

End point timeframe

Post Treatment Week 24

End point values	Group A	Group B	Group C	Group D	Group E	Group F	Group G	Group H	Group I	Group J	Group K	Group L	Group M	Group N
Number of subjects analysed	80	41	39	40	79	39	40	40	40	45	23	22	23	20
Units: percentage of participants
number (not applicable)	87.5	82.9	84.6	92.5	88.6	97.4	95	92.5	90	88.9	91.3	95.5	91.3	100

Primary analysis

Statistical analysis description

The primary efficacy endpoint was the comparison of the percentage of treatment-naïve participants with SVR24 after treatment with 3 DAAs (at the 150 mg ABT-450 dose) and ribavirin for 8 weeks (Group A) versus 12 weeks (Group G).

Comparison groups

Group G v Group A

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.406 ^[3]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

2.61

Notes
[2] - Pre-specified 2-sided significance level of 0.05.
[3] - Logistic regression with baseline log10 HCV RNA level, treatment group, Interleukin 28B genotype (CC or non-CC), HCV subgenotype (1a or non-1a), and geographic region (US or non-US) as predictors. No adjustment for multiple comparison.

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment of Different Durations With 3 Direct-acting Antiviral Agents (DAAs) and Ribavirin

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End point title

Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment of Different Durations With 3 Direct-acting Antiviral Agents (DAAs) and Ribavirin

End point description

This endpoint compares the percentage of participants achieving sustained virologic response 24 weeks after the last dose of study drug (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 3 DAAs (ABT-450/ritonavir, ABT-267, and ABT-333) and ribavirin in both treatment naïve and null-responder participants for 8 weeks (Group A) versus 12 weeks (Groups F + G + K + L) versus 24 weeks (Groups H + I + M + N). Participants with missing data were counted as non-responders.

End point type

Secondary

End point timeframe

Post-Treatment Week 24

End point values	Group A	Groups F + G + K + L	Groups H + I + M + N
Number of subjects analysed	80	124	123
Units: percentage of participants
number (not applicable)	87.5	95.2	92.7

Statistical Analysis 1

Statistical analysis description

The percentage of participants with SVR24 after treatment for 8 weeks versus 12 weeks was compared using logistic regression with treatment group, baseline log10 HCV RNA level, HCV subgenotype (1a or non-1a), geographic region (US or non-US), Interleukin 28B genotype (CC or non-CC), and ABT-450/ritonavir dose and population (treatment-naïve or null-responders) as predictors.

Comparison groups

Group A v Groups F + G + K + L

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.266 ^[5]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

2.02

Notes
[4] - Pre-specified 2-sided significance level of 0.05.
[5] - No adjustment for multiple comparison.

Statistical Analysis 2

Statistical analysis description

The percentage of participants with SVR24 after treatment for 8 weeks versus 24 weeks was compared using logistic regression with treatment group, baseline log10 HCV RNA level, HCV subgenotype (1a or non-1a), geographic region (US or non-US), Interleukin 28B genotype (CC or non-CC), ABT-450/ritonavir dose and population (treatment-naïve or null-responders) as predictors.

Comparison groups

Group A v Groups H + I + M + N

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.525 ^[7]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

2.4

Notes
[6] - Pre-specified 2-sided significance level of 0.05.
[7] - No adjustment for multiple comparison.

Statistical Analysis 3

Statistical analysis description

The percentage of participants with SVR24 after treatment for 12 weeks versus 24 weeks was compared using logistic regression with treatment group, baseline log10 HCV RNA level, HCV subgenotype (1a or non-1a), geographic region (US or non-US), Interleukin 28B genotype (CC or non-CC), ABT-450/ritonavir dose and population (treatment-naïve or null-responders) as predictors.

Comparison groups

Groups F + G + K + L v Groups H + I + M + N

Number of subjects included in analysis

247

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.375 ^[9]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

4.92

Notes
[8] - Pre-specified 2-sided significance level of 0.05.
[9] - No adjustment for multiple comparison.

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 2 DAAs and Ribavirin Versus 3 DAAs and Ribavirin

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End point title

Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 2 DAAs and Ribavirin Versus 3 DAAs and Ribavirin

End point description

This endpoint compares the percentage of participants achieving sustained virologic response 24 weeks post-dose (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 2 DAAs (ABT-450/ritonavir plus ABT-333 [Group B] or ABT-450/ritonavir plus ABT-267 [Groups C + D + J]) and ribavirin versus 3 DAAs (ABT-450/ritonavir plus ABT-333 and ABT-267) and ribavirin (Groups F + G + K + L). Participants with missing data were counted as non-responders.

End point type

Secondary

End point timeframe

Post-Treatment Week 24

End point values	Group B	Groups F + G + K + L	Groups C + D + J
Number of subjects analysed	41	124	124
Units: percentage of participants
number (not applicable)	82.9	95.2	88.7

Statistical Analysis 1

Statistical analysis description

The percentage of participants with SVR24 after treatment with 2 DAAs and ribavirin versus 3 DAAs and ribavirin was compared using stratum-adjusted Mantel-Haenszel (MH) method with Interleukin 28B genotype (CC or non-CC) and HCV subgenotype (1a or non-1a).

Comparison groups

Group B v Groups F + G + K + L

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.068 ^[11]

Method

Mantel-Haenszel

Parameter type

Difference (Group B - Groups F + G + K )

Point estimate

-12.16

Confidence interval

level

95%

sides

2-sided

lower limit

-25.2

upper limit

0.88

Notes
[10] - Pre-specified 2-sided significance level of 0.05.
[11] - The Mantel-Haenszel method was used because logistic regression failed due to separation or quasi-separation. There was no adjustment for multiple comparison.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Groups F + G + K + L v Groups C + D + J

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.065 ^[13]

Method

Mantel-Haenszel

Parameter type

Difference (Group C+D+J - Group F+G+K+L)

Point estimate

-6.75

Confidence interval

level

95%

sides

2-sided

lower limit

-13.93

upper limit

0.43

Notes
[12] - Pre-specified 2-sided significance level of 0.05.
[13] - The Mantel-Haenszel method was used because logistic regression failed due to separation or quasi-separation. No adjustment for multiple comparison.

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 3 DAAs With Versus Without Ribavirin

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End point title

Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 3 DAAs With Versus Without Ribavirin

End point description

End point type

Secondary

End point timeframe

Post-Treatment Week 24

End point values	Group E	Groups F + G + K + L
Number of subjects analysed	79	124
Units: Percentage of participants
number (not applicable)	88.6	95.2

Statistical Analysis 1

Statistical analysis description

The percentage of participants with SVR24 after treatment with 3 DAAs with and without ribavirin was compared using a stratum-adjusted Mantel-Haenszel (MH) method with Interleukin 28B genotype (CC or non-CC) and HCV subgenotype (1a or non-1a).

Comparison groups

Group E v Groups F + G + K + L

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.106 ^[15]

Method

Mantel-Haenszel

Parameter type

Difference (Group E - Group F+G+K+L)

Point estimate

-7.13

Confidence interval

level

95%

sides

2-sided

lower limit

-15.77

upper limit

1.51

Notes
[14] - Pre-specified 2-sided significance level of 0.05.
[15] - The Mantel-Haenszel method was used because logistic regression failed due to separation or quasi-separation. No adjustment for multiple comparison.

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose in Treatment-naïve Versus Null-responders

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End point title

Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose in Treatment-naïve Versus Null-responders

End point description

This endpoint compares the percentage of participants achieving sustained virologic response 24 weeks post-dose (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 3 DAAs and ribavirin in participants who were treatment-naïve versus those who were null-responders to previous HCV therapy (Groups F + G + H + I versus Groups K + L + M + N). Participants with missing data were counted as non-responders.

End point type

Secondary

End point timeframe

Post-Treatment Week 24

End point values	Groups F + G + H + I	Groups K + L + M + N
Number of subjects analysed	159	88
Units: percentage of participants
number (not applicable)	93.7	94.3

Statistical Analysis 1

Statistical analysis description

The percentage of participants with SVR24 after treatment with 3 DAAs and ribavirin in treatment-naïve versus null-responders was compared using logistic regression with treatment group, baseline log10 HCV RNA level, HCV subgenotype (1a or non-1a), geographic region (US or non-US), Interleukin 28B genotype (CC or non-CC), and ABT-450/ritonavir dose as predictors.

Comparison groups

Groups F + G + H + I v Groups K + L + M + N

Number of subjects included in analysis

247

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.616 ^[17]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

5.34

Notes
[16] - Pre-specified 2-sided significance level of 0.05.
[17] - No adjustment for multiple comparison.

Adverse events

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Timeframe for reporting adverse events

Up to 28 weeks

Adverse event reporting additional description

Treatment groups differing only in ABT-450 dose (100 mg, 150 mg or 200 mg) were combined for safety analyses.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Group A

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 8 weeks.

Reporting group title

Group B

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks.

Reporting group title

Group C + D

Reporting group description

Treatment-naïve participants received ABT-450 (100 mg or 200 mg) and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily, for 12 weeks.

Reporting group title

Group E

Reporting group description

Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ABT-333 400 mg twice daily for 12 weeks.

Reporting group title

Group F + G

Reporting group description

Reporting group title

Group H + I

Reporting group description

Reporting group title

Group J

Reporting group description

Reporting group title

Group K + L

Reporting group description

Reporting group title

Group M + N

Reporting group description

Serious adverse events	Group A	Group B	Group C + D	Group E	Group F + G	Group H + I	Group J	Group K + L	Group M + N
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	2 / 79 (2.53%)	2 / 79 (2.53%)	1 / 79 (1.27%)	1 / 80 (1.25%)	0 / 45 (0.00%)	0 / 45 (0.00%)	2 / 43 (4.65%)
number of deaths (all causes)	0	1	0	1	0	0	0	0	1
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cervicobrachial syndrome
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Lung disorder
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Affective disorder
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Group A	Group B	Group C + D	Group E	Group F + G	Group H + I	Group J	Group K + L	Group M + N
Total subjects affected by non serious adverse events
subjects affected / exposed	64 / 80 (80.00%)	33 / 41 (80.49%)	66 / 79 (83.54%)	59 / 79 (74.68%)	66 / 79 (83.54%)	74 / 80 (92.50%)	40 / 45 (88.89%)	36 / 45 (80.00%)	34 / 43 (79.07%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	7 / 80 (8.75%)	1 / 41 (2.44%)	8 / 79 (10.13%)	5 / 79 (6.33%)	3 / 79 (3.80%)	12 / 80 (15.00%)	10 / 45 (22.22%)	4 / 45 (8.89%)	4 / 43 (9.30%)
occurrences all number	7	1	8	7	4	17	11	4	4
Chest pain
subjects affected / exposed	0 / 80 (0.00%)	1 / 41 (2.44%)	2 / 79 (2.53%)	0 / 79 (0.00%)	1 / 79 (1.27%)	4 / 80 (5.00%)	1 / 45 (2.22%)	3 / 45 (6.67%)	0 / 43 (0.00%)
occurrences all number	0	1	2	0	1	4	1	3	0
Chills
subjects affected / exposed	4 / 80 (5.00%)	1 / 41 (2.44%)	1 / 79 (1.27%)	1 / 79 (1.27%)	1 / 79 (1.27%)	3 / 80 (3.75%)	1 / 45 (2.22%)	0 / 45 (0.00%)	2 / 43 (4.65%)
occurrences all number	4	1	1	1	1	3	1	0	2
Fatigue
subjects affected / exposed	29 / 80 (36.25%)	13 / 41 (31.71%)	22 / 79 (27.85%)	16 / 79 (20.25%)	22 / 79 (27.85%)	30 / 80 (37.50%)	12 / 45 (26.67%)	12 / 45 (26.67%)	9 / 43 (20.93%)
occurrences all number	33	13	25	17	23	35	13	15	12
Irritability
subjects affected / exposed	1 / 80 (1.25%)	4 / 41 (9.76%)	5 / 79 (6.33%)	5 / 79 (6.33%)	1 / 79 (1.27%)	10 / 80 (12.50%)	7 / 45 (15.56%)	2 / 45 (4.44%)	3 / 43 (6.98%)
occurrences all number	1	5	5	5	1	11	7	2	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	12 / 80 (15.00%)	5 / 41 (12.20%)	11 / 79 (13.92%)	2 / 79 (2.53%)	8 / 79 (10.13%)	12 / 80 (15.00%)	7 / 45 (15.56%)	3 / 45 (6.67%)	9 / 43 (20.93%)
occurrences all number	12	5	11	2	8	14	7	3	12
Dyspnoea
subjects affected / exposed	8 / 80 (10.00%)	3 / 41 (7.32%)	4 / 79 (5.06%)	1 / 79 (1.27%)	5 / 79 (6.33%)	8 / 80 (10.00%)	4 / 45 (8.89%)	3 / 45 (6.67%)	3 / 43 (6.98%)
occurrences all number	8	3	4	1	5	8	4	3	4
Dyspnoea exertional
subjects affected / exposed	2 / 80 (2.50%)	0 / 41 (0.00%)	3 / 79 (3.80%)	0 / 79 (0.00%)	4 / 79 (5.06%)	9 / 80 (11.25%)	0 / 45 (0.00%)	0 / 45 (0.00%)	2 / 43 (4.65%)
occurrences all number	2	0	3	0	4	11	0	0	2
Oropharyngeal pain
subjects affected / exposed	3 / 80 (3.75%)	0 / 41 (0.00%)	4 / 79 (5.06%)	0 / 79 (0.00%)	1 / 79 (1.27%)	4 / 80 (5.00%)	2 / 45 (4.44%)	4 / 45 (8.89%)	2 / 43 (4.65%)
occurrences all number	3	0	4	0	1	4	3	4	2
Sinus congestion
subjects affected / exposed	4 / 80 (5.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	1 / 79 (1.27%)	2 / 80 (2.50%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences all number	4	0	0	1	1	2	1	0	0
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	1 / 80 (1.25%)	2 / 41 (4.88%)	2 / 79 (2.53%)	1 / 79 (1.27%)	1 / 79 (1.27%)	5 / 80 (6.25%)	1 / 45 (2.22%)	1 / 45 (2.22%)	1 / 43 (2.33%)
occurrences all number	1	2	2	1	1	5	1	1	1
Anxiety
subjects affected / exposed	2 / 80 (2.50%)	2 / 41 (4.88%)	0 / 79 (0.00%)	3 / 79 (3.80%)	4 / 79 (5.06%)	6 / 80 (7.50%)	4 / 45 (8.89%)	1 / 45 (2.22%)	3 / 43 (6.98%)
occurrences all number	3	2	0	3	4	6	4	1	4
Depressed mood
subjects affected / exposed	1 / 80 (1.25%)	3 / 41 (7.32%)	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	2 / 45 (4.44%)	1 / 43 (2.33%)
occurrences all number	1	3	1	0	0	0	0	2	1
Depression
subjects affected / exposed	3 / 80 (3.75%)	3 / 41 (7.32%)	3 / 79 (3.80%)	1 / 79 (1.27%)	3 / 79 (3.80%)	12 / 80 (15.00%)	2 / 45 (4.44%)	5 / 45 (11.11%)	1 / 43 (2.33%)
occurrences all number	3	3	3	1	4	13	2	5	1
Insomnia
subjects affected / exposed	10 / 80 (12.50%)	8 / 41 (19.51%)	9 / 79 (11.39%)	6 / 79 (7.59%)	16 / 79 (20.25%)	20 / 80 (25.00%)	8 / 45 (17.78%)	6 / 45 (13.33%)	7 / 43 (16.28%)
occurrences all number	10	8	9	6	17	22	8	6	8
Sleep disorder
subjects affected / exposed	1 / 80 (1.25%)	0 / 41 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	2 / 80 (2.50%)	0 / 45 (0.00%)	4 / 45 (8.89%)	2 / 43 (4.65%)
occurrences all number	1	0	0	0	0	2	0	4	2
Investigations
Haemoglobin decreased
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	1 / 79 (1.27%)	0 / 80 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	4 / 43 (9.30%)
occurrences all number	0	0	0	1	1	0	0	1	4
Nervous system disorders
Disturbance in attention
subjects affected / exposed	2 / 80 (2.50%)	1 / 41 (2.44%)	2 / 79 (2.53%)	1 / 79 (1.27%)	2 / 79 (2.53%)	9 / 80 (11.25%)	3 / 45 (6.67%)	3 / 45 (6.67%)	3 / 43 (6.98%)
occurrences all number	2	1	2	1	2	9	4	3	4
Dizziness
subjects affected / exposed	5 / 80 (6.25%)	7 / 41 (17.07%)	2 / 79 (2.53%)	4 / 79 (5.06%)	3 / 79 (3.80%)	8 / 80 (10.00%)	4 / 45 (8.89%)	1 / 45 (2.22%)	4 / 43 (9.30%)
occurrences all number	5	8	2	4	3	8	4	1	5
Dysgeusia
subjects affected / exposed	2 / 80 (2.50%)	1 / 41 (2.44%)	3 / 79 (3.80%)	2 / 79 (2.53%)	3 / 79 (3.80%)	4 / 80 (5.00%)	0 / 45 (0.00%)	4 / 45 (8.89%)	4 / 43 (9.30%)
occurrences all number	2	1	3	2	3	4	0	4	4
Headache
subjects affected / exposed	28 / 80 (35.00%)	13 / 41 (31.71%)	23 / 79 (29.11%)	15 / 79 (18.99%)	21 / 79 (26.58%)	28 / 80 (35.00%)	15 / 45 (33.33%)	13 / 45 (28.89%)	14 / 43 (32.56%)
occurrences all number	31	18	30	15	22	29	17	13	20
Lethargy
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	2 / 79 (2.53%)	1 / 79 (1.27%)	0 / 79 (0.00%)	1 / 80 (1.25%)	1 / 45 (2.22%)	3 / 45 (6.67%)	2 / 43 (4.65%)
occurrences all number	0	0	2	1	0	1	1	4	2
Memory impairment
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	1 / 79 (1.27%)	3 / 79 (3.80%)	0 / 79 (0.00%)	5 / 80 (6.25%)	1 / 45 (2.22%)	0 / 45 (0.00%)	2 / 43 (4.65%)
occurrences all number	0	0	1	3	0	5	1	0	2
Paraesthesia
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	3 / 79 (3.80%)	1 / 79 (1.27%)	1 / 79 (1.27%)	2 / 80 (2.50%)	1 / 45 (2.22%)	0 / 45 (0.00%)	5 / 43 (11.63%)
occurrences all number	0	0	3	1	1	2	1	0	5
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 80 (6.25%)	1 / 41 (2.44%)	3 / 79 (3.80%)	1 / 79 (1.27%)	7 / 79 (8.86%)	6 / 80 (7.50%)	3 / 45 (6.67%)	3 / 45 (6.67%)	2 / 43 (4.65%)
occurrences all number	5	1	3	1	7	6	3	3	2
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 80 (1.25%)	3 / 41 (7.32%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	3 / 80 (3.75%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences all number	3	3	0	1	0	3	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 80 (0.00%)	1 / 41 (2.44%)	1 / 79 (1.27%)	3 / 79 (3.80%)	3 / 79 (3.80%)	5 / 80 (6.25%)	0 / 45 (0.00%)	2 / 45 (4.44%)	0 / 43 (0.00%)
occurrences all number	0	1	1	3	3	5	0	2	0
Abdominal pain
subjects affected / exposed	1 / 80 (1.25%)	3 / 41 (7.32%)	4 / 79 (5.06%)	3 / 79 (3.80%)	3 / 79 (3.80%)	7 / 80 (8.75%)	1 / 45 (2.22%)	6 / 45 (13.33%)	0 / 43 (0.00%)
occurrences all number	1	3	4	4	4	8	1	7	0
Abdominal pain upper
subjects affected / exposed	0 / 80 (0.00%)	2 / 41 (4.88%)	5 / 79 (6.33%)	3 / 79 (3.80%)	4 / 79 (5.06%)	4 / 80 (5.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	2 / 43 (4.65%)
occurrences all number	0	2	5	3	4	4	0	1	2
Constipation
subjects affected / exposed	3 / 80 (3.75%)	1 / 41 (2.44%)	5 / 79 (6.33%)	5 / 79 (6.33%)	1 / 79 (1.27%)	9 / 80 (11.25%)	2 / 45 (4.44%)	1 / 45 (2.22%)	4 / 43 (9.30%)
occurrences all number	4	1	5	5	2	11	2	2	4
Diarrhoea
subjects affected / exposed	8 / 80 (10.00%)	10 / 41 (24.39%)	8 / 79 (10.13%)	13 / 79 (16.46%)	10 / 79 (12.66%)	11 / 80 (13.75%)	7 / 45 (15.56%)	8 / 45 (17.78%)	8 / 43 (18.60%)
occurrences all number	8	12	8	15	11	13	9	10	12
Dry mouth
subjects affected / exposed	4 / 80 (5.00%)	0 / 41 (0.00%)	2 / 79 (2.53%)	2 / 79 (2.53%)	1 / 79 (1.27%)	2 / 80 (2.50%)	1 / 45 (2.22%)	2 / 45 (4.44%)	2 / 43 (4.65%)
occurrences all number	4	0	3	2	1	2	1	2	2
Dyspepsia
subjects affected / exposed	7 / 80 (8.75%)	1 / 41 (2.44%)	9 / 79 (11.39%)	2 / 79 (2.53%)	4 / 79 (5.06%)	6 / 80 (7.50%)	2 / 45 (4.44%)	2 / 45 (4.44%)	2 / 43 (4.65%)
occurrences all number	8	1	9	2	4	6	3	2	2
Flatulence
subjects affected / exposed	0 / 80 (0.00%)	1 / 41 (2.44%)	4 / 79 (5.06%)	4 / 79 (5.06%)	2 / 79 (2.53%)	1 / 80 (1.25%)	0 / 45 (0.00%)	1 / 45 (2.22%)	1 / 43 (2.33%)
occurrences all number	0	1	4	4	2	1	0	1	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 80 (1.25%)	0 / 41 (0.00%)	2 / 79 (2.53%)	3 / 79 (3.80%)	2 / 79 (2.53%)	2 / 80 (2.50%)	1 / 45 (2.22%)	1 / 45 (2.22%)	4 / 43 (9.30%)
occurrences all number	1	0	2	3	2	2	1	1	4
Nausea
subjects affected / exposed	12 / 80 (15.00%)	7 / 41 (17.07%)	16 / 79 (20.25%)	11 / 79 (13.92%)	19 / 79 (24.05%)	20 / 80 (25.00%)	6 / 45 (13.33%)	9 / 45 (20.00%)	8 / 43 (18.60%)
occurrences all number	13	9	16	12	21	23	6	11	8
Vomiting
subjects affected / exposed	7 / 80 (8.75%)	4 / 41 (9.76%)	4 / 79 (5.06%)	4 / 79 (5.06%)	4 / 79 (5.06%)	4 / 80 (5.00%)	4 / 45 (8.89%)	4 / 45 (8.89%)	3 / 43 (6.98%)
occurrences all number	8	4	4	4	5	5	4	4	3
Hepatobiliary disorders
Jaundice
subjects affected / exposed	3 / 80 (3.75%)	0 / 41 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)	3 / 79 (3.80%)	3 / 80 (3.75%)	1 / 45 (2.22%)	3 / 45 (6.67%)	1 / 43 (2.33%)
occurrences all number	3	0	1	0	3	3	1	3	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 80 (0.00%)	0 / 41 (0.00%)	0 / 79 (0.00%)	2 / 79 (2.53%)	0 / 79 (0.00%)	6 / 80 (7.50%)	0 / 45 (0.00%)	0 / 45 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	0	0	2	0	7	0	0	4
Dry skin
subjects affected / exposed	4 / 80 (5.00%)	3 / 41 (7.32%)	3 / 79 (3.80%)	1 / 79 (1.27%)	4 / 79 (5.06%)	6 / 80 (7.50%)	6 / 45 (13.33%)	4 / 45 (8.89%)	4 / 43 (9.30%)
occurrences all number	4	4	3	1	4	7	6	4	4
Pruritus
subjects affected / exposed	12 / 80 (15.00%)	3 / 41 (7.32%)	8 / 79 (10.13%)	3 / 79 (3.80%)	6 / 79 (7.59%)	11 / 80 (13.75%)	6 / 45 (13.33%)	7 / 45 (15.56%)	6 / 43 (13.95%)
occurrences all number	13	3	10	3	6	12	8	7	6
Pruritus generalised
subjects affected / exposed	2 / 80 (2.50%)	5 / 41 (12.20%)	0 / 79 (0.00%)	1 / 79 (1.27%)	4 / 79 (5.06%)	3 / 80 (3.75%)	5 / 45 (11.11%)	0 / 45 (0.00%)	1 / 43 (2.33%)
occurrences all number	2	5	0	2	4	3	6	0	1
Rash
subjects affected / exposed	10 / 80 (12.50%)	2 / 41 (4.88%)	6 / 79 (7.59%)	6 / 79 (7.59%)	11 / 79 (13.92%)	15 / 80 (18.75%)	2 / 45 (4.44%)	4 / 45 (8.89%)	6 / 43 (13.95%)
occurrences all number	12	2	8	6	11	18	5	4	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 80 (2.50%)	2 / 41 (4.88%)	6 / 79 (7.59%)	7 / 79 (8.86%)	5 / 79 (6.33%)	8 / 80 (10.00%)	3 / 45 (6.67%)	5 / 45 (11.11%)	7 / 43 (16.28%)
occurrences all number	2	3	6	8	6	9	3	5	7
Back pain
subjects affected / exposed	2 / 80 (2.50%)	1 / 41 (2.44%)	3 / 79 (3.80%)	4 / 79 (5.06%)	2 / 79 (2.53%)	5 / 80 (6.25%)	2 / 45 (4.44%)	2 / 45 (4.44%)	4 / 43 (9.30%)
occurrences all number	2	1	3	4	2	5	3	2	4
Muscle spasms
subjects affected / exposed	2 / 80 (2.50%)	1 / 41 (2.44%)	2 / 79 (2.53%)	1 / 79 (1.27%)	5 / 79 (6.33%)	2 / 80 (2.50%)	2 / 45 (4.44%)	0 / 45 (0.00%)	0 / 43 (0.00%)
occurrences all number	2	1	2	1	5	2	2	0	0
Myalgia
subjects affected / exposed	4 / 80 (5.00%)	3 / 41 (7.32%)	5 / 79 (6.33%)	2 / 79 (2.53%)	3 / 79 (3.80%)	9 / 80 (11.25%)	5 / 45 (11.11%)	4 / 45 (8.89%)	6 / 43 (13.95%)
occurrences all number	4	3	5	2	3	10	5	4	7
Pain in extremity
subjects affected / exposed	2 / 80 (2.50%)	1 / 41 (2.44%)	1 / 79 (1.27%)	1 / 79 (1.27%)	0 / 79 (0.00%)	3 / 80 (3.75%)	0 / 45 (0.00%)	3 / 45 (6.67%)	0 / 43 (0.00%)
occurrences all number	2	1	1	1	0	3	0	3	0
Infections and infestations
Influenza
subjects affected / exposed	1 / 80 (1.25%)	0 / 41 (0.00%)	1 / 79 (1.27%)	2 / 79 (2.53%)	1 / 79 (1.27%)	1 / 80 (1.25%)	1 / 45 (2.22%)	3 / 45 (6.67%)	0 / 43 (0.00%)
occurrences all number	1	0	1	2	2	1	1	3	0
Nasopharyngitis
subjects affected / exposed	4 / 80 (5.00%)	3 / 41 (7.32%)	4 / 79 (5.06%)	8 / 79 (10.13%)	7 / 79 (8.86%)	7 / 80 (8.75%)	2 / 45 (4.44%)	4 / 45 (8.89%)	3 / 43 (6.98%)
occurrences all number	4	3	4	8	7	8	2	4	4
Oral herpes
subjects affected / exposed	2 / 80 (2.50%)	0 / 41 (0.00%)	2 / 79 (2.53%)	2 / 79 (2.53%)	1 / 79 (1.27%)	3 / 80 (3.75%)	3 / 45 (6.67%)	3 / 45 (6.67%)	2 / 43 (4.65%)
occurrences all number	3	0	2	2	1	3	5	4	2
Rhinitis
subjects affected / exposed	1 / 80 (1.25%)	0 / 41 (0.00%)	5 / 79 (6.33%)	2 / 79 (2.53%)	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 43 (0.00%)
occurrences all number	1	0	6	2	0	0	0	1	0
Sinusitis
subjects affected / exposed	4 / 80 (5.00%)	0 / 41 (0.00%)	7 / 79 (8.86%)	2 / 79 (2.53%)	5 / 79 (6.33%)	3 / 80 (3.75%)	1 / 45 (2.22%)	2 / 45 (4.44%)	3 / 43 (6.98%)
occurrences all number	4	0	8	2	5	3	1	2	3
Tooth infection
subjects affected / exposed	2 / 80 (2.50%)	0 / 41 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	4 / 79 (5.06%)	4 / 80 (5.00%)	1 / 45 (2.22%)	1 / 45 (2.22%)	0 / 43 (0.00%)
occurrences all number	2	0	0	1	4	4	1	1	0
Upper respiratory tract infection
subjects affected / exposed	5 / 80 (6.25%)	1 / 41 (2.44%)	5 / 79 (6.33%)	5 / 79 (6.33%)	4 / 79 (5.06%)	5 / 80 (6.25%)	3 / 45 (6.67%)	4 / 45 (8.89%)	0 / 43 (0.00%)
occurrences all number	5	2	5	5	4	5	3	4	0
Urinary tract infection
subjects affected / exposed	4 / 80 (5.00%)	3 / 41 (7.32%)	2 / 79 (2.53%)	1 / 79 (1.27%)	0 / 79 (0.00%)	6 / 80 (7.50%)	2 / 45 (4.44%)	3 / 45 (6.67%)	2 / 43 (4.65%)
occurrences all number	4	3	2	2	0	6	2	4	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	8 / 80 (10.00%)	1 / 41 (2.44%)	5 / 79 (6.33%)	3 / 79 (3.80%)	3 / 79 (3.80%)	6 / 80 (7.50%)	3 / 45 (6.67%)	1 / 45 (2.22%)	1 / 43 (2.33%)
occurrences all number	8	1	5	3	3	7	3	1	2

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Were there any global substantial amendments to the protocol? Yes

19 Oct 2011

The purpose of this amendment was to: ● modify the post-treatment pregnancy monitoring to be in compliance with local labeling requirements for RBV; ● clarify that the RBV Pregnancy Registry Brochure and RBV Medication Guide were to be distributed where applicable/locally available; ● define the primary and secondary endpoints of SVR24 as HCV RNA < LLOQ 24 weeks after the last dose of study drug; ● incorporate Administrative Change 1; and ● address inconsistencies throughout the protocol

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.

None reported

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End points

Primary: Number of Participants With Adverse Events (AEs)

Primary: Number of Participants With Adverse Events (AEs)

Primary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose for 8 Weeks Versus 12 Weeks of Treatment With 3 DAAs and Ribavirin

Primary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose for 8 Weeks Versus 12 Weeks of Treatment With 3 DAAs and Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment of Different Durations With 3 Direct-acting Antiviral Agents (DAAs) and Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment of Different Durations With 3 Direct-acting Antiviral Agents (DAAs) and Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 2 DAAs and Ribavirin Versus 3 DAAs and Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 2 DAAs and Ribavirin Versus 3 DAAs and Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 3 DAAs With Versus Without Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 3 DAAs With Versus Without Ribavirin

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose in Treatment-naïve Versus Null-responders

Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose in Treatment-naïve Versus Null-responders

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Substantial protocol amendments (globally)

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
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