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Clinical Trial Results:
A Multicenter, Randomized, Placebo-controlled, Parallel Group, Double Blind, Dose-finding Phase II Trial to Study the Efficacy, Safety, Pharmacokinetic and Pharmacodynamic Effects of the Oral Partial Adenosine A1 Receptor Agonist Neladenoson Bialanate Over 20 Weeks in Patients With Chronic Heart Failure With Reduced Ejection Fraction

Summary
EudraCT number	2016-003839-38
Trial protocol	DE NL ES BE GR BG IT
Global end of trial date	16 May 2018

Results information
Results version number	v1(current)
This version publication date	28 Mar 2019
First version publication date	28 Mar 2019
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

15128

ISRCTN number

US NCT number

NCT02992288

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

16 May 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 May 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this trial was to find the optimal dose of neladenoson bialanate for the Phase III trial by detecting and characterizing a significant dose-response relationship in the two primary efficacy endpoints, absolute change from baseline in left ventricular ejection fraction (LVEF) and log-transformed N-terminal prohormone b-type natriuretic peptide (NTproBNP) at 20 weeks, in subjects with chronic heart failure with reduced ejection fraction (HFrEF), and by characterizing the safety, tolerability and pharmacodynamic effects of the compound when given in addition to standard therapy for HFrEF.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP).

Background therapy

Standard of care Heart Failure therapy as per local guidelines.

Evidence for comparator

Actual start date of recruitment

22 Feb 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 24

Country: Number of subjects enrolled

Bulgaria: 53

Country: Number of subjects enrolled

Poland: 106

Country: Number of subjects enrolled

United States: 22

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

Germany: 38

Country: Number of subjects enrolled

Spain: 34

Country: Number of subjects enrolled

Greece: 60

Country: Number of subjects enrolled

Israel: 24

Country: Number of subjects enrolled

Italy: 44

Country: Number of subjects enrolled

Netherlands: 11

Worldwide total number of subjects

427

EEA total number of subjects

357

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)

159

From 65 to 84 years

255

85 years and over

Subject disposition

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Recruitment details

Study was conducted at multiple centers in 11 countries between 22 February 2017 (first subject first visit) and 16 May 2018 (last subject last visit).

Screening details

Overall, 462 subjects were enrolled of them, 35 subjects did not complete screening due to unmet eligibility criteria, consent withdrawal, adverse events and other unspecified reasons. In total, 427 subjects were randomized and 426 subjects received study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received placebo matched to neladenoson bialanate tablets orally once daily for 20 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matched to neladenoson bialanate tablets.

Neladenoson Bialanate 5 mg

Arm description

Subjects received 5 milligrams (mg) of neladenoson bialanate tablets orally once daily for 20 weeks.

Arm type

Experimental

Investigational medicinal product name

Neladenoson Bialanate

Investigational medicinal product code

BAY1067197

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received neladenoson bialanate tablets orally.

Neladenoson Bialanate 10 mg

Arm description

Subjects received 10 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Arm type

Experimental

Investigational medicinal product name

Neladenoson Bialanate

Investigational medicinal product code

BAY1067197

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received neladenoson bialanate tablets orally.

Neladenoson Bialanate 20 mg

Arm description

Subjects received 20 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Arm type

Experimental

Investigational medicinal product name

Neladenoson Bialanate

Investigational medicinal product code

BAY1067197

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received neladenoson bialanate tablets orally.

Neladenoson Bialanate 30 mg

Arm description

Subjects received 30 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Arm type

Experimental

Investigational medicinal product name

Neladenoson Bialanate

Investigational medicinal product code

BAY1067197

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received neladenoson bialanate tablets orally.

Neladenoson Bialanate 40 mg

Arm description

Subjects received 40 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Arm type

Experimental

Investigational medicinal product name

Neladenoson Bialanate

Investigational medicinal product code

BAY1067197

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received neladenoson bialanate tablets orally.

Number of subjects in period 1	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Started	106	37	70	73	69	72
Treated	106	37	70	72	69	72
Completed	89	32	63	64	61	59
Not completed	17	5	7	9	8	13
Adverse event, serious fatal	2	-	2	1	2	-
Physician decision	3	-	1	-	-	1
Consent withdrawn by subject	4	2	1	5	3	4
Adverse event, non-fatal	8	2	2	2	2	7
Non-compliance with study drug	-	1	1	-	1	-
Lost to follow-up	-	-	-	1	-	-
Protocol deviation	-	-	-	-	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 5 mg

Reporting group description

Subjects received 5 milligrams (mg) of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 10 mg

Reporting group description

Subjects received 10 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 20 mg

Reporting group description

Subjects received 20 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 30 mg

Reporting group description

Subjects received 30 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 40 mg

Reporting group description

Subjects received 40 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg	Total
Number of subjects	106	37	70	73	69	72	427
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66.9 ( 9.4 )	66.6 ( 10.5 )	66.4 ( 11.2 )	68.1 ( 10.0 )	67.6 ( 9.8 )	67.5 ( 10.0 )	-
Sex: Female, Male
Units: Subjects
Female	18	9	11	14	12	7	71
Male	88	28	59	59	57	65	356
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	6	3	3	5	3	5	25
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	2	2	2	2	2	2	12
White	98	32	65	66	64	65	390
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	1	1	2	0	5
Not Hispanic or Latino	105	37	69	72	66	72	421
Unknown or Not Reported	0	0	0	0	1	0	1
New York Heart Association (NYHA) Class
NYHA classifies the extent of heart failure as Class I: Cardiac disease without resulting limitation of physical activity, Class II: Cardiac disease resulting in slight limitation of physical activity, Class III: Cardiac disease resulting in marked limitation of physical activity and Class IV: Cardiac disease resulting in inability to carry out any physical activity without discomfort.
Units: Subjects
Class I	0	0	1	0	0	0	1
Class II	62	23	38	44	49	49	265
Class III/IV	44	14	31	29	20	23	161
Medical history: Chronic heart failure etiology
Units: Subjects
Ischemic	65	25	45	50	37	42	264
Non-ischemic	41	12	24	23	32	30	162
Missing	0	0	1	0	0	0	1
Medical history: Atrial fibrillation
Units: Subjects
Medical history: Atrial fibrillation	44	14	27	26	27	33	171
Without Atrial fibrillation	62	23	43	47	42	39	256
Medication of interest: Beta-blocker
Units: Subjects
Medication of interest: Beta-blocker	103	37	66	70	67	69	412
Not used at Baseline	3	0	4	3	2	3	15
Medication of interest: Angiotensin-converting enzyme inhibitor
Units: Subjects
Angiotensin-converting enzyme inhibitor	58	19	41	41	36	45	240
Not used at Baseline	48	18	29	32	33	27	187
Medication of interest: Angiotensin receptor blocker
Units: Subjects
Angiotensin receptor blocker	15	6	11	14	9	9	64
Not used at Baseline	91	31	59	59	60	63	363
Medication of interest: Angiotensin receptor-neprilysin inhibitor
Units: Subjects
Angiotensin receptor-neprilysin inhibitor	20	7	9	9	12	12	69
Not used at Baseline	86	30	61	64	57	60	358
Medication of interest: Mineralocorticoid receptor antagonist
Units: Subjects
Mineralocorticoid receptor antagonist	93	33	56	60	56	57	355
Not used at Baseline	13	4	14	13	13	15	72
Left ventricular ejection fraction (LVEF)
Left ventricular ejection fraction (LVEF) is defined as the fraction of blood being pumped out of the left ventricle of the heart with each contraction.
Units: Percentage of LVEF
arithmetic mean (standard deviation)	28.24 ( 10.67 )	26.22 ( 7.99 )	27.58 ( 8.92 )	29.70 ( 10.87 )	29.87 ( 11.54 )	26.24 ( 8.92 )	-
N-terminal pro-hormone b-type natriuretic peptide (NT-proBNP)
Units: Picograms per milliliter (pg/mL)
median (full range (min-max))	2111.00 (78.0 to 30428.0)	2071.00 (155.0 to 17760.0)	2063.00 (25.5 to 49896.0)	1894.50 (56.0 to 13294.0)	2084.00 (406.0 to 24551.0)	2419.00 (60.0 to 13387.0)	-

End points

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Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 5 mg

Reporting group description

Subjects received 5 milligrams (mg) of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 10 mg

Reporting group description

Subjects received 10 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 20 mg

Reporting group description

Subjects received 20 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 30 mg

Reporting group description

Subjects received 30 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson Bialanate 40 mg

Reporting group description

Subjects received 40 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

FAS included all randomized subjects.

Subject analysis set title

Per-protocol set LVEF (PPS LVEF)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Per-protocol set (PPS) included all subjects without validity findings affecting efficacy evaluation. The subjects with invalid/missing baseline value or missing post-baseline values not due to cardiovascular (CV) death or heart failure (HF) hospitalization or with other major protocol deviation were excluded from PPS LVEF set.

Subject analysis set title

Per-protocol set BNP (PPS BNP)

Subject analysis set type

Sub-group analysis

Subject analysis set description

PPS included all subjects without validity findings affecting efficacy evaluation. The subjects with invalid/missing baseline value or missing postbaseline value not due to CV death or HF hospitalization or with other major protocol deviation were excluded from the PPS BNP.

Primary: Absolute Change From Baseline in Left Ventricular Ejection Fraction (LVEF) (%) at Week 20 Measured by Echocardiography

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End point title

Absolute Change From Baseline in Left Ventricular Ejection Fraction (LVEF) (%) at Week 20 Measured by Echocardiography

End point description

Left ventricular ejection fraction (LVEF) was measured by echocardiography. Mean and standard deviation were reported.

End point type

Primary

End point timeframe

Baseline, Week 20

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	47 ^[1]	19 ^[2]	35 ^[3]	47 ^[4]	40 ^[5]	38 ^[6]
Units: Percentage of LVEF
arithmetic mean (standard deviation)	-2.19 ( 8.39 )	2.59 ( 8.48 )	-3.01 ( 10.43 )	0.13 ( 8.74 )	-2.45 ( 10.54 )	1.53 ( 10.01 )

Notes
[1] - PPS LVEF
[2] - PPS LVEF
[3] - PPS LVEF
[4] - PPS LVEF
[5] - PPS LVEF
[6] - PPS LVEF

Linear: Dose response test

Statistical analysis description

Dose response relationship was assessed using the multiple comparison procedures (MCP)-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2297 ^[7]

Method

MCP-Mod method

Confidence interval

Notes
[7] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax 1: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4409 ^[8]

Method

MCP-Mod method

Confidence interval

Notes
[8] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax 2: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2842 ^[9]

Method

MCP-Mod method

Confidence interval

Notes
[9] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Emax: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2534 ^[10]

Method

MCP-Mod method

Confidence interval

Notes
[10] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Quadratic: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3842 ^[11]

Method

MCP-Mod method

Confidence interval

Notes
[11] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Primary: Absolute Change From Baseline in log-transformed NT-pro b-type Natriuretic Peptide (BNP) at Week 20

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End point title

Absolute Change From Baseline in log-transformed NT-pro b-type Natriuretic Peptide (BNP) at Week 20

End point description

NT-pro b-type Natriuretic Peptide (BNP) was measured. Mean and standard deviation were reported.

End point type

Primary

End point timeframe

Baseline, Week 20

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	82 ^[12]	29 ^[13]	58 ^[14]	59 ^[15]	53 ^[16]	56 ^[17]
Units: log picograms per milliliter
arithmetic mean (standard deviation)	-0.07 ( 0.70 )	-0.24 ( 0.90 )	-0.07 ( 0.52 )	-0.07 ( 0.56 )	0.07 ( 0.55 )	-0.08 ( 0.79 )

Notes
[12] - PPS BNP
[13] - PPS BNP
[14] - PPS BNP
[15] - PPS BNP
[16] - PPS BNP
[17] - PPS BNP

Linear: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8966 ^[18]

Method

MCP-Mod method

Confidence interval

Notes
[18] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax 1: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9233 ^[19]

Method

MCP-Mod method

Confidence interval

Notes
[19] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax 2: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9296 ^[20]

Method

MCP-Mod method

Confidence interval

Notes
[20] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Emax: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7357 ^[21]

Method

MCP-Mod method

Confidence interval

Notes
[21] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Quadratic: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9083 ^[22]

Method

MCP-Mod method

Confidence interval

Notes
[22] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Secondary: Change From Baseline in Left Ventricular End-Systolic Volume (LVESV) at Week 20

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End point title

Change From Baseline in Left Ventricular End-Systolic Volume (LVESV) at Week 20

End point description

LVESV was defined as the volume of blood in the left ventricle at the end of contraction, or systole and the beginning of filling or diastole. Mean and standard deviation were reported.

End point type

Secondary

End point timeframe

Baseline, Week 20

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	47 ^[23]	19 ^[24]	35 ^[25]	47 ^[26]	40 ^[27]	38 ^[28]
Units: Milliliters (mL)
arithmetic mean (standard deviation)	-5.44 ( 33.29 )	-21.41 ( 48.13 )	-2.82 ( 35.12 )	-4.32 ( 29.73 )	-3.12 ( 33.96 )	-15.16 ( 39.65 )

Notes
[23] - PPS LVEF
[24] - PPS LVEF
[25] - PPS LVEF
[26] - PPS LVEF
[27] - PPS LVEF
[28] - PPS LVEF

Linear: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4596 ^[29]

Method

MCP-Mod method

Confidence interval

Notes
[29] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax 1: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg v Placebo

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7859 ^[30]

Method

MCP-Mod method

Confidence interval

Notes
[30] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax2: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5562 ^[31]

Method

MCP-Mod method

Confidence interval

Notes
[31] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Emax: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5338 ^[32]

Method

MCP-Mod method

Confidence interval

Notes
[32] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test

Quadratic: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7303 ^[33]

Method

MCP-Mod method

Confidence interval

Notes
[33] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Secondary: Change From Baseline in Left Ventricular End-Diastolic Volume (LVEDV) at Week 20

Top of page

End point title

Change From Baseline in Left Ventricular End-Diastolic Volume (LVEDV) at Week 20

End point description

LVEDV was defined as the volume of blood in the left ventricle at end load or filling in diastole or the amount of blood in the ventricles just before systole. Mean and standard deviation were reported.

End point type

Secondary

End point timeframe

Baseline, Week 20

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	47 ^[34]	19 ^[35]	35 ^[36]	47 ^[37]	40 ^[38]	38 ^[39]
Units: Milliliters (mL)
arithmetic mean (standard deviation)	-13.16 ( 40.23 )	-21.65 ( 61.96 )	-12.44 ( 39.84 )	-5.92 ( 30.89 )	-11.17 ( 42.32 )	-19.69 ( 48.38 )

Notes
[34] - PPS LVEF
[35] - PPS LVEF
[36] - PPS LVEF
[37] - PPS LVEF
[38] - PPS LVEF
[39] - PPS LVEF

Linear: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5703 ^[40]

Method

MCP-Mod method

Confidence interval

Notes
[40] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax1: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8253 ^[41]

Method

MCP-Mod method

Confidence interval

Notes
[41] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax2: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6506 ^[42]

Method

MCP-Mod method

Confidence interval

Notes
[42] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Emax: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6923 ^[43]

Method

MCP-Mod method

Confidence interval

Notes
[43] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Quadratic: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8036 ^[44]

Method

MCP-Mod method

Confidence interval

Notes
[44] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Secondary: Change From Baseline in High Sensitivity Troponin T (hs-TNT) at Week 20

Top of page

End point title

Change From Baseline in High Sensitivity Troponin T (hs-TNT) at Week 20

End point description

High sensitivity troponin T (hs-TNT) was measured. Mean and standard deviation were reported.

End point type

Secondary

End point timeframe

Baseline, Week 20

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	82 ^[45]	29 ^[46]	58 ^[47]	59 ^[48]	53 ^[49]	56 ^[50]
Units: Picograms per milliliter (pg/mL)
arithmetic mean (standard deviation)	0.13 ( 9.98 )	6.46 ( 33.04 )	3.77 ( 22.32 )	7.43 ( 37.79 )	2.59 ( 12.90 )	7.03 ( 24.81 )

Notes
[45] - PPS BNP
[46] - PPS BNP
[47] - PPS BNP
[48] - PPS BNP
[49] - PPS BNP
[50] - PPS BNP

Linear: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9955 ^[51]

Method

MCP-Mod method

Confidence interval

Notes
[51] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax1: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9946 ^[52]

Method

MCP-Mod method

Confidence interval

Notes
[52] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Sigmoidal Emax2: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9913 ^[53]

Method

MCP-Mod method

Confidence interval

Notes
[53] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Emax: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9982 ^[54]

Method

MCP-Mod method

Confidence interval

Notes
[54] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Quadratic: Dose response test

Statistical analysis description

Dose response relationship was assessed using the MCP-Mod method combining MCP principles with modeling techniques under model uncertainty.

Comparison groups

Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg

Number of subjects included in analysis

337

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9959 ^[55]

Method

MCP-Mod method

Confidence interval

Notes
[55] - The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

Secondary: Number of Subjects With Composite Efficacy Outcome

Top of page

End point title

Number of Subjects With Composite Efficacy Outcome

End point description

Composite efficacy outcome was the first occurrence of CV death, HF hospitalization or urgent visit for HF. Number of subjects with composite efficacy outcome were reported.

End point type

Secondary

End point timeframe

Baseline up to Week 26

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	82 ^[56]	29 ^[57]	58 ^[58]	59 ^[59]	53 ^[60]	56 ^[61]
Units: Subjects	10	4	10	9	7	8

Notes
[56] - PPS BNP
[57] - PPS BNP
[58] - PPS BNP
[59] - PPS BNP
[60] - PPS BNP
[61] - PPS BNP

No statistical analyses for this end point

Secondary: Number of Subjects With Cardiovascular (CV) Mortality

Top of page

End point title

Number of Subjects With Cardiovascular (CV) Mortality

End point description

Cardiovascular (CV) mortality was assessed. Number of subjects with CV mortality were reported.

End point type

Secondary

End point timeframe

Baseline up to Week 26

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	82 ^[62]	29 ^[63]	58 ^[64]	59 ^[65]	53 ^[66]	56 ^[67]
Units: Subjects	1	1	3	1	2	1

Notes
[62] - PPS BNP
[63] - PPS BNP
[64] - PPS BNP
[65] - PPS BNP
[66] - PPS BNP
[67] - PPS BNP

No statistical analyses for this end point

Secondary: Number of Subjects With Heart Failure (HF) Hospitalization and Urgent Visits for Heart Failure (HF)

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End point title

Number of Subjects With Heart Failure (HF) Hospitalization and Urgent Visits for Heart Failure (HF)

End point description

Number of subjects with HF hospitalization and urgent visits for HF were reported.

End point type

Secondary

End point timeframe

Baseline up to Week 26

End point values	Placebo	Neladenoson Bialanate 5 mg	Neladenoson Bialanate 10 mg	Neladenoson Bialanate 20 mg	Neladenoson Bialanate 30 mg	Neladenoson Bialanate 40 mg
Number of subjects analysed	82 ^[68]	29 ^[69]	58 ^[70]	59 ^[71]	53 ^[72]	56 ^[73]
Units: Subjects	10	4	9	8	5	8

Notes
[68] - PPS BNP
[69] - PPS BNP
[70] - PPS BNP
[71] - PPS BNP
[72] - PPS BNP
[73] - PPS BNP

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From start of study drug administration up to 26 weeks

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson bialanate 5mg

Reporting group description

Subjects received 5 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson bialanate 10mg

Reporting group description

Subjects received 10 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson bialanate 20mg

Reporting group description

Subjects received 20 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson bialanate 30mg

Reporting group description

Subjects received 30 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Reporting group title

Neladenoson bialanate 40mg

Reporting group description

Subjects received 40 mg of neladenoson bialanate tablets orally once daily for 20 weeks.

Serious adverse events	Placebo	Neladenoson bialanate 5mg	Neladenoson bialanate 10mg	Neladenoson bialanate 20mg	Neladenoson bialanate 30mg	Neladenoson bialanate 40mg
Total subjects affected by serious adverse events
subjects affected / exposed	31 / 106 (29.25%)	13 / 37 (35.14%)	28 / 70 (40.00%)	22 / 72 (30.56%)	28 / 69 (40.58%)	26 / 72 (36.11%)
number of deaths (all causes)	8	1	5	1	2	2
number of deaths resulting from adverse events	1	0	0	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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 / 1
Renal cancer metastatic
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Hypotension
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	1 / 70 (1.43%)	1 / 72 (1.39%)	1 / 69 (1.45%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	1 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Atrial septal defect repair
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac pacemaker insertion
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac pacemaker replacement
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Implantable defibrillator insertion
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	2 / 70 (2.86%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular assist device insertion
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Implantable defibrillator replacement
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac resynchronisation therapy
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	1 / 72 (1.39%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colectomy
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	1 / 72 (1.39%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
Oedema due to cardiac disease
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Dyspnoea
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	1 / 70 (1.43%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Pulmonary congestion
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Product issues
Device failure
alternative assessment type: Systematic
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Investigations
Arteriogram coronary
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood pressure decreased
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device function test
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic pain
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Angina pectoris
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 106 (1.89%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	3 / 72 (4.17%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	2 / 70 (2.86%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	2 / 70 (2.86%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	15 / 106 (14.15%)	7 / 37 (18.92%)	12 / 70 (17.14%)	6 / 72 (8.33%)	10 / 69 (14.49%)	11 / 72 (15.28%)
occurrences causally related to treatment / all	0 / 20	0 / 8	0 / 14	0 / 10	0 / 17	0 / 16
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1
Cardiac failure acute
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	1 / 72 (1.39%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Cardiac failure chronic
subjects affected / exposed	5 / 106 (4.72%)	1 / 37 (2.70%)	2 / 70 (2.86%)	3 / 72 (4.17%)	2 / 69 (2.90%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	2 / 8	0 / 1	0 / 2	0 / 7	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	3 / 106 (2.83%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Low cardiac output syndrome
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Mitral valve incompetence
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 106 (0.94%)	1 / 37 (2.70%)	2 / 70 (2.86%)	1 / 72 (1.39%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac ventricular thrombosis
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Paraparesis
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Presyncope
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Seizure
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 106 (1.89%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	2 / 69 (2.90%)	2 / 72 (2.78%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	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
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	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
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Jaundice
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	2 / 72 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	2 / 70 (2.86%)	1 / 72 (1.39%)	2 / 69 (2.90%)	3 / 72 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	2 / 106 (1.89%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	2 / 72 (2.78%)
occurrences causally related to treatment / all	0 / 2	0 / 1	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
Acute kidney injury
subjects affected / exposed	2 / 106 (1.89%)	0 / 37 (0.00%)	0 / 70 (0.00%)	1 / 72 (1.39%)	1 / 69 (1.45%)	2 / 72 (2.78%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	1 / 69 (1.45%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Peritonitis
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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 / 1
Pneumonia
subjects affected / exposed	2 / 106 (1.89%)	0 / 37 (0.00%)	1 / 70 (1.43%)	2 / 72 (2.78%)	1 / 69 (1.45%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Septic shock
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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 / 1
Serratia sepsis
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	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
Hypokalaemia
subjects affected / exposed	2 / 106 (1.89%)	0 / 37 (0.00%)	1 / 70 (1.43%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	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	Placebo	Neladenoson bialanate 5mg	Neladenoson bialanate 10mg	Neladenoson bialanate 20mg	Neladenoson bialanate 30mg	Neladenoson bialanate 40mg
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 106 (22.64%)	10 / 37 (27.03%)	15 / 70 (21.43%)	18 / 72 (25.00%)	24 / 69 (34.78%)	19 / 72 (26.39%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 106 (0.00%)	1 / 37 (2.70%)	5 / 70 (7.14%)	4 / 72 (5.56%)	3 / 69 (4.35%)	2 / 72 (2.78%)
occurrences all number	0	1	6	4	3	2
Cardiac disorders
Cardiac failure
subjects affected / exposed	9 / 106 (8.49%)	2 / 37 (5.41%)	2 / 70 (2.86%)	1 / 72 (1.39%)	3 / 69 (4.35%)	3 / 72 (4.17%)
occurrences all number	9	2	2	1	3	6
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 106 (2.83%)	0 / 37 (0.00%)	1 / 70 (1.43%)	2 / 72 (2.78%)	4 / 69 (5.80%)	4 / 72 (5.56%)
occurrences all number	3	0	1	2	4	4
Headache
subjects affected / exposed	3 / 106 (2.83%)	1 / 37 (2.70%)	2 / 70 (2.86%)	0 / 72 (0.00%)	6 / 69 (8.70%)	1 / 72 (1.39%)
occurrences all number	3	1	2	0	8	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	1 / 70 (1.43%)	2 / 72 (2.78%)	4 / 69 (5.80%)	0 / 72 (0.00%)
occurrences all number	2	0	1	2	4	0
Fatigue
subjects affected / exposed	2 / 106 (1.89%)	2 / 37 (5.41%)	1 / 70 (1.43%)	2 / 72 (2.78%)	1 / 69 (1.45%)	0 / 72 (0.00%)
occurrences all number	2	2	1	2	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 106 (0.94%)	2 / 37 (5.41%)	1 / 70 (1.43%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences all number	1	2	1	3	0	0
Nausea
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	0 / 70 (0.00%)	0 / 72 (0.00%)	2 / 69 (2.90%)	5 / 72 (6.94%)
occurrences all number	2	0	0	0	2	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 106 (0.00%)	0 / 37 (0.00%)	3 / 70 (4.29%)	4 / 72 (5.56%)	3 / 69 (4.35%)	3 / 72 (4.17%)
occurrences all number	0	0	3	6	3	3
Renal and urinary disorders
Renal impairment
subjects affected / exposed	6 / 106 (5.66%)	1 / 37 (2.70%)	0 / 70 (0.00%)	4 / 72 (5.56%)	6 / 69 (8.70%)	7 / 72 (9.72%)
occurrences all number	7	1	0	4	6	7
Infections and infestations
Urinary tract infection
subjects affected / exposed	1 / 106 (0.94%)	0 / 37 (0.00%)	1 / 70 (1.43%)	0 / 72 (0.00%)	0 / 69 (0.00%)	4 / 72 (5.56%)
occurrences all number	1	0	1	0	0	4
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	2 / 106 (1.89%)	2 / 37 (5.41%)	0 / 70 (0.00%)	1 / 72 (1.39%)	0 / 69 (0.00%)	0 / 72 (0.00%)
occurrences all number	2	2	0	1	0	0

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Were there any global substantial amendments to the protocol? Yes

17 Feb 2017

1. Justification of the study drug dose was included. 2. Exclusion criteria related to asthma, prohibited therapy and allergies or hypersensitivities were added. 3. Tablet combination for subjects in 10 mg and 20 mg dose arms was changed.

Were there any global interruptions to the trial? No

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

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Absolute Change From Baseline in Left Ventricular Ejection Fraction (LVEF) (%) at Week 20 Measured by Echocardiography

Primary: Absolute Change From Baseline in Left Ventricular Ejection Fraction (LVEF) (%) at Week 20 Measured by Echocardiography

Primary: Absolute Change From Baseline in log-transformed NT-pro b-type Natriuretic Peptide (BNP) at Week 20

Primary: Absolute Change From Baseline in log-transformed NT-pro b-type Natriuretic Peptide (BNP) at Week 20

Secondary: Change From Baseline in Left Ventricular End-Systolic Volume (LVESV) at Week 20

Secondary: Change From Baseline in Left Ventricular End-Systolic Volume (LVESV) at Week 20

Secondary: Change From Baseline in Left Ventricular End-Diastolic Volume (LVEDV) at Week 20

Secondary: Change From Baseline in Left Ventricular End-Diastolic Volume (LVEDV) at Week 20

Secondary: Change From Baseline in High Sensitivity Troponin T (hs-TNT) at Week 20

Secondary: Change From Baseline in High Sensitivity Troponin T (hs-TNT) at Week 20

Secondary: Number of Subjects With Composite Efficacy Outcome

Secondary: Number of Subjects With Composite Efficacy Outcome

Secondary: Number of Subjects With Cardiovascular (CV) Mortality

Secondary: Number of Subjects With Cardiovascular (CV) Mortality

Secondary: Number of Subjects With Heart Failure (HF) Hospitalization and Urgent Visits for Heart Failure (HF)

Secondary: Number of Subjects With Heart Failure (HF) Hospitalization and Urgent Visits for Heart Failure (HF)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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