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Clinical Trial Results:
A multicenter, randomized, double-blind, placebocontrolled, parallel-group phase II study on efficacy and safety of DEB025 combined with pegIFNalpha2a and ribavirin in chronic hepatitis C genotype 1 relapsers and non-responders to previous pegIFN plus ribavirin treatment

Summary
EudraCT number	2010-020033-14
Trial protocol	GB HU DE FR ES BE IT PL
Global end of trial date	09 May 2013

Results information
Results version number	v1(current)
This version publication date	29 Sep 2016
First version publication date	29 Sep 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

CDEB025A2210

ISRCTN number

US NCT number

NCT01183169

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,

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

09 May 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 May 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to demonstrate that in chronic hepatitis C G1 patients with previous non-response to pegIFN/RBV or with previous relapse after pegIFN/RBV treatment: • triple therapy with DEB025 600 mg BID (loading dose) / 600 mg QD plus pegIFNα2a/RBV leads to a superior cEVR (by Limit of Quantification [LOQ] i.e. HCV RNA < 25 IU/mL) rate as compared to pegIFNα2a/RBV AND/OR • triple therapy with DEB025 600 mg BID (loading dose) / 800 mg QD plus pegIFNα2a/RBV leads to a superior cEVR rate (by LOQ) as compared to pegIFNα2a/RBV AND/OR • triple therapy with DEB025 400 mg BID plus pegIFNα2a/RBV leads to a superior cEVR rate (by LOQ) as compared to pegIFNα2a/RBV

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Aug 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 29

Country: Number of subjects enrolled

Romania: 76

Country: Number of subjects enrolled

Spain: 29

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Germany: 37

Country: Number of subjects enrolled

Hungary: 29

Country: Number of subjects enrolled

Italy: 36

Country: Number of subjects enrolled

United States: 59

Country: Number of subjects enrolled

Australia: 29

Country: Number of subjects enrolled

Taiwan: 80

Country: Number of subjects enrolled

Turkey: 30

Worldwide total number of subjects

459

EEA total number of subjects

261

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)

444

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

It was planned to enroll 344 patients. A total of 459 patients were randomized and included in the Full Analysis Set (FAS).

Period 1 title

Initial treatment period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

At Visit 2 (baseline visit) all eligible patients were randomized via Interactive Response Technology (IRT) to one of the four treatment arms. In order to blind all treatment arms, the placebo-treated patients of arm C were split into two sub-arms of (C1 and C2) in 1:1 ratio.

Are arms mutually exclusive

Arm A: DEB025 600 mg QD

Arm description

DEB025 600 mg once daily (QD) with PEG and RBV for up to 48 weeks

Arm type

Experimental

Investigational medicinal product name

DEB025

Investigational medicinal product code

Other name

Alisporivir

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

DEB025 was supplied as 200 mg soft gel capsules.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Arm B: DEB 800 QD

Arm description

DEB025 800 mg QD with PEG and RBV for up to 48 weeks.

Arm type

Experimental

Investigational medicinal product name

DEB025

Investigational medicinal product code

Other name

Alisporivir

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

DEB025 was supplied as 200 mg soft gel capsules.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Arm C1- Placebo QD

Arm description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving complete early virologic response (cEVR: HCV RNA <LOQ after 12 weeks of treatment) may switch to active ALV 600 mg QD with PEG and RBV. Note: For one patient in arm C the corresponding end-of treatment CRF page was by mistake not entered into the database before the database was locked (the patient completed the treatment phase on 31-Mar-2012). Therefore, this patient is not included or in other summaries dependent on end-of-treatment status.

Arm type

Placebo

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Investigational medicinal product name

Placebo to DEB025

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Placebo soft gel capsules administered orally

Arm C2- Placebo BID

Arm description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving cEVR may switch to active ALV 400 mg twice daily (BID) with PEG and RBV.

Arm type

Placebo

Investigational medicinal product name

Placebo to DEB025

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Placebo soft gel capsules administered orally

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Arm D DEB 400 BID

Arm description

DEB025 400 mg twice daily BID with PEG and RBV for up to 48 weeks

Arm type

Experimental

Investigational medicinal product name

DEB025

Investigational medicinal product code

Other name

Alisporivir

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

DEB025 was supplied as 200 mg soft gel capsules.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Arm C- Placebo

Arm description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving complete early virologic response (cEVR: HCV RNA <LOQ after 12 weeks of treatment) may switch to active ALV 600 mg QD with PEG and RBV. Note: For one patient in arm C the corresponding end-of treatment CRF page was by mistake not entered into the database before the database was locked (the patient completed the treatment phase on 31-Mar-2012). Therefore, this patient is not included in Table 10-1 or in other summaries dependent on end-of-treatment status.

Arm type

Placebo

Investigational medicinal product name

Placebo to DEB025

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Placebo soft gel capsules administered orally

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Number of subjects in period 1	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm C1- Placebo QD	Arm C2- Placebo BID	Arm D DEB 400 BID	Arm C- Placebo
Started	121	115	59	55	109	114
Completed	72	78	18	17	77	35
Not completed	49	37	41	38	32	79
Abnormal laboratory value(s)	-	2	1	1	1	2
Consent withdrawn by subject	7	5	1	2	9	3
Disease progression	1	-	-	-	-	-
Adverse event, non-fatal	12	9	3	2	18	5
Unsatisfactory therapeutic effect	25	20	1	3	3	4
Administrative problems	2	-	-	-	1	-
Non-compliance	1	-	-	-	-	-
Protocol deviation	1	1	-	-	-	-
Switch to DEB025	-	-	35	30	-	65

Period 2 title

After week 16 switch to DEB025

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Are arms mutually exclusive

Arm C1-A

Arm description

Placebo to DEB 600 QD

Arm type

Experimental

Investigational medicinal product name

DEB025

Investigational medicinal product code

Other name

Alisporivir

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

DEB025 was supplied as 200 mg soft gel capsules.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Arm C2-A

Arm description

Placebo to DEB 400 BID

Arm type

Experimental

Investigational medicinal product name

DEB025

Investigational medicinal product code

Other name

Alisporivir

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

DEB025 was supplied as 200 mg soft gel capsules.

Investigational medicinal product name

Peginterferon alfa-2a

Investigational medicinal product code

Other name

Pegasys®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG 180 μg administered via subcutaneous (s.c.) injection once weekly

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Copegus®

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

RBV 200 mg tablets (weight-based dose: < 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose.

Number of subjects in period 2	Arm C1-A	Arm C2-A
Started	35	30
Completed	12	13
Not completed	23	17
Abnormal laboratory value(s)	-	1
Consent withdrawn by subject	2	-
Adverse event, non-fatal	3	3
Unsatisfactory therapeutic effect	17	9
Administrative problems	1	4

Baseline characteristics

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Reporting group title

Arm A: DEB025 600 mg QD

Reporting group description

DEB025 600 mg once daily (QD) with PEG and RBV for up to 48 weeks

Reporting group title

Arm B: DEB 800 QD

Reporting group description

DEB025 800 mg QD with PEG and RBV for up to 48 weeks.

Reporting group title

Arm C1- Placebo QD

Reporting group description

Reporting group title

Arm C2- Placebo BID

Reporting group description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving cEVR may switch to active ALV 400 mg twice daily (BID) with PEG and RBV.

Reporting group title

Arm D DEB 400 BID

Reporting group description

DEB025 400 mg twice daily BID with PEG and RBV for up to 48 weeks

Reporting group title

Arm C- Placebo

Reporting group description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving complete early virologic response (cEVR: HCV RNA <LOQ after 12 weeks of treatment) may switch to active ALV 600 mg QD with PEG and RBV. Note: For one patient in arm C the corresponding end-of treatment CRF page was by mistake not entered into the database before the database was locked (the patient completed the treatment phase on 31-Mar-2012). Therefore, this patient is not included in Table 10-1 or in other summaries dependent on end-of-treatment status.

Reporting group values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm C1- Placebo QD	Arm C2- Placebo BID	Arm D DEB 400 BID	Arm C- Placebo	Total
Number of subjects	121	115	59	55	109	114	459
Age categorical
Units: Subjects
Adults (18-64 years)	118	111	57	55	103	112	444
From 65-84 years	3	4	2	0	6	2	15
Age continuous
Units: years
arithmetic mean (standard deviation)	50.2 ± 9.24	50.9 ± 10.11	51.5 ± 8.99	49.4 ± 11.91	51 ± 9.68	50.5 ± 10.5	-
Gender categorical
Units: Subjects
Female	58	47	19	17	40	36	181
Male	63	68	40	38	69	78	278

End points

Top of page

Reporting group title

Arm A: DEB025 600 mg QD

Reporting group description

DEB025 600 mg once daily (QD) with PEG and RBV for up to 48 weeks

Reporting group title

Arm B: DEB 800 QD

Reporting group description

DEB025 800 mg QD with PEG and RBV for up to 48 weeks.

Reporting group title

Arm C1- Placebo QD

Reporting group description

Reporting group title

Arm C2- Placebo BID

Reporting group description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving cEVR may switch to active ALV 400 mg twice daily (BID) with PEG and RBV.

Reporting group title

Arm D DEB 400 BID

Reporting group description

DEB025 400 mg twice daily BID with PEG and RBV for up to 48 weeks

Reporting group title

Arm C- Placebo

Reporting group description

Placebo with PEG and RBV for up to 48 weeks; participants not achieving complete early virologic response (cEVR: HCV RNA <LOQ after 12 weeks of treatment) may switch to active ALV 600 mg QD with PEG and RBV. Note: For one patient in arm C the corresponding end-of treatment CRF page was by mistake not entered into the database before the database was locked (the patient completed the treatment phase on 31-Mar-2012). Therefore, this patient is not included in Table 10-1 or in other summaries dependent on end-of-treatment status.

Reporting group title

Arm C1-A

Reporting group description

Placebo to DEB 600 QD

Reporting group title

Arm C2-A

Reporting group description

Placebo to DEB 400 BID

Primary: Percentage of Participants With Complete Early Viral Response (cEVR)-LOQ

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End point title

Percentage of Participants With Complete Early Viral Response (cEVR)-LOQ ^[1]

End point description

cEVR-LOQ was defined as serum HCV RNA below the limit of quantification (< LOQ; i.e., 25 IU/mL) after 12 weeks of treatment. Post-switch groups were assessed 12 weeks after the switch.

End point type

Primary

End point timeframe

12 weeks

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C1-A	Arm C2-A	Arm C- Placebo
Number of subjects analysed	110 ^[2]	108 ^[3]	109 ^[4]	33 ^[5]	30 ^[6]	110 ^[7]
Units: percent
number (not applicable)	48.2	61.1	74.3	45.5	80	35.5

Notes
[2] - Full Analysis Set (FAS): all patients to whom study treatment had been assigned
[3] - FAS
[4] - FAS
[5] - FAS
[6] - FAS
[7] - FAS

Arm A: Comparison with Arm C (Placebo)

Comparison groups

Arm A: DEB025 600 mg QD v Arm C- Placebo

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0131

Method

Hochberg

Parameter type

Cochran-Mantel-Haenszel test

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

1.082

upper limit

1.951

Arm B: Comparison with Arm C (Placebo)

Comparison groups

Arm B: DEB 800 QD v Arm C- Placebo

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.0001

Method

Hochberg

Parameter type

Cochran-Mantel-Haenszel test

Point estimate

1.78

Confidence interval

level

95%

sides

2-sided

lower limit

1.358

upper limit

2.325

Arm D: Comparison with Arm C (Placebo)

Comparison groups

Arm C- Placebo v Arm D DEB 400 BID

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.0001

Method

Hochberg

Parameter type

Cochran-Mantel-Haenszel test

Point estimate

2.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.656

upper limit

2.889

Secondary: Percentage of participants who achieved sustained virologic response (SVR) 12 weeks post treatment

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End point title

Percentage of participants who achieved sustained virologic response (SVR) 12 weeks post treatment ^[8]

End point description

Data is based on patients randomized after the 2nd protocol amendment only.

End point type

Secondary

End point timeframe

12 weeks post treatment

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C1-A	Arm C2-A	Arm C- Placebo
Number of subjects analysed	110 ^[9]	108 ^[10]	109	33 ^[11]	30 ^[12]	110 ^[13]
Units: percent
number (not applicable)	42.7	51.9	65.1	18.2	53.3	14.5

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

Arm A: Comparison with Arm C (Placebo)

Comparison groups

Arm A: DEB025 600 mg QD v Arm C- Placebo

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.0001

Method

Hochberg

Parameter type

Cochran-Mantel-Haenszel test

Point estimate

3.12

Confidence interval

level

95%

sides

2-sided

lower limit

1.917

upper limit

5.063

Arm B: Comparison with Arm C (Placebo)

Comparison groups

Arm C- Placebo v Arm B: DEB 800 QD

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.0001

Method

Hochberg

Parameter type

Cochran-Mantel-Haenszel test

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

2.31

upper limit

5.963

Arm D: Comparison with Arm C (Placebo)

Comparison groups

Arm C- Placebo v Arm D DEB 400 BID

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.0001

Method

Hochberg

Parameter type

Cochran-Mantel-Haenszel test

Point estimate

4.55

Confidence interval

level

95%

sides

2-sided

lower limit

2.799

upper limit

7.41

Secondary: Percentage of participants who achieved virologic response by level of quantification (LOQ)

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End point title

Percentage of participants who achieved virologic response by level of quantification (LOQ) ^[14]

End point description

Data is based on patients randomized after the 2nd protocol amendment only.

End point type

Secondary

End point timeframe

12 weeks post treatment

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C- Placebo
Number of subjects analysed	110 ^[15]	108 ^[16]	109 ^[17]	110 ^[18]
Units: percent
number (not applicable)
RVR (rapid virologic response)	20.9	25	41.3	7.3
cEVR (complete early virologic response)	48.2	61.1	74.3	35.5
EDTR (end of DEB025-treatment virologic response)	72.7	77.8	87.2	33.6
ETR (end of treatment virologic response)	68.2	74.1	82.6	33.6
SVR4 (sustained virologic response 4 weeks)	50	57.4	69.7	21.8
SVR12 (sustained virologic response 12 weeks)	42.7	51.9	65.1	14.5
SVR24 (sustained virologic response 24 weeks)	41.8	51.9	65.1	14.5

Notes
[15] - FAS
[16] - FAS
[17] - FAS
[18] - FAS

No statistical analyses for this end point

Secondary: Percentage of participants who achieved virologic response by LOQ by response status to previous treatment

Top of page

End point title

Percentage of participants who achieved virologic response by LOQ by response status to previous treatment ^[19]

End point description

Data is based on patients randomized after the 2nd protocol amendment only.

End point type

Secondary

End point timeframe

12 weeks post treatment

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: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C- Placebo
Number of subjects analysed	110 ^[20]	108 ^[21]	109 ^[22]	110 ^[23]
Units: percent
number (not applicable)
Relapser - cEVR	64.6	77.6	77.1	57.4
Relapser - EDTR	85.4	83.7	85.4	59.3
Relapser - ETR	87.5	83.7	85.4	59.3
Relapser - SVR12	60.4	63.3	64.6	25.9
Relapser - SVR24	58.3	65.3	64.6	25.9
Non-responder - cEVR	35.5	47.35	72.1	14.3
Non-responder - EDTR	62.9	72.9	88.5	8.9
Non-responder - ETR	53.2	66.1	80.3	8.9
Non-responder - SVR12	29	42.4	65.6	3.6
Non-responder - SVR24	29	40.7	65.6	3.6
Null non-responder - cEVR	33.3	40.5	70.6	11.1
Null non-responder - EDTR	60.4	70.3	82.4	8.3
Null non-responder - ETR	50	64.9	73.5	8.3
Null non-responder - SVR12	22.9	40.5	67.6	2.8
Null non-responder - SVR24	22.9	37.8	67.6	2.8
Partial non-responder / unspecified – cEVR	42.9	59.1	74.1	20
Partial non-responder / unspecified – EDTR	71.4	77.3	96.3	10
Partial non-responder / unspecified – ETR	64.3	68.2	88.9	10
Partial non-responder / unspecified – SVR12	50	45.5	63	5
Partial non-responder / unspecified – SVR24	50	45.5	63	5

Notes
[20] - FAS: n= 48, 62, 48, 14
[21] - FAS: n = 49, 59, 37, 22
[22] - FAS: n = 48, 61, 34, 27
[23] - FAS: n = 54, 56, 36, 20

No statistical analyses for this end point

Secondary: Percentage of participants who achieved virologic response by LOQ by IL28B polymorphism

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End point title

Percentage of participants who achieved virologic response by LOQ by IL28B polymorphism ^[24]

End point description

Data is based on patients randomized after the 2nd protocol amendment only.

End point type

Secondary

End point timeframe

12 weeks post treatment

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C- Placebo
Number of subjects analysed	110 ^[25]	108 ^[26]	109 ^[27]	110 ^[28]
Units: percent
number (not applicable)
CC - cEVR	71.4	90.5	85	60.9
CC - EDTR	81	95.2	100	65.2
CC - ETR	81	95.2	100	65.2
CC - SVR12	66.7	85.7	65	26.1
CC - SVR24	66.7	81	65	26.1
CT/TT - cEVR	42.7	54	71.9	28.7
CT/TT - EDTR	70.8	73.6	84.3	25.3
CT/TT - ETR	65.2	69	78.7	25.3
CT/TT - SVR12	37.1	43.7	65.2	11.5
CT/TT - SVR24	36	44.8	65.2	11.5

Notes
[25] - FAS: n = 21, 89
[26] - FAS: n = 21, 87
[27] - FAS: n = 20, 89
[28] - FAS: n = 23, 87

No statistical analyses for this end point

Secondary: Percentage of participants who achieved virologic response by LOQ by cirrhosis or transition to cirrhosis

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End point title

Percentage of participants who achieved virologic response by LOQ by cirrhosis or transition to cirrhosis ^[29]

End point description

Data is based on patients randomized after the 2nd protocol amendment only.

End point type

Secondary

End point timeframe

12 weeks post treatment

Notes
[29] - 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: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C- Placebo
Number of subjects analysed	110 ^[30]	108 ^[31]	109 ^[32]	110 ^[33]
Units: percent
number (not applicable)
Cirrhosis or transition to cirrhosis - cEVR	40.7	57.1	60.9	20.7
Cirrhosis or transition to cirrhosis - EDTR	70.4	68.6	73.9	17.2
Cirrhosis or transition to cirrhosis - ETR	55.6	65.7	69.6	17.2
Cirrhosis or transition to cirrhosis - SVR12	33.3	40	52.2	0
Cirrhosis or transition to cirrhosis - SVR24	33.3	40	52.2	0
No cirrhosis or transition to cirrhosis - cEVR	51.2	64.3	78	39.2
No cirrhosis or transition to cirrhosis - EDTR	74.4	81.4	91.5	38
No cirrhosis or transition to cirrhosis - ETR	73.2	78.6	86.6	38
No cirrhosis or transition to cirrhosis - SVR12	46.3	58.6	68.3	20.3
No cirrhosis or transition to cirrhosis - SVR24	45.1	58.6	68.3	20.3

Notes
[30] - FAS: n= 27, 82
[31] - FAS: n= 35, 70
[32] - FAS: n= 23, 82
[33] - FAS: n= 29, 79

No statistical analyses for this end point

Secondary: Percentage of participants who achieved virologic response by LOQ by HCV genotype 1 subtype

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End point title

Percentage of participants who achieved virologic response by LOQ by HCV genotype 1 subtype ^[34]

End point description

Data is based on patients randomized after the 2nd protocol amendment only.

End point type

Secondary

End point timeframe

12 weeks post treatment

Notes
[34] - 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: Statistics are represented for all arms. The Placebo arm is represented one arm (total) and as the two arms as a result of the switch at week 16.

End point values	Arm A: DEB025 600 mg QD	Arm B: DEB 800 QD	Arm D DEB 400 BID	Arm C- Placebo
Number of subjects analysed	110 ^[35]	108 ^[36]	109 ^[37]	110 ^[38]
Units: percent
number (not applicable)
1a - cEVR	50	63	66.7	32.3
1a - EDTR	73.3	74.1	86.1	35.5
1a - ETR	73.3	66.7	77.8	35.5
1a - SVR12	46.7	59.3	55.6	12.9
1a - SVR24	46.7	59.3	55.6	12.9
1b - cEVR	47.5	60.5	78.1	36.7
1b - EDTR	72.5	79	87.7	32.9
1b - ETR	66.3	76.5	84.9	32.9
1b - SVR12	41.3	49.4	69.9	15.2
1b - SVR24	40	49.4	69.9	15.2

Notes
[35] - FAS: n= 30, 80
[36] - FAS: n= 27, 81
[37] - FAS: n= 36, 73
[38] - FAS: n= 31, 79

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Arm A DEB 600 QD

Reporting group description

Arm A DEB 600 QD

Reporting group title

Arm B DEB 800 QD

Reporting group description

Arm B DEB 800 QD

Reporting group title

Arm C1 Placebo QD

Reporting group description

Arm C1 Placebo QD

Reporting group title

Arm C2 Placebo BID

Reporting group description

Arm C2 Placebo BID

Reporting group title

Arm C Placebo

Reporting group description

Arm C Placebo

Reporting group title

Arm D DEB 400 BID

Reporting group description

Arm D DEB 400 BID

Reporting group title

Total

Reporting group description

Total

Serious adverse events	Arm A DEB 600 QD	Arm B DEB 800 QD	Arm C1 Placebo QD	Arm C2 Placebo BID	Arm C Placebo	Arm D DEB 400 BID	Total
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 120 (5.83%)	11 / 115 (9.57%)	5 / 59 (8.47%)	1 / 55 (1.82%)	6 / 114 (5.26%)	18 / 108 (16.67%)	42 / 457 (9.19%)
number of deaths (all causes)	0	0	0	0	0	1	1
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer stage I
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 120 (0.83%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	2 / 108 (1.85%)	4 / 457 (0.88%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	2 / 108 (1.85%)	4 / 457 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	1 / 1	1 / 2	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug interaction
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	2 / 457 (0.44%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometriosis
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	2 / 457 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Disorientation
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Vascular pseudoaneurysm
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Supraventricular tachycardia
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	2 / 457 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	2 / 108 (1.85%)	2 / 457 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebrobasilar insufficiency
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	1 / 55 (1.82%)	1 / 114 (0.88%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 120 (0.00%)	2 / 115 (1.74%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	3 / 457 (0.66%)
occurrences causally related to treatment / all	0 / 0	5 / 5	0 / 0	0 / 0	0 / 0	1 / 1	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	1 / 108 (0.93%)	3 / 457 (0.66%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash erythematous
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypopituitarism
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 120 (0.00%)	2 / 115 (1.74%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	2 / 457 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis viral
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear infection
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis C
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 120 (0.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	3 / 108 (2.78%)	4 / 457 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	2 / 3	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Urinary tract infection
subjects affected / exposed	1 / 120 (0.83%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	0 / 108 (0.00%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperamylasaemia
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperlipasaemia
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 120 (0.00%)	0 / 115 (0.00%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	1 / 108 (0.93%)	1 / 457 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arm A DEB 600 QD	Arm B DEB 800 QD	Arm C1 Placebo QD	Arm C2 Placebo BID	Arm C Placebo	Arm D DEB 400 BID	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	116 / 120 (96.67%)	108 / 115 (93.91%)	54 / 59 (91.53%)	50 / 55 (90.91%)	104 / 114 (91.23%)	106 / 108 (98.15%)	434 / 457 (94.97%)
Vascular disorders
Hypertension
subjects affected / exposed	21 / 120 (17.50%)	22 / 115 (19.13%)	0 / 59 (0.00%)	2 / 55 (3.64%)	2 / 114 (1.75%)	28 / 108 (25.93%)	73 / 457 (15.97%)
occurrences all number	21	24	0	2	2	31	78
General disorders and administration site conditions
Asthenia
subjects affected / exposed	19 / 120 (15.83%)	30 / 115 (26.09%)	9 / 59 (15.25%)	12 / 55 (21.82%)	21 / 114 (18.42%)	17 / 108 (15.74%)	87 / 457 (19.04%)
occurrences all number	19	31	11	13	24	18	92
Chest pain
subjects affected / exposed	3 / 120 (2.50%)	4 / 115 (3.48%)	1 / 59 (1.69%)	4 / 55 (7.27%)	5 / 114 (4.39%)	4 / 108 (3.70%)	16 / 457 (3.50%)
occurrences all number	3	4	1	4	5	4	16
Chills
subjects affected / exposed	14 / 120 (11.67%)	13 / 115 (11.30%)	6 / 59 (10.17%)	3 / 55 (5.45%)	9 / 114 (7.89%)	14 / 108 (12.96%)	50 / 457 (10.94%)
occurrences all number	19	15	7	4	11	18	63
Fatigue
subjects affected / exposed	47 / 120 (39.17%)	45 / 115 (39.13%)	21 / 59 (35.59%)	20 / 55 (36.36%)	41 / 114 (35.96%)	45 / 108 (41.67%)	178 / 457 (38.95%)
occurrences all number	53	48	23	24	47	50	198
Influenza like illness
subjects affected / exposed	13 / 120 (10.83%)	10 / 115 (8.70%)	15 / 59 (25.42%)	6 / 55 (10.91%)	21 / 114 (18.42%)	11 / 108 (10.19%)	55 / 457 (12.04%)
occurrences all number	18	11	18	6	24	14	67
Injection site erythema
subjects affected / exposed	8 / 120 (6.67%)	11 / 115 (9.57%)	5 / 59 (8.47%)	3 / 55 (5.45%)	8 / 114 (7.02%)	3 / 108 (2.78%)	30 / 457 (6.56%)
occurrences all number	8	13	5	3	8	4	33
Injection site rash
subjects affected / exposed	1 / 120 (0.83%)	1 / 115 (0.87%)	4 / 59 (6.78%)	1 / 55 (1.82%)	5 / 114 (4.39%)	0 / 108 (0.00%)	7 / 457 (1.53%)
occurrences all number	1	1	4	1	5	0	7
Irritability
subjects affected / exposed	8 / 120 (6.67%)	7 / 115 (6.09%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	6 / 108 (5.56%)	26 / 457 (5.69%)
occurrences all number	8	7	3	2	5	6	26
Malaise
subjects affected / exposed	9 / 120 (7.50%)	8 / 115 (6.96%)	1 / 59 (1.69%)	2 / 55 (3.64%)	3 / 114 (2.63%)	9 / 108 (8.33%)	29 / 457 (6.35%)
occurrences all number	14	8	2	4	6	12	40
Pyrexia
subjects affected / exposed	32 / 120 (26.67%)	34 / 115 (29.57%)	16 / 59 (27.12%)	16 / 55 (29.09%)	32 / 114 (28.07%)	28 / 108 (25.93%)	126 / 457 (27.57%)
occurrences all number	48	48	20	49	69	48	213
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	38 / 120 (31.67%)	29 / 115 (25.22%)	17 / 59 (28.81%)	12 / 55 (21.82%)	29 / 114 (25.44%)	16 / 108 (14.81%)	112 / 457 (24.51%)
occurrences all number	43	33	19	13	32	18	126
Dyspnoea
subjects affected / exposed	21 / 120 (17.50%)	8 / 115 (6.96%)	6 / 59 (10.17%)	4 / 55 (7.27%)	10 / 114 (8.77%)	16 / 108 (14.81%)	55 / 457 (12.04%)
occurrences all number	21	8	6	4	10	17	56
Dyspnoea exertional
subjects affected / exposed	6 / 120 (5.00%)	9 / 115 (7.83%)	3 / 59 (5.08%)	4 / 55 (7.27%)	7 / 114 (6.14%)	8 / 108 (7.41%)	30 / 457 (6.56%)
occurrences all number	9	11	3	5	8	8	36
Epistaxis
subjects affected / exposed	5 / 120 (4.17%)	3 / 115 (2.61%)	3 / 59 (5.08%)	0 / 55 (0.00%)	3 / 114 (2.63%)	10 / 108 (9.26%)	21 / 457 (4.60%)
occurrences all number	6	4	3	0	3	13	26
Oropharyngeal pain
subjects affected / exposed	9 / 120 (7.50%)	8 / 115 (6.96%)	5 / 59 (8.47%)	3 / 55 (5.45%)	8 / 114 (7.02%)	8 / 108 (7.41%)	33 / 457 (7.22%)
occurrences all number	11	9	6	3	9	8	37
Psychiatric disorders
Anxiety
subjects affected / exposed	19 / 120 (15.83%)	8 / 115 (6.96%)	3 / 59 (5.08%)	3 / 55 (5.45%)	6 / 114 (5.26%)	11 / 108 (10.19%)	44 / 457 (9.63%)
occurrences all number	19	8	3	3	6	12	45
Depression
subjects affected / exposed	22 / 120 (18.33%)	14 / 115 (12.17%)	8 / 59 (13.56%)	4 / 55 (7.27%)	12 / 114 (10.53%)	13 / 108 (12.04%)	61 / 457 (13.35%)
occurrences all number	24	14	10	4	14	14	66
Insomnia
subjects affected / exposed	35 / 120 (29.17%)	24 / 115 (20.87%)	10 / 59 (16.95%)	15 / 55 (27.27%)	25 / 114 (21.93%)	17 / 108 (15.74%)	101 / 457 (22.10%)
occurrences all number	45	25	10	19	29	22	121
Nervousness
subjects affected / exposed	1 / 120 (0.83%)	1 / 115 (0.87%)	2 / 59 (3.39%)	4 / 55 (7.27%)	6 / 114 (5.26%)	2 / 108 (1.85%)	10 / 457 (2.19%)
occurrences all number	1	1	2	4	6	2	10
Restlessness
subjects affected / exposed	7 / 120 (5.83%)	4 / 115 (3.48%)	1 / 59 (1.69%)	2 / 55 (3.64%)	3 / 114 (2.63%)	1 / 108 (0.93%)	15 / 457 (3.28%)
occurrences all number	10	5	1	2	3	1	19
Sleep disorder
subjects affected / exposed	2 / 120 (1.67%)	4 / 115 (3.48%)	3 / 59 (5.08%)	0 / 55 (0.00%)	3 / 114 (2.63%)	2 / 108 (1.85%)	11 / 457 (2.41%)
occurrences all number	2	4	3	0	3	2	11
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	6 / 120 (5.00%)	1 / 115 (0.87%)	0 / 59 (0.00%)	1 / 55 (1.82%)	1 / 114 (0.88%)	3 / 108 (2.78%)	11 / 457 (2.41%)
occurrences all number	9	1	0	1	1	3	14
Lipase increased
subjects affected / exposed	2 / 120 (1.67%)	1 / 115 (0.87%)	4 / 59 (6.78%)	1 / 55 (1.82%)	5 / 114 (4.39%)	5 / 108 (4.63%)	13 / 457 (2.84%)
occurrences all number	3	1	4	2	6	6	16
Total bile acids increased
subjects affected / exposed	5 / 120 (4.17%)	3 / 115 (2.61%)	1 / 59 (1.69%)	1 / 55 (1.82%)	2 / 114 (1.75%)	8 / 108 (7.41%)	18 / 457 (3.94%)
occurrences all number	7	4	1	2	3	17	31
Weight decreased
subjects affected / exposed	9 / 120 (7.50%)	9 / 115 (7.83%)	2 / 59 (3.39%)	2 / 55 (3.64%)	4 / 114 (3.51%)	9 / 108 (8.33%)	31 / 457 (6.78%)
occurrences all number	10	9	2	2	4	10	33
Cardiac disorders
Palpitations
subjects affected / exposed	11 / 120 (9.17%)	7 / 115 (6.09%)	3 / 59 (5.08%)	1 / 55 (1.82%)	4 / 114 (3.51%)	2 / 108 (1.85%)	24 / 457 (5.25%)
occurrences all number	12	7	3	1	4	2	25
Nervous system disorders
Disturbance in attention
subjects affected / exposed	9 / 120 (7.50%)	10 / 115 (8.70%)	3 / 59 (5.08%)	3 / 55 (5.45%)	6 / 114 (5.26%)	4 / 108 (3.70%)	29 / 457 (6.35%)
occurrences all number	10	10	3	3	6	5	31
Dizziness
subjects affected / exposed	20 / 120 (16.67%)	22 / 115 (19.13%)	10 / 59 (16.95%)	4 / 55 (7.27%)	14 / 114 (12.28%)	15 / 108 (13.89%)	71 / 457 (15.54%)
occurrences all number	27	30	12	5	17	18	92
Dysgeusia
subjects affected / exposed	5 / 120 (4.17%)	7 / 115 (6.09%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	9 / 108 (8.33%)	26 / 457 (5.69%)
occurrences all number	5	7	3	2	5	10	27
Headache
subjects affected / exposed	59 / 120 (49.17%)	47 / 115 (40.87%)	23 / 59 (38.98%)	18 / 55 (32.73%)	41 / 114 (35.96%)	38 / 108 (35.19%)	185 / 457 (40.48%)
occurrences all number	92	69	30	23	53	53	267
Hypoaesthesia
subjects affected / exposed	6 / 120 (5.00%)	2 / 115 (1.74%)	1 / 59 (1.69%)	1 / 55 (1.82%)	2 / 114 (1.75%)	2 / 108 (1.85%)	12 / 457 (2.63%)
occurrences all number	7	2	1	1	2	2	13
Memory impairment
subjects affected / exposed	5 / 120 (4.17%)	4 / 115 (3.48%)	2 / 59 (3.39%)	3 / 55 (5.45%)	5 / 114 (4.39%)	3 / 108 (2.78%)	17 / 457 (3.72%)
occurrences all number	5	4	2	3	5	4	18
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	49 / 120 (40.83%)	41 / 115 (35.65%)	17 / 59 (28.81%)	10 / 55 (18.18%)	27 / 114 (23.68%)	51 / 108 (47.22%)	168 / 457 (36.76%)
occurrences all number	79	63	24	17	41	87	270
Leukopenia
subjects affected / exposed	17 / 120 (14.17%)	13 / 115 (11.30%)	7 / 59 (11.86%)	5 / 55 (9.09%)	12 / 114 (10.53%)	20 / 108 (18.52%)	62 / 457 (13.57%)
occurrences all number	33	27	14	5	19	50	129
Lymphopenia
subjects affected / exposed	5 / 120 (4.17%)	2 / 115 (1.74%)	3 / 59 (5.08%)	0 / 55 (0.00%)	3 / 114 (2.63%)	8 / 108 (7.41%)	18 / 457 (3.94%)
occurrences all number	5	4	5	0	5	21	35
Neutropenia
subjects affected / exposed	49 / 120 (40.83%)	40 / 115 (34.78%)	15 / 59 (25.42%)	12 / 55 (21.82%)	27 / 114 (23.68%)	46 / 108 (42.59%)	162 / 457 (35.45%)
occurrences all number	88	72	25	19	44	97	301
Thrombocytopenia
subjects affected / exposed	24 / 120 (20.00%)	19 / 115 (16.52%)	3 / 59 (5.08%)	1 / 55 (1.82%)	4 / 114 (3.51%)	28 / 108 (25.93%)	75 / 457 (16.41%)
occurrences all number	39	28	4	3	7	45	119
Eye disorders
Dry eye
subjects affected / exposed	7 / 120 (5.83%)	7 / 115 (6.09%)	2 / 59 (3.39%)	0 / 55 (0.00%)	2 / 114 (1.75%)	3 / 108 (2.78%)	19 / 457 (4.16%)
occurrences all number	7	7	2	0	2	3	19
Ocular icterus
subjects affected / exposed	5 / 120 (4.17%)	8 / 115 (6.96%)	1 / 59 (1.69%)	2 / 55 (3.64%)	3 / 114 (2.63%)	14 / 108 (12.96%)	30 / 457 (6.56%)
occurrences all number	8	13	1	4	5	18	44
Vision blurred
subjects affected / exposed	4 / 120 (3.33%)	8 / 115 (6.96%)	1 / 59 (1.69%)	0 / 55 (0.00%)	1 / 114 (0.88%)	3 / 108 (2.78%)	16 / 457 (3.50%)
occurrences all number	4	10	1	0	1	6	21
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 120 (1.67%)	5 / 115 (4.35%)	0 / 59 (0.00%)	1 / 55 (1.82%)	1 / 114 (0.88%)	7 / 108 (6.48%)	15 / 457 (3.28%)
occurrences all number	3	6	0	1	1	8	18
Abdominal pain
subjects affected / exposed	9 / 120 (7.50%)	7 / 115 (6.09%)	6 / 59 (10.17%)	3 / 55 (5.45%)	9 / 114 (7.89%)	6 / 108 (5.56%)	31 / 457 (6.78%)
occurrences all number	9	9	6	3	9	6	33
Abdominal pain upper
subjects affected / exposed	15 / 120 (12.50%)	8 / 115 (6.96%)	5 / 59 (8.47%)	4 / 55 (7.27%)	9 / 114 (7.89%)	13 / 108 (12.04%)	45 / 457 (9.85%)
occurrences all number	15	9	5	5	10	15	49
Aphthous stomatitis
subjects affected / exposed	6 / 120 (5.00%)	3 / 115 (2.61%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	6 / 108 (5.56%)	20 / 457 (4.38%)
occurrences all number	6	5	4	2	6	9	26
Cheilitis
subjects affected / exposed	1 / 120 (0.83%)	6 / 115 (5.22%)	1 / 59 (1.69%)	1 / 55 (1.82%)	2 / 114 (1.75%)	3 / 108 (2.78%)	12 / 457 (2.63%)
occurrences all number	1	7	1	1	2	3	13
Constipation
subjects affected / exposed	10 / 120 (8.33%)	7 / 115 (6.09%)	1 / 59 (1.69%)	3 / 55 (5.45%)	4 / 114 (3.51%)	15 / 108 (13.89%)	36 / 457 (7.88%)
occurrences all number	11	7	1	3	4	16	38
Diarrhoea
subjects affected / exposed	19 / 120 (15.83%)	18 / 115 (15.65%)	8 / 59 (13.56%)	6 / 55 (10.91%)	14 / 114 (12.28%)	10 / 108 (9.26%)	61 / 457 (13.35%)
occurrences all number	27	18	8	7	15	13	73
Dry mouth
subjects affected / exposed	15 / 120 (12.50%)	10 / 115 (8.70%)	5 / 59 (8.47%)	6 / 55 (10.91%)	11 / 114 (9.65%)	10 / 108 (9.26%)	46 / 457 (10.07%)
occurrences all number	17	11	5	9	14	10	52
Dyspepsia
subjects affected / exposed	15 / 120 (12.50%)	4 / 115 (3.48%)	5 / 59 (8.47%)	2 / 55 (3.64%)	7 / 114 (6.14%)	15 / 108 (13.89%)	41 / 457 (8.97%)
occurrences all number	18	4	6	2	8	17	47
Mouth ulceration
subjects affected / exposed	7 / 120 (5.83%)	10 / 115 (8.70%)	2 / 59 (3.39%)	5 / 55 (9.09%)	7 / 114 (6.14%)	3 / 108 (2.78%)	27 / 457 (5.91%)
occurrences all number	16	11	2	5	7	3	37
Nausea
subjects affected / exposed	46 / 120 (38.33%)	35 / 115 (30.43%)	17 / 59 (28.81%)	12 / 55 (21.82%)	29 / 114 (25.44%)	51 / 108 (47.22%)	161 / 457 (35.23%)
occurrences all number	57	55	22	12	34	59	205
Toothache
subjects affected / exposed	3 / 120 (2.50%)	3 / 115 (2.61%)	3 / 59 (5.08%)	1 / 55 (1.82%)	4 / 114 (3.51%)	2 / 108 (1.85%)	12 / 457 (2.63%)
occurrences all number	3	4	3	2	5	2	14
Vomiting
subjects affected / exposed	19 / 120 (15.83%)	18 / 115 (15.65%)	4 / 59 (6.78%)	5 / 55 (9.09%)	9 / 114 (7.89%)	19 / 108 (17.59%)	65 / 457 (14.22%)
occurrences all number	39	27	5	7	12	32	110
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	19 / 120 (15.83%)	14 / 115 (12.17%)	2 / 59 (3.39%)	0 / 55 (0.00%)	2 / 114 (1.75%)	36 / 108 (33.33%)	71 / 457 (15.54%)
occurrences all number	25	16	2	0	2	56	99
Jaundice
subjects affected / exposed	14 / 120 (11.67%)	11 / 115 (9.57%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	18 / 108 (16.67%)	48 / 457 (10.50%)
occurrences all number	17	12	4	2	6	19	54
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	22 / 120 (18.33%)	23 / 115 (20.00%)	6 / 59 (10.17%)	5 / 55 (9.09%)	11 / 114 (9.65%)	19 / 108 (17.59%)	75 / 457 (16.41%)
occurrences all number	22	23	6	5	11	19	75
Dermatitis
subjects affected / exposed	3 / 120 (2.50%)	2 / 115 (1.74%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	0 / 108 (0.00%)	10 / 457 (2.19%)
occurrences all number	4	2	3	4	7	0	13
Dry skin
subjects affected / exposed	15 / 120 (12.50%)	16 / 115 (13.91%)	8 / 59 (13.56%)	9 / 55 (16.36%)	17 / 114 (14.91%)	16 / 108 (14.81%)	64 / 457 (14.00%)
occurrences all number	20	17	8	9	17	16	70
Erythema
subjects affected / exposed	6 / 120 (5.00%)	7 / 115 (6.09%)	0 / 59 (0.00%)	0 / 55 (0.00%)	0 / 114 (0.00%)	5 / 108 (4.63%)	18 / 457 (3.94%)
occurrences all number	6	7	0	0	0	5	18
Hyperhidrosis
subjects affected / exposed	2 / 120 (1.67%)	1 / 115 (0.87%)	4 / 59 (6.78%)	2 / 55 (3.64%)	6 / 114 (5.26%)	3 / 108 (2.78%)	12 / 457 (2.63%)
occurrences all number	3	1	4	3	7	3	14
Pruritus
subjects affected / exposed	36 / 120 (30.00%)	30 / 115 (26.09%)	20 / 59 (33.90%)	12 / 55 (21.82%)	32 / 114 (28.07%)	32 / 108 (29.63%)	130 / 457 (28.45%)
occurrences all number	52	42	24	14	38	39	171
Rash
subjects affected / exposed	23 / 120 (19.17%)	22 / 115 (19.13%)	14 / 59 (23.73%)	6 / 55 (10.91%)	20 / 114 (17.54%)	17 / 108 (15.74%)	82 / 457 (17.94%)
occurrences all number	29	29	16	6	22	20	100
Endocrine disorders
Hypothyroidism
subjects affected / exposed	7 / 120 (5.83%)	6 / 115 (5.22%)	0 / 59 (0.00%)	3 / 55 (5.45%)	3 / 114 (2.63%)	14 / 108 (12.96%)	30 / 457 (6.56%)
occurrences all number	7	7	0	3	3	15	32
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	19 / 120 (15.83%)	19 / 115 (16.52%)	7 / 59 (11.86%)	6 / 55 (10.91%)	13 / 114 (11.40%)	9 / 108 (8.33%)	60 / 457 (13.13%)
occurrences all number	21	21	7	9	16	9	67
Back pain
subjects affected / exposed	20 / 120 (16.67%)	5 / 115 (4.35%)	4 / 59 (6.78%)	5 / 55 (9.09%)	9 / 114 (7.89%)	10 / 108 (9.26%)	44 / 457 (9.63%)
occurrences all number	24	5	4	5	9	15	53
Muscle spasms
subjects affected / exposed	14 / 120 (11.67%)	12 / 115 (10.43%)	3 / 59 (5.08%)	3 / 55 (5.45%)	6 / 114 (5.26%)	17 / 108 (15.74%)	49 / 457 (10.72%)
occurrences all number	15	14	4	4	8	24	61
Myalgia
subjects affected / exposed	23 / 120 (19.17%)	21 / 115 (18.26%)	15 / 59 (25.42%)	11 / 55 (20.00%)	26 / 114 (22.81%)	18 / 108 (16.67%)	88 / 457 (19.26%)
occurrences all number	29	28	16	16	32	20	109
Neck pain
subjects affected / exposed	4 / 120 (3.33%)	1 / 115 (0.87%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	3 / 108 (2.78%)	13 / 457 (2.84%)
occurrences all number	4	1	3	3	6	3	14
Osteopenia
subjects affected / exposed	5 / 120 (4.17%)	6 / 115 (5.22%)	0 / 59 (0.00%)	2 / 55 (3.64%)	2 / 114 (1.75%)	6 / 108 (5.56%)	19 / 457 (4.16%)
occurrences all number	5	6	0	2	2	6	19
Pain in extremity
subjects affected / exposed	7 / 120 (5.83%)	5 / 115 (4.35%)	2 / 59 (3.39%)	1 / 55 (1.82%)	3 / 114 (2.63%)	5 / 108 (4.63%)	20 / 457 (4.38%)
occurrences all number	8	5	2	2	4	5	22
Infections and infestations
Nasopharyngitis
subjects affected / exposed	6 / 120 (5.00%)	5 / 115 (4.35%)	1 / 59 (1.69%)	3 / 55 (5.45%)	4 / 114 (3.51%)	4 / 108 (3.70%)	19 / 457 (4.16%)
occurrences all number	7	5	1	3	4	7	23
Oral herpes
subjects affected / exposed	4 / 120 (3.33%)	7 / 115 (6.09%)	2 / 59 (3.39%)	0 / 55 (0.00%)	2 / 114 (1.75%)	3 / 108 (2.78%)	16 / 457 (3.50%)
occurrences all number	4	7	2	0	2	3	16
Pharyngitis
subjects affected / exposed	4 / 120 (3.33%)	3 / 115 (2.61%)	2 / 59 (3.39%)	1 / 55 (1.82%)	3 / 114 (2.63%)	6 / 108 (5.56%)	16 / 457 (3.50%)
occurrences all number	4	6	2	1	3	6	19
Upper respiratory tract infection
subjects affected / exposed	12 / 120 (10.00%)	5 / 115 (4.35%)	2 / 59 (3.39%)	4 / 55 (7.27%)	6 / 114 (5.26%)	6 / 108 (5.56%)	29 / 457 (6.35%)
occurrences all number	17	5	3	4	7	6	35
Urinary tract infection
subjects affected / exposed	7 / 120 (5.83%)	2 / 115 (1.74%)	3 / 59 (5.08%)	2 / 55 (3.64%)	5 / 114 (4.39%)	9 / 108 (8.33%)	23 / 457 (5.03%)
occurrences all number	9	2	3	2	5	10	26
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	31 / 120 (25.83%)	23 / 115 (20.00%)	8 / 59 (13.56%)	8 / 55 (14.55%)	16 / 114 (14.04%)	26 / 108 (24.07%)	96 / 457 (21.01%)
occurrences all number	35	26	9	8	17	26	104
Hypertriglyceridaemia
subjects affected / exposed	16 / 120 (13.33%)	21 / 115 (18.26%)	2 / 59 (3.39%)	2 / 55 (3.64%)	4 / 114 (3.51%)	18 / 108 (16.67%)	59 / 457 (12.91%)
occurrences all number	19	22	2	2	4	23	68

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Were there any global substantial amendments to the protocol? Yes

30 Nov 2010

The amendment introduced the following change(s): • Exclusion criteria were changed to make sure women of child-bearing potential used highly effective contraception i.e. total abstinence, sterilization, male partner sterilization, or a combination of two specified methods. • A rationale for birth control to be used in this study was added • Substrates of cytochrome P450 3A for which a clinically important drug-drug interactions with DEB025 could not be excluded because it was not yet investigated (e.g., hormonal contraceptives, etc.) had been added to the list of prohibited treatment

14 Dec 2010

The amendment introduced the following change(s): • Changes were made to the protocol in the inclusion of HCV genotype 1 patients that have relapsed after pegIFNα2a/RBV treatment, as well as the addition of a further treatment arm to allow 400mg BID treatment with the study medication. • inconsistencies and typos in the original protocol were corrected.

26 Apr 2012

The amendment introduced the following change(s): • Patients on treatment with DEB025/placebo in combination with pegIFNα2a /RBV had already been requested to immediately discontinue DEB025/placebo treatment. These patients were asked to continue their treatment with the combination of pegIFNα2a and RBV and to continue in the study as scheduled in the protocol in order to achieve SVR. • All patients were to receive an addendum to the Informed Consent Form they have already signed. The addendum provided the most recent safety information and all patients were expected to sign that they have received and understood the addendum. Investigators were previously sent a safety alert to discontinue patients from DEB025/placebo with triglyceride levels above 350 mg/dL. This alert meanwhile became redundant due to the discontinuation of DEB025/placebo in all patients. However, since patients were still treated with pegIFNα2a, it was recommended that the management of triglyceride levels should follow the ATPIII guideline (NIH 2001). • According to the requirements of the study protocol, all patients who were still on study treatment by 18-Apr-2012, had responded to treatment and had reached a viral load for HCV RNA < 25 IU/mL. • To better understand the benefit-risk profile for the patients, a second Interim Analysis was to be performed on Week 24 data. • Furthermore, investigators were to be unblinded to the HCV RNA data i.e. they would have access to all HCV RNA data from their patients. • End-of-treatment assessments were to be performed at the next visit after DEB025/placebo discontinuation, including bone density X-ray assessments.

14 Aug 2012

This amendment was a follow-up to the urgent safety Amendment 3, i.e. the termination of the DEB025/placebo treatment in all patients as a result of the partial clinical hold. As planned at the time protocol Amendment 3 was issued, the protocol sections which were affected were fully updated after the impact of these safety measures had been assessed in detail.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
18 Apr 2012	Upon request from the US FDA, the study design was modified to immediately discontinue DEB025/placebo treatment in all patients (urgent safety measure). Patients remained on pegIFNα2a/RBV treatment.	-

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

None reported

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Clinical trials

Clinical Trial Results:
A multicenter, randomized, double-blind, placebocontrolled, parallel-group phase II study on efficacy and safety of DEB025 combined with pegIFNalpha2a and ribavirin in chronic hepatitis C genotype 1 relapsers and non-responders to previous pegIFN plus ribavirin treatment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Complete Early Viral Response (cEVR)-LOQ

Primary: Percentage of Participants With Complete Early Viral Response (cEVR)-LOQ

Secondary: Percentage of participants who achieved sustained virologic response (SVR) 12 weeks post treatment

Secondary: Percentage of participants who achieved sustained virologic response (SVR) 12 weeks post treatment

Secondary: Percentage of participants who achieved virologic response by level of quantification (LOQ)

Secondary: Percentage of participants who achieved virologic response by level of quantification (LOQ)

Secondary: Percentage of participants who achieved virologic response by LOQ by response status to previous treatment

Secondary: Percentage of participants who achieved virologic response by LOQ by response status to previous treatment

Secondary: Percentage of participants who achieved virologic response by LOQ by IL28B polymorphism

Secondary: Percentage of participants who achieved virologic response by LOQ by IL28B polymorphism

Secondary: Percentage of participants who achieved virologic response by LOQ by cirrhosis or transition to cirrhosis

Secondary: Percentage of participants who achieved virologic response by LOQ by cirrhosis or transition to cirrhosis

Secondary: Percentage of participants who achieved virologic response by LOQ by HCV genotype 1 subtype

Secondary: Percentage of participants who achieved virologic response by LOQ by HCV genotype 1 subtype

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A multicenter, randomized, double-blind, placebocontrolled, parallel-group phase II study on efficacy and safety of DEB025 combined with pegIFNalpha2a and ribavirin in chronic hepatitis C genotype 1 relapsers and non-responders to previous pegIFN plus ribavirin treatment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Complete Early Viral Response (cEVR)-LOQ

Primary: Percentage of Participants With Complete Early Viral Response (cEVR)-LOQ

Secondary: Percentage of participants who achieved sustained virologic response (SVR) 12 weeks post treatment

Secondary: Percentage of participants who achieved sustained virologic response (SVR) 12 weeks post treatment

Secondary: Percentage of participants who achieved virologic response by level of quantification (LOQ)

Secondary: Percentage of participants who achieved virologic response by level of quantification (LOQ)

Secondary: Percentage of participants who achieved virologic response by LOQ by response status to previous treatment

Secondary: Percentage of participants who achieved virologic response by LOQ by response status to previous treatment

Secondary: Percentage of participants who achieved virologic response by LOQ by IL28B polymorphism

Secondary: Percentage of participants who achieved virologic response by LOQ by IL28B polymorphism

Secondary: Percentage of participants who achieved virologic response by LOQ by cirrhosis or transition to cirrhosis

Secondary: Percentage of participants who achieved virologic response by LOQ by cirrhosis or transition to cirrhosis

Secondary: Percentage of participants who achieved virologic response by LOQ by HCV genotype 1 subtype

Secondary: Percentage of participants who achieved virologic response by LOQ by HCV genotype 1 subtype

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multicenter, randomized, double-blind, placebocontrolled, parallel-group phase II study on efficacy and safety of DEB025 combined with pegIFNalpha2a and ribavirin in chronic hepatitis C genotype 1 relapsers and non-responders to previous pegIFN plus ribavirin treatment