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Clinical Trial Results:
Safety, antiviral effect and pharmacokinetics of BI 207127 in combination with BI 201335 and with or without ribavirin for 4, 16, 24, 28 or 40 weeks in patients with chronic HCV genotype 1 infection (randomized Phase Ib/II).

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

Summary
EudraCT number	2009-018197-66
Trial protocol	PT FR DE AT ES
Global end of trial date	30 Oct 2014

Results information
Results version number	v1(current)
This version publication date	05 May 2016
First version publication date	05 May 2016
Other versions

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

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Trial information

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Sponsor protocol code

1241.21

ISRCTN number

US NCT number

NCT01132313

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

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

Scientific contact

Boehringer Ingelheim Pharma GmbH & Co. KG, QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, +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

11 Dec 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Oct 2014

Global end of trial reached?

Yes

Global end of trial date

30 Oct 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of Part 1 to 4 of this trial was to investigate safety, antiviral effect, and pharmacokinetics of deleobuvir (DBV/BI 207127) in combination with faldaprevir (FDV/BI 201335) and ribavirin (RBV) for 4, 16, 24, 28, or 40 weeks in patients with chronic hepatitis C virus (HCV) Genotype 1 (GT-1) infection.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were 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. Rescue medication was allowed for all patients as required.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 May 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

67 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 105

Country: Number of subjects enrolled

France: 138

Country: Number of subjects enrolled

Switzerland: 68

Country: Number of subjects enrolled

Germany: 94

Country: Number of subjects enrolled

Australia: 33

Country: Number of subjects enrolled

New Zealand: 14

Country: Number of subjects enrolled

Austria: 20

Country: Number of subjects enrolled

Spain: 127

Country: Number of subjects enrolled

Portugal: 37

Country: Number of subjects enrolled

Romania: 71

Worldwide total number of subjects

707

EEA total number of subjects

487

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)

648

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients with chronic hepatitis C infection GT-1 were to be enrolled in the trial. Patients were recruited by hepatologists or infectious disease specialists experienced in treating HCV patients. This trial was conducted in 4 parts, each consisting of randomised, open-label treatments.

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 allocated 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

Not blinded

Are arms mutually exclusive

Yes

Part 1: 400mg DBV and 120mg FDV - 4w

Arm description

Part 1: 4 weeks of 400mg Deleobuvir tablet TID (Three times per day) and 120mg Faldaprevir soft gelatin capsule QD (Once daily) in combination with RBV tablet. From Week 5 to Week 24, patients received treatment with FDV 120 mg QD in combination with standard of care (SOC) PegIFN/RBV (triple therapy period). Two patients were randomised to the Part 1: 400mg DBV and 120mg FDV - 4w arm, however these patients were not treated. Consequently, number of subject that started is 17 but only 15 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

4 weeks of 400mg Deleobuvir tablet administered orally TID.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

4 weeks of 120mg Faldaprevir soft gelatin capsule administered orally QD.

Part 1: 600mg DBV and 120mg FDV - 4w

Arm description

Part 1: 4 weeks of 600mg Deleobuvir (DBV, BI 207127) tablet three times per day (TID) and 120mg Faldaprevir (FDV, BI 201335) soft gelatin capsule once daily (QD) in combination with Ribavirin (RBV) tablet. From Week 5 to Week 24, patients received treatment with FDV 120 mg QD in combination with standard of care (SOC) PegIFN/RBV (triple therapy period).

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

4 weeks of 600mg Deleobuvir tablet administered orally TID.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

16 weeks of 120mg Faldaprevir tablet orally QD.

Part 2: 600mg DBV and 120mg FDV - 16w

Arm description

Part 2: 16 weeks of 600mg Deleobuvir tablet TID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

16 weeks of 600mg Deleobuvir tablet administered orally TID.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

16 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Part 2: 600mg DBV TID and 120mg FDV - 28w

Arm description

Part 2: 28 weeks of 600mg Deleobuvir tablet TID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

28 weeks of 600mg Deleobuvir tablet orally TID.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

28 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 2: 600mg DBV and 120mg FDV - 40w

Arm description

Part 2: 40 weeks of 600mg Deleobuvir tablet TID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks. Two patients were randomised to the Part 2: 600mg DBV and 120mg FDV - 40w arm, however these patients were not treated. Consequently, number of subject that started is 79 but only 77 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40 weeks of 600mg Deleobuvir tablet orally TID.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

40 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 2: 600mg DBV BID and 120mg FDV - 28w

Arm description

Part 2: 28 weeks of 600mg Deleobuvir tablet twice a day (BID) and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks. One patient was randomised to the Part 2: 600mg DBV BID and 120mg FDV - 28w arm, however this patient was not treated. Consequently, number of subject that started is 79 but only 78 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

28 weeks of 600mg Deleobuvir tablet administered orally BID.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

28 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 2: 600mg DBV and 120mg FDV, no RBV - 28w

Arm description

Part 2: 28 weeks of 600mg Deleobuvir tablet TID and 120mg Faldaprevir soft gelatin capsule QD, without RBV. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks. Three patients were randomised to the Part 2: 600mg DBV and 120mg FDV, no RBV - 28w arm, however these patients were not treated. Consequently, number of subject that started is 49 but only 46 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

28 weeks of 600mg Deleobuvir tablet orally TID.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

28 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 3: 600mg DBV and 120mg FDV - 16w

Arm description

Part 3: 16 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

16 weeks of 600mg Deleobuvir tablet administered orally BID.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

16 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Part 3: 800mg DBV and 120mg FDV - 24w

Arm description

Part 3: 24 weeks of 800mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

24 weeks of 800mg Deleobuvir tablet orally BID.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

24 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 3: 600mg DBV and 120mg FDV - 24w

Arm description

Part 3: 24 weeks of 600mg Deleobuvir tablet TID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet. Patients who discontinued their assigned treatment early due to lack of antiviral activity, could receive additional treatment with PegIFN/RBV for up to 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

24 weeks of 600mg Deleobuvir tablet orally TID.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

PegIFN

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PegIFN 180μg per week was administered by injection subcutaneously.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

24 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 4: 600 mg DBV and 120mg FDV - 16w

Arm description

Part 4: 16 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

16 weeks of 600mg Deleobuvir tablet orally BID.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

16 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Part 4: 600 mg DBV and 120mg FDV - 24w

Arm description

Part 4: 24 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Arm type

Experimental

Investigational medicinal product name

Deleobuvir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

24 weeks of 600mg Deleobuvir tablet administered orally BID.

Investigational medicinal product name

RBV (Copegus®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ribavirin tablet 200mg tablets was administered as 1000mg if <75kg, or 1200mg if ≥75kg, distributed in 2 divided doses.

Investigational medicinal product name

Faldaprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

24 weeks of 120mg Faldaprevir soft gelatin capsule orally QD.

Number of subjects in period 1 ^[1]	Part 1: 400mg DBV and 120mg FDV - 4w	Part 1: 600mg DBV and 120mg FDV - 4w	Part 2: 600mg DBV and 120mg FDV - 16w	Part 2: 600mg DBV TID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV - 40w	Part 2: 600mg DBV BID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV, no RBV - 28w	Part 3: 600mg DBV and 120mg FDV - 16w	Part 3: 800mg DBV and 120mg FDV - 24w	Part 3: 600mg DBV and 120mg FDV - 24w	Part 4: 600 mg DBV and 120mg FDV - 16w	Part 4: 600 mg DBV and 120mg FDV - 24w
Started	15	17	81	80	77	78	46	32	26	25	1	2
Completed	14	17	61	48	34	54	19	24	5	5	0	2
Not completed	1	0	20	32	43	24	27	8	21	20	1	0
Adverse event, serious fatal	-	-	-	-	-	1	-	-	-	-	-	-
Other reason not defined above	-	-	-	-	-	-	-	1	-	-	-	-
Consent withdrawn by subject	-	-	3	3	6	-	1	-	-	2	-	-
Adverse event, non-fatal	-	-	4	10	19	5	5	3	7	2	-	-
Lack of antiviral response	-	-	12	18	18	18	21	-	-	-	1	-
Lost to follow-up	-	-	1	-	-	-	-	1	-	-	-	-
Lack of efficacy	1	-	-	-	-	-	-	3	14	16	-	-
Protocol deviation	-	-	-	1	-	-	-	-	-	-	-	-

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 trial medication.

Baseline characteristics

Top of page

Reporting group title

Part 1: 400mg DBV and 120mg FDV - 4w

Reporting group description

Reporting group title

Part 1: 600mg DBV and 120mg FDV - 4w

Reporting group description

Reporting group title

Part 2: 600mg DBV and 120mg FDV - 16w

Reporting group description

Reporting group title

Part 2: 600mg DBV TID and 120mg FDV - 28w

Reporting group description

Reporting group title

Part 2: 600mg DBV and 120mg FDV - 40w

Reporting group description

Reporting group title

Part 2: 600mg DBV BID and 120mg FDV - 28w

Reporting group description

Reporting group title

Part 2: 600mg DBV and 120mg FDV, no RBV - 28w

Reporting group description

Reporting group title

Part 3: 600mg DBV and 120mg FDV - 16w

Reporting group description

Reporting group title

Part 3: 800mg DBV and 120mg FDV - 24w

Reporting group description

Reporting group title

Part 3: 600mg DBV and 120mg FDV - 24w

Reporting group description

Reporting group title

Part 4: 600 mg DBV and 120mg FDV - 16w

Reporting group description

Part 4: 16 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Reporting group title

Part 4: 600 mg DBV and 120mg FDV - 24w

Reporting group description

Part 4: 24 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Reporting group values	Part 1: 400mg DBV and 120mg FDV - 4w	Part 1: 600mg DBV and 120mg FDV - 4w	Part 2: 600mg DBV and 120mg FDV - 16w	Part 2: 600mg DBV TID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV - 40w	Part 2: 600mg DBV BID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV, no RBV - 28w	Part 3: 600mg DBV and 120mg FDV - 16w	Part 3: 800mg DBV and 120mg FDV - 24w	Part 3: 600mg DBV and 120mg FDV - 24w	Part 4: 600 mg DBV and 120mg FDV - 16w	Part 4: 600 mg DBV and 120mg FDV - 24w	Total
Number of subjects	15	17	81	80	77	78	46	32	26	25	1	2	480
Age categorical
Units: Subjects
Age Continuous \|
Treated Set (TS): Treated set which included all patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment regardless of randomisation. 99999: SD is not calculable due to only one patient in treatment group.
Units: years
arithmetic mean (standard deviation)	50.8 ± 10	50.8 ± 11.5	48.6 ± 11.3	47.3 ± 11.2	48.9 ± 10.7	47.9 ± 11.1	45.3 ± 13	48.9 ± 11.8	47.2 ± 13.4	46.5 ± 12.5	59 ± 99999	52.5 ± 4.9	-
Gender, Male/Female
Units: Participants
Female	7	7	36	39	41	37	22	20	11	11	1	2	234
Male	8	10	45	41	36	41	24	12	15	14	0	0	246

End points

Top of page

Reporting group title

Part 1: 400mg DBV and 120mg FDV - 4w

Reporting group description

Reporting group title

Part 1: 600mg DBV and 120mg FDV - 4w

Reporting group description

Reporting group title

Part 2: 600mg DBV and 120mg FDV - 16w

Reporting group description

Reporting group title

Part 2: 600mg DBV TID and 120mg FDV - 28w

Reporting group description

Reporting group title

Part 2: 600mg DBV and 120mg FDV - 40w

Reporting group description

Reporting group title

Part 2: 600mg DBV BID and 120mg FDV - 28w

Reporting group description

Reporting group title

Part 2: 600mg DBV and 120mg FDV, no RBV - 28w

Reporting group description

Reporting group title

Part 3: 600mg DBV and 120mg FDV - 16w

Reporting group description

Reporting group title

Part 3: 800mg DBV and 120mg FDV - 24w

Reporting group description

Reporting group title

Part 3: 600mg DBV and 120mg FDV - 24w

Reporting group description

Reporting group title

Part 4: 600 mg DBV and 120mg FDV - 16w

Reporting group description

Part 4: 16 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Reporting group title

Part 4: 600 mg DBV and 120mg FDV - 24w

Reporting group description

Part 4: 24 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Primary: Part 1: Rapid virological response (RVR)

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End point title

Part 1: Rapid virological response (RVR) ^[1] ^[2]

End point description

Part 1: Rapid virological response (RVR), defined as Hepatitis C Virus Ribonucleic acid (HCV RNA) <25IU/mL at Week 4 of treatment. Full Analysis Set (FAS): Full Analysis Set which included all randomised patients who were dispensed study medication and were documented to have taken at least one dose of study medication.

End point type

Primary

End point timeframe

4 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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1: 400mg DBV and 120mg FDV - 4w	Part 1: 600mg DBV and 120mg FDV - 4w
Number of subjects analysed	15 ^[3]	17 ^[4]
Units: Percentage of participants
number (confidence interval 95%)	73.3 (47.6 to 89)	100 (84.7 to 100)

Notes
[3] - FAS
[4] - FAS

No statistical analyses for this end point

Primary: Part 2: Sustained virological response (SVR)

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End point title

Part 2: Sustained virological response (SVR) ^[5] ^[6]

End point description

Part 2: Sustained virological response (SVR), defined as HCV RNA <25 IU/mL and undetectable at 12 weeks after end of treatment.

End point type

Primary

End point timeframe

From drug administration until 12 weeks after end of treatment, up to 52 weeks

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2: 600mg DBV and 120mg FDV - 16w	Part 2: 600mg DBV TID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV - 40w	Part 2: 600mg DBV BID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV, no RBV - 28w
Number of subjects analysed	81 ^[7]	80 ^[8]	77 ^[9]	78 ^[10]	46 ^[11]
Units: Percentage of participants
number (not applicable)	59.3	58.8	51.9	69.2	39.1

Notes
[7] - FAS
[8] - FAS
[9] - FAS
[10] - FAS
[11] - FAS

No statistical analyses for this end point

Primary: Part 3 and 4: Sustained virological response (SVR)

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End point title

Part 3 and 4: Sustained virological response (SVR) ^[12] ^[13]

End point description

Part 3 and 4: Sustained virological response (SVR) defined as HCV RNA <25IU/mL and undetectable at 12 weeks after end of treatment. 99999: Summary statistics were not calculated due to early termination of study.

End point type

Primary

End point timeframe

From drug administration until 12 weeks after end of treatment, up to 36 weeks

Notes
[12] - 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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 3: 600mg DBV and 120mg FDV - 16w	Part 3: 800mg DBV and 120mg FDV - 24w	Part 3: 600mg DBV and 120mg FDV - 24w	Part 4: 600 mg DBV and 120mg FDV - 16w	Part 4: 600 mg DBV and 120mg FDV - 24w
Number of subjects analysed	32 ^[14]	26 ^[15]	25 ^[16]	1 ^[17]	2 ^[18]
Units: Percentage of participants
number (confidence interval 95%)	65.6 (46.8 to 81.4)	19.2 (6.6 to 39.4)	12 (2.5 to 31.2)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[14] - FAS
[15] - FAS
[16] - FAS
[17] - FAS The study was stopped before data were collected from the participants in Part 4.
[18] - FAS

No statistical analyses for this end point

Secondary: Part 1: Time to virological response

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End point title

Part 1: Time to virological response ^[19]

End point description

Part 1: Time to virological response, defined as the timepoint of the first measurement of plasma HCV RNA level <25 IU/mL. The percentage of participants who achieved virological response within each time period are displayed for this outcome measure.

End point type

Secondary

End point timeframe

From drug administration until end of drug administration, up to 4 weeks

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1: 400mg DBV and 120mg FDV - 4w	Part 1: 600mg DBV and 120mg FDV - 4w
Number of subjects analysed	15 ^[20]	17 ^[21]
Units: Percentage of participants
number (not applicable)
<= 2 weeks	6.7	11.8
<= 4 weeks	20	47.1
<= 8 weeks	53.3	41.2
<= 12 weeks	0	0
<= 16 weeks	6.7	0
<= 28 weeks	0	0
<= 32 weeks	6.7	0
<= 40 weeks	0	0
> 40 weeks	0	0
Never	6.7	0

Notes
[20] - FAS
[21] - FAS

No statistical analyses for this end point

Secondary: Part 2: Time to virological response

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End point title

Part 2: Time to virological response ^[22]

End point description

Part 2: Time to virological response, defined as the timepoint of the first measurement of plasma HCV RNA level <25 IU/mL. The percentage of participants who achieved virological response within each time period are displayed for this outcome measure.

End point type

Secondary

End point timeframe

From drug administration until end of drug administration, up to 40 weeks

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2: 600mg DBV and 120mg FDV - 16w	Part 2: 600mg DBV TID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV - 40w	Part 2: 600mg DBV BID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV, no RBV - 28w
Number of subjects analysed	81	80	77	78	46
Units: Percentage of participants
number (not applicable)
Day 0 (N=81, 80, 77, 78, 46)	0	0	0	0	0
Day 8(N=75, 72, 72, 75, 44)	3.8	7.7	1.4	2.6	2.2
Day 15 (N=62, 61, 63, 60, 33)	19.4	20.7	9.9	22.1	19.3
Day 29 (N=29, 32, 27, 32, 21)	61.5	55.5	59.4	57.7	48.6
Day 43 (N=16, 12, 13, 18, 12)	78.8	83.3	80.5	76.2	70.7
Day 57 (N=9, 8, 9, 11, 9)	88.1	88.9	85.1	85.5	78
Day 85 (N=9, 7, 8, 11, 9)	88.1	90.3	86.8	85.5	78
Day 113 (N=9, 7, 8, 11, 8)	88.1	90.3	86.8	85.5	80.4
Day 141 (N=9, 7, 8, 11, 8)	88.1	90.3	86.8	85.5	80.4
Day 169 (N=9, 7, 8, 11, 8)	88.1	90.3	86.8	85.5	80.4
Day 197 (N=9, 7, 8, 11, 8)	88.1	90.3	86.8	85.5	80.4

No statistical analyses for this end point

Secondary: Part 1 and 2: Plasma HCV RNA level not detectable at Week 4

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End point title

Part 1 and 2: Plasma HCV RNA level not detectable at Week 4 ^[23]

End point description

Part 1 and 2: Plasma Hepatitis C Virus Ribonucleic acid (HCV RNA) level not detectable at Week 4.

End point type

Secondary

End point timeframe

4 weeks

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1: 400mg DBV and 120mg FDV - 4w	Part 1: 600mg DBV and 120mg FDV - 4w	Part 2: 600mg DBV and 120mg FDV - 16w	Part 2: 600mg DBV TID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV - 40w	Part 2: 600mg DBV BID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV, no RBV - 28w
Number of subjects analysed	15 ^[24]	17 ^[25]	81 ^[26]	80 ^[27]	77 ^[28]	78 ^[29]	46 ^[30]
Units: Percentage of participants
number (not applicable)	20	70.6	65.4	60	63.6	56.4	50

Notes
[24] - FAS
[25] - FAS
[26] - FAS
[27] - FAS
[28] - FAS
[29] - FAS
[30] - FAS

No statistical analyses for this end point

Secondary: Part 2: Sustained virological response at 4 and 24 weeks after end of treatment

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End point title

Part 2: Sustained virological response at 4 and 24 weeks after end of treatment ^[31]

End point description

Part 2: Sustained virological response at 4 and 24 weeks after end of treatment.

End point type

Secondary

End point timeframe

4 weeks and 24 weeks after the end of treatment, up to 64 weeks

Notes
[31] - 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 comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2: 600mg DBV and 120mg FDV - 16w	Part 2: 600mg DBV TID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV - 40w	Part 2: 600mg DBV BID and 120mg FDV - 28w	Part 2: 600mg DBV and 120mg FDV, no RBV - 28w
Number of subjects analysed	81 ^[32]	80 ^[33]	77 ^[34]	78 ^[35]	46 ^[36]
Units: Percentage of participants
number (not applicable)
SVR4	60.5	62.5	54.5	69.2	43.5
SVR24	58	58.8	49.4	69.2	39.1

Notes
[32] - FAS
[33] - FAS
[34] - FAS
[35] - FAS
[36] - FAS

No statistical analyses for this end point

Secondary: Part 3 and 4: Plasma HCV RNA level <25 IU/mL at week 4 and 12 of treatment

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End point title

Part 3 and 4: Plasma HCV RNA level <25 IU/mL at week 4 and 12 of treatment ^[37]

End point description

Part 3 and 4: Plasma Hepatitis C Virus Ribonucleic acid (HCV RNA) level <25 IU/mL at week 4 and 12 of treatment. 99999: Summary statistics were not calculated due to early termination of study.

End point type

Secondary

End point timeframe

Week 4 and 12

Notes
[37] - 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 comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 3: 600mg DBV and 120mg FDV - 16w	Part 3: 800mg DBV and 120mg FDV - 24w	Part 3: 600mg DBV and 120mg FDV - 24w	Part 4: 600 mg DBV and 120mg FDV - 16w	Part 4: 600 mg DBV and 120mg FDV - 24w
Number of subjects analysed	32 ^[38]	26 ^[39]	25 ^[40]	1 ^[41]	2 ^[42]
Units: Percentage of participants
number (not applicable)	75	26.9	32	99999	99999

Notes
[38] - FAS
[39] - FAS
[40] - FAS
[41] - FAS The study was stopped before data were collected from the participants in Part 4.
[42] - FAS The study was stopped before data were collected from the participants in Part 4.

No statistical analyses for this end point

Secondary: Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment

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End point title

Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment ^[43]

End point description

Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment. 99999: Summary statistics were not calculated due to early termination of study.

End point type

Secondary

End point timeframe

up to 28 weeks

Notes
[43] - 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 comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 3: 600mg DBV and 120mg FDV - 16w	Part 3: 800mg DBV and 120mg FDV - 24w	Part 3: 600mg DBV and 120mg FDV - 24w	Part 4: 600 mg DBV and 120mg FDV - 16w	Part 4: 600 mg DBV and 120mg FDV - 24w
Number of subjects analysed	32 ^[44]	26 ^[45]	25 ^[46]	1 ^[47]	2 ^[48]
Units: Percentage of participants
number (confidence interval 95%)	75 (56.6 to 88.5)	19.2 (6.6 to 39.4)	12 (2.5 to 31.2)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[44] - FAS
[45] - FAS
[46] - FAS
[47] - FAS The study was stopped before data were collected from the participants in Part 4.
[48] - FAS The study was stopped before data were collected from the participants in Part 4.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first drug administration until 30 days after last drug administration for parts 1, 2 and 4 and until 28 days after last drug administration for part 3, up to 361 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

P1:BI combi 400mg+RBV

Reporting group description

Reporting group title

P1:BI combi 600mg+RBV

Reporting group description

Reporting group title

P2:TID_16wks

Reporting group description

Reporting group title

P2:TID_28wks

Reporting group description

Reporting group title

P2:TID_40wks

Reporting group description

Reporting group title

P2:BID_28wks

Reporting group description

Reporting group title

P3:BID600_16wks

Reporting group description

Reporting group title

P2:NRBV_28wks

Reporting group description

Reporting group title

P3:BID800_24wks

Reporting group description

Reporting group title

P4:BID600_16wks

Reporting group description

Part 4: 16 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

Reporting group title

P3:TID600_24wks

Reporting group description

Reporting group title

P4:BID600_24wks

Reporting group description

Part 4: 24 weeks of 600mg Deleobuvir tablet BID and 120mg Faldaprevir soft gelatin capsule QD in combination with RBV tablet.

P1:BI combi 400mg+RBV

P1:BI combi 600mg+RBV

P2:TID_16wks

P2:TID_28wks

P2:TID_40wks

P2:BID_28wks

P3:BID600_16wks

P2:NRBV_28wks

P3:BID800_24wks

P4:BID600_16wks

P3:TID600_24wks

P4:BID600_24wks

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

3 / 81 (3.70%)

8 / 80 (10.00%)

6 / 77 (7.79%)

8 / 78 (10.26%)

1 / 32 (3.13%)

3 / 46 (6.52%)

3 / 26 (11.54%)

0 / 1 (0.00%)

2 / 25 (8.00%)

0 / 2 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

B-cell lymphoma

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

1 / 26 (3.85%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Asthenia

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Psychiatric disorders

Depression

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

1 / 25 (4.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychotic disorder

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Blood potassium decre

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Electrocardiogram QT

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Accident at work

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gun shot wound

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

1 / 46 (2.17%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Limb traumatic amputa

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Radius fracture

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute myocardial infa

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

1 / 25 (4.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Angina unstable

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

1 / 25 (4.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bundle branch block l

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac arrest

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiopulmonary failu

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Coronary artery disea

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

1 / 25 (4.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Coronary artery steno

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myocardial infarction

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ventricular fibrillat

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Brain injury

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Convulsion

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Retinal tear

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

1 / 26 (3.85%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

1 / 32 (3.13%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhoids

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholecystitis

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

1 / 26 (3.85%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Drug eruption

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

1 / 46 (2.17%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dry skin

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Erythema nodosum

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

1 / 81 (1.23%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Photosensitivity reac

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

1 / 81 (1.23%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Purpura

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

1 / 46 (2.17%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rash

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

1 / 81 (1.23%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Toxic skin eruption

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

1 / 77 (1.30%)

0 / 78 (0.00%)

0 / 32 (0.00%)

1 / 46 (2.17%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Prerenal failure

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

1 / 32 (3.13%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal failure acute

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Cellulitis pharyngeal

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

1 / 81 (1.23%)

0 / 80 (0.00%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

0 / 78 (0.00%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Herpes zoster

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

0 / 80 (0.00%)

0 / 77 (0.00%)

1 / 78 (1.28%)

0 / 32 (0.00%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 15 (0.00%)

0 / 17 (0.00%)

0 / 81 (0.00%)

1 / 80 (1.25%)

0 / 77 (0.00%)

1 / 78 (1.28%)

1 / 32 (3.13%)

0 / 46 (0.00%)

0 / 26 (0.00%)

0 / 1 (0.00%)

0 / 25 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	P1:BI combi 400mg+RBV	P1:BI combi 600mg+RBV	P2:TID_16wks	P2:TID_28wks	P2:TID_40wks	P2:BID_28wks	P3:BID600_16wks	P2:NRBV_28wks	P3:BID800_24wks	P4:BID600_16wks	P3:TID600_24wks	P4:BID600_24wks
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	76 / 81 (93.83%)	71 / 80 (88.75%)	74 / 77 (96.10%)	73 / 78 (93.59%)	30 / 32 (93.75%)	43 / 46 (93.48%)	26 / 26 (100.00%)	1 / 1 (100.00%)	25 / 25 (100.00%)	2 / 2 (100.00%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	24 / 81 (29.63%)	28 / 80 (35.00%)	25 / 77 (32.47%)	21 / 78 (26.92%)	7 / 32 (21.88%)	7 / 46 (15.22%)	4 / 26 (15.38%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	26	29	25	21	7	7	4	0	1	0
Chest pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	0 / 80 (0.00%)	0 / 77 (0.00%)	1 / 78 (1.28%)	2 / 32 (6.25%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	1 / 25 (4.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	1	2	0	0	0	1	1
Chills
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	5 / 81 (6.17%)	2 / 80 (2.50%)	3 / 77 (3.90%)	2 / 78 (2.56%)	1 / 32 (3.13%)	2 / 46 (4.35%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	5	2	3	2	1	2	1	0	0	0
Fatigue
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	18 / 81 (22.22%)	14 / 80 (17.50%)	22 / 77 (28.57%)	21 / 78 (26.92%)	9 / 32 (28.13%)	7 / 46 (15.22%)	9 / 26 (34.62%)	1 / 1 (100.00%)	10 / 25 (40.00%)	0 / 2 (0.00%)
occurrences all number	0	0	18	15	23	22	9	7	9	1	10	0
Influenza like illnes
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	2 / 81 (2.47%)	6 / 80 (7.50%)	5 / 77 (6.49%)	5 / 78 (6.41%)	0 / 32 (0.00%)	2 / 46 (4.35%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	2	7	6	5	0	2	0	0	0	0
Irritability
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	8 / 81 (9.88%)	6 / 80 (7.50%)	4 / 77 (5.19%)	2 / 78 (2.56%)	0 / 32 (0.00%)	1 / 46 (2.17%)	1 / 26 (3.85%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	8	6	4	2	0	1	1	0	2	0
Oedema peripheral
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	2 / 80 (2.50%)	0 / 77 (0.00%)	0 / 78 (0.00%)	2 / 32 (6.25%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	0	0	2	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	4 / 80 (5.00%)	4 / 77 (5.19%)	4 / 78 (5.13%)	1 / 32 (3.13%)	1 / 46 (2.17%)	2 / 26 (7.69%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	4	6	4	1	1	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	7 / 81 (8.64%)	4 / 80 (5.00%)	10 / 77 (12.99%)	9 / 78 (11.54%)	2 / 32 (6.25%)	2 / 46 (4.35%)	2 / 26 (7.69%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	7	4	11	9	2	2	2	0	2	0
Dyspnoea
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	2 / 81 (2.47%)	8 / 80 (10.00%)	10 / 77 (12.99%)	4 / 78 (5.13%)	0 / 32 (0.00%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	2	9	11	4	0	0	1	0	0	1
Epistaxis
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	1 / 80 (1.25%)	4 / 77 (5.19%)	1 / 78 (1.28%)	0 / 32 (0.00%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	2	5	1	0	0	1	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	3 / 81 (3.70%)	4 / 80 (5.00%)	7 / 77 (9.09%)	4 / 78 (5.13%)	2 / 32 (6.25%)	0 / 46 (0.00%)	2 / 26 (7.69%)	0 / 1 (0.00%)	0 / 25 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	3	4	7	4	2	0	2	0	0	1
Depressed mood
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	2 / 80 (2.50%)	5 / 77 (6.49%)	2 / 78 (2.56%)	0 / 32 (0.00%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	2	5	2	0	0	1	0	0	0
Depression
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	10 / 80 (12.50%)	5 / 77 (6.49%)	5 / 78 (6.41%)	0 / 32 (0.00%)	1 / 46 (2.17%)	2 / 26 (7.69%)	0 / 1 (0.00%)	2 / 25 (8.00%)	1 / 2 (50.00%)
occurrences all number	0	0	1	10	5	5	0	1	2	0	2	1
Insomnia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	11 / 81 (13.58%)	8 / 80 (10.00%)	12 / 77 (15.58%)	7 / 78 (8.97%)	4 / 32 (12.50%)	2 / 46 (4.35%)	3 / 26 (11.54%)	0 / 1 (0.00%)	5 / 25 (20.00%)	0 / 2 (0.00%)
occurrences all number	0	0	11	8	12	7	4	2	3	0	5	0
Sleep disorder
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	3 / 81 (3.70%)	4 / 80 (5.00%)	7 / 77 (9.09%)	4 / 78 (5.13%)	0 / 32 (0.00%)	2 / 46 (4.35%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	3	4	7	4	0	2	1	0	0	0
Investigations
Weight decreased
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	8 / 81 (9.88%)	6 / 80 (7.50%)	11 / 77 (14.29%)	8 / 78 (10.26%)	0 / 32 (0.00%)	4 / 46 (8.70%)	2 / 26 (7.69%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	8	6	12	8	0	4	2	0	2	0
Injury, poisoning and procedural complications
Sunburn
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	6 / 81 (7.41%)	4 / 80 (5.00%)	9 / 77 (11.69%)	6 / 78 (7.69%)	1 / 32 (3.13%)	8 / 46 (17.39%)	2 / 26 (7.69%)	0 / 1 (0.00%)	4 / 25 (16.00%)	0 / 2 (0.00%)
occurrences all number	0	0	6	4	11	7	1	9	2	0	4	0
Nervous system disorders
Disturbance in attent
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	3 / 81 (3.70%)	4 / 80 (5.00%)	4 / 77 (5.19%)	3 / 78 (3.85%)	1 / 32 (3.13%)	3 / 46 (6.52%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	3	4	4	3	1	3	1	0	0	0
Dizziness
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	3 / 80 (3.75%)	5 / 77 (6.49%)	3 / 78 (3.85%)	5 / 32 (15.63%)	1 / 46 (2.17%)	1 / 26 (3.85%)	0 / 1 (0.00%)	3 / 25 (12.00%)	1 / 2 (50.00%)
occurrences all number	0	0	4	3	5	3	5	1	1	0	3	1
Dysgeusia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	3 / 81 (3.70%)	4 / 80 (5.00%)	5 / 77 (6.49%)	2 / 78 (2.56%)	0 / 32 (0.00%)	2 / 46 (4.35%)	2 / 26 (7.69%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	3	4	5	2	0	2	2	0	0	0
Headache
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	11 / 81 (13.58%)	8 / 80 (10.00%)	15 / 77 (19.48%)	11 / 78 (14.10%)	4 / 32 (12.50%)	7 / 46 (15.22%)	3 / 26 (11.54%)	0 / 1 (0.00%)	2 / 25 (8.00%)	2 / 2 (100.00%)
occurrences all number	0	0	12	9	18	12	4	7	3	0	2	2
Hypoaesthesia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	1 / 80 (1.25%)	1 / 77 (1.30%)	2 / 78 (2.56%)	0 / 32 (0.00%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	3 / 25 (12.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	1	2	0	0	1	0	3	0
Lethargy
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	1 / 80 (1.25%)	2 / 77 (2.60%)	1 / 78 (1.28%)	2 / 32 (6.25%)	1 / 46 (2.17%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	1	2	1	2	1	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	10 / 81 (12.35%)	9 / 80 (11.25%)	6 / 77 (7.79%)	4 / 78 (5.13%)	0 / 32 (0.00%)	5 / 46 (10.87%)	3 / 26 (11.54%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	10	10	7	4	0	5	3	0	2	0
Somnolence
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	2 / 80 (2.50%)	0 / 77 (0.00%)	0 / 78 (0.00%)	1 / 32 (3.13%)	0 / 46 (0.00%)	4 / 26 (15.38%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	0	0	1	0	4	0	0	0
Syncope
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	2 / 80 (2.50%)	5 / 77 (6.49%)	6 / 78 (7.69%)	0 / 32 (0.00%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	2	5	6	0	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	1 / 80 (1.25%)	1 / 77 (1.30%)	1 / 78 (1.28%)	2 / 32 (6.25%)	1 / 46 (2.17%)	0 / 26 (0.00%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	1	1	2	1	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	9 / 80 (11.25%)	10 / 77 (12.99%)	7 / 78 (8.97%)	8 / 32 (25.00%)	0 / 46 (0.00%)	3 / 26 (11.54%)	1 / 1 (100.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	10	12	7	8	0	3	1	2	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 78 (0.00%)	2 / 32 (6.25%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	0 / 80 (0.00%)	3 / 77 (3.90%)	1 / 78 (1.28%)	2 / 32 (6.25%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	3	1	2	0	0	0	0	0
Ocular icterus
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	2 / 81 (2.47%)	0 / 80 (0.00%)	3 / 77 (3.90%)	5 / 78 (6.41%)	2 / 32 (6.25%)	0 / 46 (0.00%)	2 / 26 (7.69%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	2	0	3	5	2	0	2	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	1 / 80 (1.25%)	1 / 77 (1.30%)	6 / 78 (7.69%)	4 / 32 (12.50%)	0 / 46 (0.00%)	2 / 26 (7.69%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	1	1	7	4	0	2	0	2	0
Abdominal distension
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	3 / 80 (3.75%)	7 / 77 (9.09%)	4 / 78 (5.13%)	1 / 32 (3.13%)	3 / 46 (6.52%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	4	3	7	4	1	3	1	0	0	0
Abdominal pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	7 / 81 (8.64%)	7 / 80 (8.75%)	6 / 77 (7.79%)	12 / 78 (15.38%)	0 / 32 (0.00%)	8 / 46 (17.39%)	3 / 26 (11.54%)	0 / 1 (0.00%)	3 / 25 (12.00%)	0 / 2 (0.00%)
occurrences all number	0	0	7	7	6	13	0	8	3	0	3	0
Abdominal pain upper
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	6 / 81 (7.41%)	15 / 80 (18.75%)	12 / 77 (15.58%)	2 / 78 (2.56%)	3 / 32 (9.38%)	2 / 46 (4.35%)	5 / 26 (19.23%)	0 / 1 (0.00%)	2 / 25 (8.00%)	1 / 2 (50.00%)
occurrences all number	0	0	6	15	13	2	3	2	5	0	2	1
Constipation
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	1 / 80 (1.25%)	6 / 77 (7.79%)	3 / 78 (3.85%)	4 / 32 (12.50%)	1 / 46 (2.17%)	4 / 26 (15.38%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	4	1	7	3	4	1	4	0	1	0
Diarrhoea
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	34 / 81 (41.98%)	33 / 80 (41.25%)	36 / 77 (46.75%)	29 / 78 (37.18%)	7 / 32 (21.88%)	12 / 46 (26.09%)	9 / 26 (34.62%)	0 / 1 (0.00%)	9 / 25 (36.00%)	0 / 2 (0.00%)
occurrences all number	0	0	39	44	49	39	7	12	9	0	9	0
Dry mouth
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	0 / 80 (0.00%)	4 / 77 (5.19%)	0 / 78 (0.00%)	0 / 32 (0.00%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	5	0	0	0	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	6 / 81 (7.41%)	5 / 80 (6.25%)	8 / 77 (10.39%)	14 / 78 (17.95%)	6 / 32 (18.75%)	4 / 46 (8.70%)	4 / 26 (15.38%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	6	5	8	16	6	4	4	0	1	0
Flatulence
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	3 / 81 (3.70%)	5 / 80 (6.25%)	4 / 77 (5.19%)	4 / 78 (5.13%)	2 / 32 (6.25%)	2 / 46 (4.35%)	1 / 26 (3.85%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	3	5	4	4	2	2	1	0	1	0
Gastrooesophageal ref
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	4 / 80 (5.00%)	2 / 77 (2.60%)	2 / 78 (2.56%)	1 / 32 (3.13%)	0 / 46 (0.00%)	2 / 26 (7.69%)	0 / 1 (0.00%)	2 / 25 (8.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	4	2	2	1	0	2	0	2	1
Hypoaesthesia oral
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	1 / 80 (1.25%)	0 / 77 (0.00%)	0 / 78 (0.00%)	1 / 32 (3.13%)	1 / 46 (2.17%)	0 / 26 (0.00%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	1	1	0	0	2	0
Lip dry
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	2 / 80 (2.50%)	1 / 77 (1.30%)	1 / 78 (1.28%)	0 / 32 (0.00%)	4 / 46 (8.70%)	0 / 26 (0.00%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	2	1	1	0	4	0	0	1	0
Nausea
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	41 / 81 (50.62%)	43 / 80 (53.75%)	41 / 77 (53.25%)	39 / 78 (50.00%)	18 / 32 (56.25%)	26 / 46 (56.52%)	16 / 26 (61.54%)	1 / 1 (100.00%)	18 / 25 (72.00%)	1 / 2 (50.00%)
occurrences all number	0	0	44	48	51	47	18	28	16	1	18	1
Vomiting
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	24 / 81 (29.63%)	29 / 80 (36.25%)	23 / 77 (29.87%)	20 / 78 (25.64%)	11 / 32 (34.38%)	13 / 46 (28.26%)	6 / 26 (23.08%)	0 / 1 (0.00%)	5 / 25 (20.00%)	0 / 2 (0.00%)
occurrences all number	0	0	35	43	38	29	11	16	6	0	5	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	2 / 80 (2.50%)	3 / 77 (3.90%)	0 / 78 (0.00%)	3 / 32 (9.38%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	2	3	0	3	0	0	0	0	1
Jaundice
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	25 / 81 (30.86%)	22 / 80 (27.50%)	15 / 77 (19.48%)	16 / 78 (20.51%)	6 / 32 (18.75%)	2 / 46 (4.35%)	5 / 26 (19.23%)	0 / 1 (0.00%)	4 / 25 (16.00%)	0 / 2 (0.00%)
occurrences all number	0	0	25	22	16	16	6	2	5	0	4	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	7 / 80 (8.75%)	2 / 77 (2.60%)	7 / 78 (8.97%)	1 / 32 (3.13%)	4 / 46 (8.70%)	2 / 26 (7.69%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	7	2	7	1	4	2	0	0	0
Dermatitis
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	1 / 80 (1.25%)	0 / 77 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	2	0
Dry skin
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	12 / 81 (14.81%)	12 / 80 (15.00%)	11 / 77 (14.29%)	18 / 78 (23.08%)	3 / 32 (9.38%)	7 / 46 (15.22%)	2 / 26 (7.69%)	0 / 1 (0.00%)	2 / 25 (8.00%)	0 / 2 (0.00%)
occurrences all number	0	0	12	12	11	18	3	7	2	0	2	0
Eczema
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	2 / 81 (2.47%)	3 / 80 (3.75%)	2 / 77 (2.60%)	4 / 78 (5.13%)	0 / 32 (0.00%)	3 / 46 (6.52%)	1 / 26 (3.85%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	2	3	3	4	0	3	1	0	1	0
Erythema
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	1 / 80 (1.25%)	1 / 77 (1.30%)	2 / 78 (2.56%)	1 / 32 (3.13%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	3 / 25 (12.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	2	4	1	0	1	0	5	0
Pain of skin
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	2 / 25 (8.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	2	1
Papule
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	0 / 80 (0.00%)	0 / 77 (0.00%)	1 / 78 (1.28%)	2 / 32 (6.25%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	1	0	0	0
Photosensitivity reac
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	20 / 81 (24.69%)	23 / 80 (28.75%)	23 / 77 (29.87%)	19 / 78 (24.36%)	4 / 32 (12.50%)	11 / 46 (23.91%)	3 / 26 (11.54%)	0 / 1 (0.00%)	8 / 25 (32.00%)	1 / 2 (50.00%)
occurrences all number	0	0	21	25	25	21	4	11	3	0	8	1
Pruritus
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	16 / 81 (19.75%)	24 / 80 (30.00%)	31 / 77 (40.26%)	23 / 78 (29.49%)	7 / 32 (21.88%)	14 / 46 (30.43%)	6 / 26 (23.08%)	0 / 1 (0.00%)	7 / 25 (28.00%)	2 / 2 (100.00%)
occurrences all number	0	0	17	27	39	24	7	14	6	0	7	2
Rash
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	21 / 81 (25.93%)	11 / 80 (13.75%)	28 / 77 (36.36%)	15 / 78 (19.23%)	0 / 32 (0.00%)	13 / 46 (28.26%)	9 / 26 (34.62%)	0 / 1 (0.00%)	10 / 25 (40.00%)	2 / 2 (100.00%)
occurrences all number	0	0	25	13	39	19	0	15	9	0	10	2
Rash papulosquamous
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	0 / 81 (0.00%)	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 78 (0.00%)	2 / 32 (6.25%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	5 / 80 (6.25%)	4 / 77 (5.19%)	4 / 78 (5.13%)	0 / 32 (0.00%)	3 / 46 (6.52%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	4	5	5	4	0	3	1	0	0	0
Back pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	3 / 81 (3.70%)	3 / 80 (3.75%)	1 / 77 (1.30%)	6 / 78 (7.69%)	1 / 32 (3.13%)	0 / 46 (0.00%)	1 / 26 (3.85%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	3	3	1	7	1	0	1	0	1	0
Muscle spasms
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	1 / 80 (1.25%)	6 / 77 (7.79%)	3 / 78 (3.85%)	1 / 32 (3.13%)	1 / 46 (2.17%)	2 / 26 (7.69%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	4	1	7	3	1	1	2	0	1	0
Myalgia
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	4 / 80 (5.00%)	4 / 77 (5.19%)	3 / 78 (3.85%)	2 / 32 (6.25%)	1 / 46 (2.17%)	1 / 26 (3.85%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	4	4	3	2	1	1	0	0	0
Pain in extremity
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	2 / 81 (2.47%)	1 / 80 (1.25%)	2 / 77 (2.60%)	3 / 78 (3.85%)	1 / 32 (3.13%)	1 / 46 (2.17%)	2 / 26 (7.69%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	2	1	2	4	1	1	2	0	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	8 / 80 (10.00%)	7 / 77 (9.09%)	6 / 78 (7.69%)	2 / 32 (6.25%)	6 / 46 (13.04%)	0 / 26 (0.00%)	0 / 1 (0.00%)	0 / 25 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	4	9	8	7	2	6	0	0	0	0
Urinary tract infecti
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	1 / 81 (1.23%)	2 / 80 (2.50%)	0 / 77 (0.00%)	2 / 78 (2.56%)	2 / 32 (6.25%)	1 / 46 (2.17%)	0 / 26 (0.00%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	2	0	2	2	1	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 15 (0.00%)	0 / 17 (0.00%)	4 / 81 (4.94%)	15 / 80 (18.75%)	10 / 77 (12.99%)	8 / 78 (10.26%)	3 / 32 (9.38%)	0 / 46 (0.00%)	0 / 26 (0.00%)	0 / 1 (0.00%)	1 / 25 (4.00%)	0 / 2 (0.00%)
occurrences all number	0	0	4	15	10	8	3	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

23 Apr 2010

Protocol Amendment 1, dated 23 Apr 2010, was implemented before patient enrolment began, in order to clarify: 1. That the aims and design of Part 1 of the 1241.21 clinical trial is typical of a Phase Ib study (drug-drug interaction, short term safety and on-treatment activity in a small cohort of patients), while Part 2 will extend treatment duration and establish proof of concept (sustained virological response), thus representing a phase II study. The trial phase was changed from II to Ib/II in title page and synopsis. 2. The time-points when targeted physical exams took place. 3. How the eCRF pages were to be completed in case of early end of treatment of a patient. 4. The time-point of the End of Observation in case of viral relapse and to add a time point for End of Observation visit. 5. Which assessments was part of the end of treatment (EOT) visit for patients who have their EOT visit at Week 24. 6. How PK sample for DBV and its metabolites were collected and analysed.

05 Oct 2010

Protocol amendment 2, dated 05 Oct 2010, was implemented in order to increase patient safety. HCV RNA related stopping rules were modified and are no longer based on 'lower limit of quantification' (<25 IU/ml) but on 'lower limit of detection' (approximately 10 IU/ml) according to FDA Draft Guidance for Developing new HCV Treatments from Sep 2010. Changes to planned analysis in Part 1: Changes to the planned analyses from the protocol concerned sustained virological response (SVR12) which was not determined as secondary efficacy endpoint as stated in the CTP. Comparison to historical data was performed with trials 1220.2 (monotherapy with FDV) and trial 1241.7 (triple therapy with DBV). Data from trials 1241.2, 1220.5, and 1220.40 were not used for historical comparison; these trials were written up in protocol Section 3.2 for completeness, but in the end they did not provide data that were directly comparable with those of the present trial. The final analysis contained no model search for response, as there were almost no cases in which no SVR occurred. Changes in Part 2: Global protocol amendments in Part 2. In the course of Part 2, 4 amendments to the CTP were issued (global protocol amendments 3 to 6). All of these amendments required approval by the IEC and CA.

20 Oct 2010

Protocol amendment 3, dated 20 Oct 2010 were implemented due to the excellent antiviral response rates and good tolerability and safety observed in Part 1. 1. The sample size per treatment arm was increased from n = 30 to n = 80 to support a full Phase IIb trial design. This was planned to accelerate the clinical development of FDV/DBV combination therapy. 2. Re-randomisation was deleted in the new Part 2 design to simplify the design. 3. The DBV 600 mg BID dose was introduced: Based on the observed dose-dependent difference in tolerability over 4 weeks in Part 1 with very robust antiviral effect in both dose groups, investigation of a second dose that was lower than 600 mg TID was justified for long-term treatment in Part 2. 4. Treatment durations of 16, 28, and 40 weeks were tested. 5. Patients with cirrhosis Child A were allowed to participate in Part 2, based on safety, pharmacokinetics and efficacy data from cirrhotic patients in the Phase Ib/II trials 1220.2 (FDV+SOC for 4 weeks), 1220.40 (FDV+SOC for 12-24 weeks) and 1241.2 (DBV monotherapy for 5 days). 6. Furthermore Protocol Amendment 3 was implemented based on the recently published Food and Drug Administration (FDA). 7. Patients who achieved SVR were followed for 144 weeks after EOT. Patients who discontinued early on investigational treatment were followed for at least 48 weeks. Genotyping of IL28B, was included as a stratifying factor. As an association of the IL28B genotype with spontaneous cure from acute HCV infection or response to PegIFN therapy was reported, it was important to understand the impact of the IL28B genotype on the response to PegIFN-sparing direct-acting antiviral combinations and, therefore, IL28B genotype was considered in the analysis of efficacy data. 9. Additional follow-up visits were added to ensure that HCV RNA was measured for all patients (incl. those that discontinued prematurely) at 12 weeks and at 24 weeks after EOT.

04 Feb 2011

Protocol amendment 4, dated 4 Feb 2011, was issued to stop recruitment to treatment arm NRBV, due to evidence presented for other direct acting antiviral agents raising concerns about an increased risk of virological breakthrough with RBV-free treatment regimens.

18 Apr 2011

Protocol amendment 5, dated 18 Apr 2011, included: 1. Further drugs which were not allowed to be used or were to be avoided concomitantly. 2. A new version of rash management plan. 3. Clarification of the DBV dose reduction. 4. Recommendations for symptomatic treatment of gastrointestinal (GI) AEs. 5. The use of urine instead of serum pregnancy tests. 6. Correction of storage conditions for FDV. 7. The need to confirm virological breakthrough with a second measurement was omitted for patients with plasma HCV RNA ≥1000 IU/mL in the initial measurement of breakthrough. As HCV RNA generally rebounds rapidly during virological breakthrough, and low viral load (VL) level is associated with a better sustained viral response to PegIFN/RBV therapy, the aim is to switch patients to SOC treatment as soon as possible after the detection of virological breakthrough. 8. The achievement of an undetectable HCV RNA level at Week 4 was added as a secondary efficacy endpoint. 9. The time windows for later protocol visits were shortened, to ensure that the amount of dispensed medication be sufficient to cover the periods between clinical visits.

14 Jul 2011

Protocol amendment 6, dated 14 Jul 2011, was implemented for the following reasons: 1. Exclusion criterion 25 (HbA1c >8.5%) was adapted. 2. A confirmed definition for virological relapse was provided. 3. Prompt treatment initiation with PegIFN and RBV was required in patients with confirmed virological relapse. 4. The assignment of AEs to treatment phases was made clearer. Changes in conduct of Part 2.Enrolment in the ribavirin-free arm (NRBV 28wks group) was stopped on 03 Feb 2011 on request of the FDA after 49 patients were randomised, following the observation from other studies that breakthrough was more common in IFN-free regimens that did not contain ribavirin. Changes to planned analysis in Part 2: Prior to the internal unblinding of the data and the signature of the TSAP for Part 2, the primary endpoint was changed from SVR24 (plasma HCV RNA level not detectable at 24 weeks after completion of all therapy) to SVR12. SVR24 was defined as secondary endpoint. Other additional analyses not specified in the CTP or TSAP (Part 2) include: 5. Analysis of PPV of SVR4 to SVR24, SVR12 to SVR24, and SVR24 to SVR48 (using available data) were also calculated for the VES. 6. The predictive value (positive and negative) of earlier endpoints for the occurrence of later endpoints was investigated from the observed data using the VES population. 7. The assessments of the incidence, prevalence, and duration of rash, photosensitivity, nausea, vomiting, and diarrhoea. Time windows used in these analyses differ from those specified in the minutes of the final blinded report planning meeting (BRPM) (September 10, 2012) in order to display the timing of the episodes of these AEs more clearly. 8. Efficacy and safety tabulations by cirrhosis (yes/no) 9.8.3.1 Global protocol amendments in Part 3. In the course of Part 3, 3 global protocol amendments to the CTP were issued (amendment 7, 8, and 9). All of these amendments required approval by the IEC and CA.

30 Dec 2011

Protocol amendment 7, dated 30 Dec 2011, implemented Part 3 to the trial protocol. This resulted in a number of changes throughout the protocol, among them: 1. Changes to the protocol title. 2. Addition of the treatment groups for Part 3. 3. New endpoints for Part 3. 4. New criteria for PK. 5. New futility rules. 6. A new definition for lack of antiviral activity. 7. Changes in inclusion and exclusion criteria. 8. Addition of new skin and GI management plans.

16 May 2012

Protocol amendment 8, dated 16 May 2012 included some additional updates and adjustments: 1. Changes to inclusion and exclusion criteria. 2. The primary endpoint was changed to be SVR12 (plasma HCV RNA undetectable 12 weeks after end of all therapy). 3. Accordingly, SVR4 was used as a secondary endpoint. 4. Intensity of all adverse events was to be assessed according to the DAIDS (Division of AIDS) grading system of the US National Institute of Allergy and Infectious Diseases. 5. Bayer Trugene® Hepatitis C virus genotyping assay was to be used, when a GT-1 subtype could not be determined using the iNNO-LiPA HCV 2.0 genotyping assay. 6. Added one interim analysis to obtain Week 4 on-treatment results in treatment group BID 600 mg 16wks.

01 Aug 2012

Protocol amendment 9, dated 01 August 2012 implemented: 1. The requirement to confirm virological breakthrough, if the VL was <1000 IU/mL, was deleted for the 24wks groups as these patients were at higher risk for virological failure. 2. Inclusion criterion No. 7 was changed to require two non hormonal methods for contraception as interaction of the two trial drugs with oral contraceptives may lead to reduced efficacy of these. Changes in conduct of Part 3: In Part 3, the following changes were made in the conduct of the trial: The requirement to confirm virological breakthrough, if the VL was <1000 IU/mL was deleted for treatment groups BID 800 mg 24wks and TID 600 mg 24wks. This was done because in an interim analysis the patients in these groups appeared to be at higher risk for virological failure.Part 3, patients in the BID 24wks group (Group 9; FDV 120 mg QD + DBV 800 mg BID + RBV) and the TID 24wks group (Group 10; FDV 120 mg QD + DBV 600 mg TID + RBV) were at greater risk to experience virological failure with emergent resistance to both direct-acting antivirals. Although all patients in these 2 arms were among the more difficult to treat, i.e. GT-1a with unfavourable IL28B non-CC genotype, the DMC recommended to stop further randomisation into the BID 800 mg 24wks and TID 600 mg 24wks groups. Due to this, the BID 800 mg 24wks and TID 600 mg 24wks groups consisted of 26 and 25 patients, respectively, instead of the 30 patients planned per group. Changes to planned analysis in Part 3: AEs occurring up to 28 days after last administration of trial medication were attributed to the trial period instead of the 30 days stated in the CTP. Changes in Part 4: Global protocol amendments in Part 4. In the course of Part 4 of this trial, 4 global protocol amendments to the CTP were issued. These amendments required approval by the IEC and CA.

17 Dec 2012

Protocol amendment 10, dated 17 Dec 2012, added Part 4 to the CTP. In this part, patients with chronic HCV GT-1b infection and previous non-response to combination treatment with PegIFN and RBV were enroled. The major changes introduced by protocol amendment 10 were: 1. Change of the number of recruited patients: 30 additional patients were to be enrolled. 2. Changes to inclusion criterion 2 and 3. Addition of treatment groups for Part 4. Clarification that an Interactive Voice Response System (IVRS) was not used in Part 4 of this trial. 5. Low density lipoprotein (LDL) was deleted from the list of substrates to be analysed, as it had been listed by mistake.

21 Jun 2013

Protocol amendment 11, dated 21 Jun 2013, included the following changes: 1. Change of PK-sample collection method: PK-samples which are collected outside of the intensive PK-sampling in Part 4 were not to be collected at any time during the visit days but in fasting condition and prior to the intake of study medication. 2. Update of lists of restricted medications (Appendices 10.3 and 10.4 of the CTP). The most current medications list was to be included in the ISF Section 11 'Safety Information'. 3. Addition of Appendix 10.5 in the CTP: List of comedications that should be used with caution as the levels of these drugs might decrease in studies with the combination of FDV and DBV. The most current medications list was to be included in the ISF Section 11 'Safety Information'. 4. Adjustment of the inclusion criterion 3, Part 4. 5. Updated frequency of ECG measurements. 6. Updated benefit-risk section with no change in the benefit-risk relationship. 7. Information was added that skin reactions of moderate or higher severity was to be adjudicated by an external panel of dermatology specialists. 8. Inclusion of DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) into the definition of Potentially Life-Threatening (Grade IV) skin events. 9. Virology samples for resistance testing were no longer shipped to the BI facility in Laval, Canada but to Janssen Diagnostics in Belgium.

29 Oct 2013

Protocol amendment 12, dated 29 Oct 2013, implemented changes in the benefit-risk assessement and the criteria for removal of patients: 1. Benefit-risk assessment: Potential risk of agranulocytosis/neutropenia were added, as cases of Grade IV neutropenia were recently observed. 2. Removal of individual patients: Added that treatment was to be discontinued if absolute neutrophil count was ≤500 cell/mm3 to ensure treatment discontinuation in case of life-threatening neutropenia.

14 Mar 2014

Protocol amendment 13, dated 14 Mar 2014, introduced the following changes due to the termination of the developmental programme for DBVand FDV by the sponsor: 1. Flow Chart 8 for Part 4: The follow-up period in Part 4 was shortened to 24 weeks after EOT; only 3 patients were randomised in Part 4 of this trial by the time of DBV development termination. The long term follow-up in Part 4 was not needed. 2. Interim Analysis: The interim analysis was not needed. Changes in conduct of Part 4: Enrolment in Part 4 of trial 1241.21 was stopped on 17 January 2014 as the sponsor Boehringer Ingelheim decided to discontinue the developmental programmes of DBV and FDV. All pending marketing applications for FDV were withdrawn and further HCV drug development was discontinued. The decision was taken as there is no longer an unmet medical need for the FDV interferon-based regimen. Changes to planned analysis in Part 4: In Part 4 of this trial, only 3 patients with previous 'null-response' to HCV therapy were entered, because Part 4 had been terminated early. Therefore, no formal analysis of efficacy was performed. Safety and efficacy data for these patients are described based on listings.The TSAP for this final CTR that defines analyses for Parts 2 to 4, mentions SVR24 as a secondary endpoint for both, Parts 2 and 3. However, SVR24 was defined as a secondary only for Part 2 of this trial; for Part 3 it was defined as a further (tertiary) endpoint.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
17 Jan 2014	As trial 1241.21 was terminated early and in Part 4 only 3 patients were entered, no formal analysis of efficacy data was performed. For part 4, only descriptive statistics of HCV RNA viral load are presented.	-

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

There were only 3 patients entered in part 4 of the trial, therefore no formal analyses of efficacy data were performed. Long term follow-up: Part 1: 168 Days, Part2: 144 Weeks, Part3: 96 Weeks, Part4: 24 Weeks.

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Clinical trials

Clinical Trial Results:
Safety, antiviral effect and pharmacokinetics of BI 207127 in combination with BI 201335 and with or without ribavirin for 4, 16, 24, 28 or 40 weeks in patients with chronic HCV genotype 1 infection (randomized Phase Ib/II).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Rapid virological response (RVR)

Primary: Part 1: Rapid virological response (RVR)

Primary: Part 2: Sustained virological response (SVR)

Primary: Part 2: Sustained virological response (SVR)

Primary: Part 3 and 4: Sustained virological response (SVR)

Primary: Part 3 and 4: Sustained virological response (SVR)

Secondary: Part 1: Time to virological response

Secondary: Part 1: Time to virological response

Secondary: Part 2: Time to virological response

Secondary: Part 2: Time to virological response

Secondary: Part 1 and 2: Plasma HCV RNA level not detectable at Week 4

Secondary: Part 1 and 2: Plasma HCV RNA level not detectable at Week 4

Secondary: Part 2: Sustained virological response at 4 and 24 weeks after end of treatment

Secondary: Part 2: Sustained virological response at 4 and 24 weeks after end of treatment

Secondary: Part 3 and 4: Plasma HCV RNA level <25 IU/mL at week 4 and 12 of treatment

Secondary: Part 3 and 4: Plasma HCV RNA level <25 IU/mL at week 4 and 12 of treatment

Secondary: Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment

Secondary: Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Safety, antiviral effect and pharmacokinetics of BI 207127 in combination with BI 201335 and with or without ribavirin for 4, 16, 24, 28 or 40 weeks in patients with chronic HCV genotype 1 infection (randomized Phase Ib/II).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Rapid virological response (RVR)

Primary: Part 1: Rapid virological response (RVR)

Primary: Part 2: Sustained virological response (SVR)

Primary: Part 2: Sustained virological response (SVR)

Primary: Part 3 and 4: Sustained virological response (SVR)

Primary: Part 3 and 4: Sustained virological response (SVR)

Secondary: Part 1: Time to virological response

Secondary: Part 1: Time to virological response

Secondary: Part 2: Time to virological response

Secondary: Part 2: Time to virological response

Secondary: Part 1 and 2: Plasma HCV RNA level not detectable at Week 4

Secondary: Part 1 and 2: Plasma HCV RNA level not detectable at Week 4

Secondary: Part 2: Sustained virological response at 4 and 24 weeks after end of treatment

Secondary: Part 2: Sustained virological response at 4 and 24 weeks after end of treatment

Secondary: Part 3 and 4: Plasma HCV RNA level <25 IU/mL at week 4 and 12 of treatment

Secondary: Part 3 and 4: Plasma HCV RNA level <25 IU/mL at week 4 and 12 of treatment

Secondary: Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment

Secondary: Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Safety, antiviral effect and pharmacokinetics of BI 207127 in combination with BI 201335 and with or without ribavirin for 4, 16, 24, 28 or 40 weeks in patients with chronic HCV genotype 1 infection (randomized Phase Ib/II).