Trial Outcomes & Findings for A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction (NCT NCT01065454)

Last Updated: 2025-08-28

Results Overview

Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

202 participants

Primary outcome timeframe

Baseline and visit 6 (16 weeks)

Results posted on

2025-08-28

Participant Flow

Only subjects with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD) could participate in this study. Subjects must have been pre-treated with optimized CHF therapy.

301 subjects were screened in 84 study centers in 18 countries worldwide. 99 of the 301 screened subjects were not randomized (adverse event \[1\], protocol violation \[1\], screen failure \[87\], withdrawal by subject \[10\]). Of the 202 subjects randomized, one subject did not receive any study medication.

Participant milestones

Participant milestones
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Participants received riociguat 0.5 mg tid (fixed dose).	Placebo Participants received placebo tid.
Treatment STARTED	67	33	32	69
Treatment COMPLETED	54	28	23	57
Treatment NOT COMPLETED	13	5	9	12
Follow up STARTED	54	28	23	57
Follow up Entering Follow-up	49	27	23	51
Follow up COMPLETED	15	4	6	13
Follow up NOT COMPLETED	39	24	17	44

Reasons for withdrawal

Reasons for withdrawal
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Participants received riociguat 0.5 mg tid (fixed dose).	Placebo Participants received placebo tid.
Treatment Adverse Event	7	4	3	6
Treatment Death	1	0	0	0
Treatment Non-compliance	1	0	0	1
Treatment Protocol Decision	0	0	3	2
Treatment Protocol Violation	1	0	1	0
Treatment Withdrawal by Subject	3	1	2	3
Follow up Adverse Event	1	0	0	1
Follow up Death	0	1	1	0
Follow up Lost to Follow-up	0	0	0	1
Follow up Progressive disease	0	0	0	1
Follow up Withdrawal by Subject	1	1	1	0
Follow up study ongoing	37	22	15	41

Baseline Characteristics

A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=67 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=33 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=32 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=69 Participants Participants received placebo tid.	Total n=201 Participants Total of all reporting groups
Age, Continuous	59.3 Years STANDARD_DEVIATION 10.8 • n=5 Participants	55.1 Years STANDARD_DEVIATION 13.2 • n=7 Participants	57.2 Years STANDARD_DEVIATION 9.9 • n=5 Participants	58.9 Years STANDARD_DEVIATION 11.2 • n=4 Participants	58.1 Years STANDARD_DEVIATION 11.2 • n=21 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants	8 Participants n=4 Participants	29 Participants n=21 Participants
Sex: Female, Male Male	55 Participants n=5 Participants	30 Participants n=7 Participants	26 Participants n=5 Participants	61 Participants n=4 Participants	172 Participants n=21 Participants
Body mass index	28.87 kg/m^2 STANDARD_DEVIATION 5.27 • n=5 Participants	28.16 kg/m^2 STANDARD_DEVIATION 4.72 • n=7 Participants	29.20 kg/m^2 STANDARD_DEVIATION 5.64 • n=5 Participants	28.65 kg/m^2 STANDARD_DEVIATION 5.89 • n=4 Participants	28.73 kg/m^2 STANDARD_DEVIATION 5.44 • n=21 Participants
6-minute walking distance	380.9 Meters STANDARD_DEVIATION 125.80 • n=5 Participants	401.9 Meters STANDARD_DEVIATION 101.75 • n=7 Participants	416.6 Meters STANDARD_DEVIATION 95.77 • n=5 Participants	382.1 Meters STANDARD_DEVIATION 123.51 • n=4 Participants	390.5 Meters STANDARD_DEVIATION 116.94 • n=21 Participants
Left ventricular ejection fraction (LVEF)	28.4 Percentage STANDARD_DEVIATION 5.72 • n=5 Participants	28.8 Percentage STANDARD_DEVIATION 4.54 • n=7 Participants	27.0 Percentage STANDARD_DEVIATION 5.21 • n=5 Participants	27.1 Percentage STANDARD_DEVIATION 5.02 • n=4 Participants	27.8 Percentage STANDARD_DEVIATION 5.24 • n=21 Participants
Etiology Ischemic cardiomyopathy	30 Participants n=5 Participants	12 Participants n=7 Participants	14 Participants n=5 Participants	34 Participants n=4 Participants	90 Participants n=21 Participants
Etiology Non-ischemic cardiomyopathy	37 Participants n=5 Participants	20 Participants n=7 Participants	17 Participants n=5 Participants	34 Participants n=4 Participants	108 Participants n=21 Participants
Etiology Data missing	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
WHO (World Health Organization) functional class II	35 Participants n=5 Participants	20 Participants n=7 Participants	23 Participants n=5 Participants	42 Participants n=4 Participants	120 Participants n=21 Participants
WHO (World Health Organization) functional class III	31 Participants n=5 Participants	13 Participants n=7 Participants	9 Participants n=5 Participants	23 Participants n=4 Participants	76 Participants n=21 Participants
WHO (World Health Organization) functional class IV	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants	5 Participants n=21 Participants
Number of participants with diabetes mellitus (including subtypes)	30 Participants n=5 Participants	10 Participants n=7 Participants	13 Participants n=5 Participants	34 Participants n=4 Participants	87 Participants n=21 Participants
Glomerular filtration rate (GFR)	65.1 mL/min/1.73m^2 STANDARD_DEVIATION 19.10 • n=5 Participants	72.6 mL/min/1.73m^2 STANDARD_DEVIATION 22.70 • n=7 Participants	72.0 mL/min/1.73m^2 STANDARD_DEVIATION 17.90 • n=5 Participants	68.7 mL/min/1.73m^2 STANDARD_DEVIATION 19.90 • n=4 Participants	68.7 mL/min/1.73m^2 STANDARD_DEVIATION 19.91 • n=21 Participants
Number of participants with atrial fibrillation	9 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	9 Participants n=4 Participants	24 Participants n=21 Participants
Number of participants with atrial flutter	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Number of participants with pacemaker rhythm	17 Participants n=5 Participants	9 Participants n=7 Participants	7 Participants n=5 Participants	17 Participants n=4 Participants	50 Participants n=21 Participants
Baseline drug and device therapy Cardiac devices	38 Participants n=5 Participants	17 Participants n=7 Participants	21 Participants n=5 Participants	44 Participants n=4 Participants	120 Participants n=21 Participants
Baseline drug and device therapy Angiotensin-converting enzyme inhibitors	50 Participants n=5 Participants	25 Participants n=7 Participants	21 Participants n=5 Participants	46 Participants n=4 Participants	142 Participants n=21 Participants
Baseline drug and device therapy Angiotensin II receptor blockers	20 Participants n=5 Participants	8 Participants n=7 Participants	10 Participants n=5 Participants	19 Participants n=4 Participants	57 Participants n=21 Participants
Baseline drug and device therapy Aldosterone antagonists	51 Participants n=5 Participants	26 Participants n=7 Participants	23 Participants n=5 Participants	53 Participants n=4 Participants	153 Participants n=21 Participants
Baseline drug and device therapy Beta-blockers	31 Participants n=5 Participants	16 Participants n=7 Participants	21 Participants n=5 Participants	32 Participants n=4 Participants	100 Participants n=21 Participants
Baseline drug and device therapy Beta-blockers with alpha-blocking activity	30 Participants n=5 Participants	15 Participants n=7 Participants	11 Participants n=5 Participants	30 Participants n=4 Participants	86 Participants n=21 Participants
Baseline drug and device therapy Loop diuretics	62 Participants n=5 Participants	31 Participants n=7 Participants	29 Participants n=5 Participants	68 Participants n=4 Participants	190 Participants n=21 Participants
Baseline drug and device therapy Thiazide diuretics	12 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants	10 Participants n=4 Participants	32 Participants n=21 Participants
Baseline drug and device therapy Cardiac glycosides	28 Participants n=5 Participants	12 Participants n=7 Participants	6 Participants n=5 Participants	28 Participants n=4 Participants	74 Participants n=21 Participants
Baseline drug and device therapy Oral anticoagulants	38 Participants n=5 Participants	16 Participants n=7 Participants	15 Participants n=5 Participants	33 Participants n=4 Participants	102 Participants n=21 Participants
Baseline drug and device therapy Amiodarone	9 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants	24 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Population: Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF \[safety analysis set\]/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.

Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Pulmonary Artery Mean Pressure (PAPmean) at Rest - Change From Baseline to Week 16	-6.1 mmHg Standard Deviation 9.68	-0.8 mmHg Standard Deviation 8.41	-4.5 mmHg Standard Deviation 7.35	-4.0 mmHg Standard Deviation 9.00

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Population: Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.

The mixed venous oxygen saturation rate (SvO2) is a directly measured hemodynamic parameter. SvO2 is recorded during a right heart catheterization.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=45 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=23 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=19 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=48 Participants Participants received placebo tid.
Venous Oxygen Saturation (SvO2) - Change From Baseline to Week 16	1.98 Percentage Standard Deviation 7.084	0.46 Percentage Standard Deviation 7.866	-0.21 Percentage Standard Deviation 5.969	1.28 Percentage Standard Deviation 9.259

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The pulmonary vascular resistance (PVR) is a calculated hemodynamic parameter. PVR is derived from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP), divided by the cardiac output (CO). PVR and PAPmean are acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: PVR = 80\*(PAPmean - PCWP)/CO

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=53 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16	-78.15 dynscm^-5 Standard Deviation 125.261	-33.05 dynscm^-5 Standard Deviation 99.322	-51.44 dynscm^-5 Standard Deviation 124.107	-36.97 dynscm^-5 Standard Deviation 157.523

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The pulmonary vascular resistance index (PVRi) is a calculated hemodynamic parameter. PVRi is derived from the pulmonary vascular resistance (PVR) normalized by the body surface area (BSA). Formula: PVRi = 80\*(PAPmean - PCWP)\*BSA/CO

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=53 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Pulmonary Vascular Resistance Index (PVRi) - Change From Baseline to Week 16	-152.60 dynscm^-5*m^2 Standard Deviation 250.366	-61.763 dynscm^-5*m^2 Standard Deviation 202.138	-91.65 dynscm^-5*m^2 Standard Deviation 237.256	-76.47 dynscm^-5*m^2 Standard Deviation 311.693

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The systemic vascular resistance (SVR) is a calculated hemodynamic parameter. SVR is derived from the directly measured parameter mean right atrial pressure (RAPmean) and the calculated parameter mean systemic arterial pressure (SAPmean) divided by the cardiac output (CO). RAPmean is acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: SVR = 80\*(SAPmean - RAPmean)/CO

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=53 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Systemic Vascular Resistance (SVR) - Change From Baseline to Week 16	-340.44 dynscm^-5 Standard Deviation 394.87	-118.72 dynscm^-5 Standard Deviation 369.865	-67.46 dynscm^-5 Standard Deviation 315.097	-94.37 dynscm^-5 Standard Deviation 431.049

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The systemic vascular resistance index (SVRi) is a calculated hemodynamic parameter. SVRi is derived from the systemic vascular resistance (SVR) normalized by the body surface area (BSA). Formula: SVRi = 80\*(SAPmean - RAPmean)\*BSA/CO

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=53 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Systemic Vascular Resistance Index (SVRi) - Change From Baseline to Week 16	-651.98 dynscm^-5*m^2 Standard Deviation 757.617	-217.14 dynscm^-5*m^2 Standard Deviation 742.465	-100.31 dynscm^-5*m^2 Standard Deviation 612.460	-195.11 dynscm^-5*m^2 Standard Deviation 853.927

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The transpulmonary pressure gradient (TPG) is a calculated hemodynamic parameter. TPG is calculated from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP). These 2 parameters are acquired during a right heart catheterization. Formula: TPG = PAPmean - PCWP

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=53 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Transpulmonary Pressure Gradient (TPG) - Change From Baseline to Week 16	-2.16 mmHg Standard Deviation 4.795	-1.01 mmHg Standard Deviation 5.224	-1.65 mmHg Standard Deviation 4.652	-1.37 mmHg Standard Deviation 7.001

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Pulmonary capillary wedge pressure (PCWP) is a directly measured hemodynamic parameter acquired during a right heart catheterization.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=53 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
Pulmonary Capillary Wedge Pressure (PCWP) - Change From Baseline to Week 16	-3.93 mmHg Standard Deviation 9.381	0.25 mmHg Standard Deviation 9.001	-2.818 mmHg Standard Deviation 7.842	-2.68 mmHg Standard Deviation 7.791

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The tricuspid annular plane systolic excursion (TAPSE) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=45 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=23 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=21 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=51 Participants Participants received placebo tid.
Tricuspid Annular Plane Systolic Excursion (TAPSE) - Change From Baseline to Week 16	0.584 mm Standard Deviation 2.344	1.140 mm Standard Deviation 2.986	0.304 mm Standard Deviation 2.109	0.393 mm Standard Deviation 1.586

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Systolic pulmonary arterial pressure (PAPsyst) is a directly measured hemodynamic parameter acquired during a right heart catheterization.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=55 Participants Participants received placebo tid.
Systolic Pulmonary Arterial Pressure (PAPsyst) - Change From Baseline to Week 16	-7.69 mmHg Standard Deviation 14.251	-2.89 mmHg Standard Deviation 12.333	-5.86 mmHg Standard Deviation 11.589	-4.49 mmHg Standard Deviation 13.717

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). These 2 parameters are acquired during a non-invasive echocardiography examination. Formula: LEVF = 100\*(LVEDV - LVESV)/LVEDV

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=52 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=51 Participants Participants received placebo tid.
Left Ventricular Ejection Fraction (LVEF) - Change From Baseline to Week 16	6.599 Percentage Standard Deviation 43.187	12.659 Percentage Standard Deviation 41.769	5.529 Percentage Standard Deviation 48.322	11.121 Percentage Standard Deviation 42.989

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Left ventricular end-systolic volume (LVESV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=52 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=51 Participants Participants received placebo tid.
Left Ventricular End-systolic Volume (LVESV) - Change From Baseline to Week 16	1.805 mL Standard Deviation 31.735	6.415 mL Standard Deviation 28.832	1.507 mL Standard Deviation 34.033	7.295 mL Standard Deviation 32.311

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Left ventricular end-diastolic volume (LVEDV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=52 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=51 Participants Participants received placebo tid.
Left Ventricular End-diastolic Volume (LVEDV) - Change From Baseline to Week 16	6.599 mL Standard Deviation 43.187	12.659 mL Standard Deviation 41.769	5.529 mL Standard Deviation 48.322	11.121 mL Standard Deviation 42.989

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

E-wave deceleration time is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=49 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=22 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=21 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=53 Participants Participants received placebo tid.
E-wave Deceleration Time - Change From Baseline to Week 16	2.857 msec Standard Deviation 31.470	-0.636 msec Standard Deviation 38.138	8.000 msec Standard Deviation 39.542	-1.208 msec Standard Deviation 43.937

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

E/A ratio is a measured echocardiography parameter and describes the ratio of mitral peak velocity of early filling to mitral peak velocity of late filling. It is acquired during a non-invasive echocardiography examination.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=44 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=20 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=20 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=48 Participants Participants received placebo tid.
Ratio of Mitral Peak Velocity of Early Filling to Mitral Peak Velocity of Late Filling (E/A) - Change From Baseline to Week 16	-0.247 E/A ratio Standard Deviation 0.957	0.141 E/A ratio Standard Deviation 1.261	-0.063 E/A ratio Standard Deviation 0.884	-0.175 E/A ratio Standard Deviation 1.079

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

6-minute walking distance (6MWD) is a measure for the objective evaluation of a patient's functional exercise capacity.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=55 Participants Participants received placebo tid.
6-minute Walking Distance (6MWD) - Change From Baseline to Week 16	31.425 m Standard Deviation 83.386	25.379 m Standard Deviation 84.244	-2.784 m Standard Deviation 90.324	17.857 m Standard Deviation 80.851

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement, changes to a higher functional class resemble deterioration of PAH.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
WHO (World Health Organization) Functional Class - Change From Baseline to Week 16 -1	20.4 Percentage of participants	21.4 Percentage of participants	22.7 Percentage of participants	19.6 Percentage of participants
WHO (World Health Organization) Functional Class - Change From Baseline to Week 16 0	74.1 Percentage of participants	75 Percentage of participants	68.2 Percentage of participants	71.4 Percentage of participants
WHO (World Health Organization) Functional Class - Change From Baseline to Week 16 1	5.6 Percentage of participants	3.6 Percentage of participants	9.1 Percentage of participants	8.9 Percentage of participants

SECONDARY outcome

Timeframe: At visit 6 (16 weeks)

Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one post-baseline measurement were included in the analysis.

The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all cause mortality, including cardiovascular mortality; first hospitalization for a cardiovascular event, including heart failure, acute myocardial infarction, stroke or ventricular arrhythmia; upgrade of the HTx (heart transplantation) status to next higher level; need for IV diuretics; persistent worsening of WHO functional class due to deterioration of PH or cardiac function.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=67 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=33 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=32 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=69 Participants Participants received placebo tid.
Percentage of Participants With Clinical Worsening	23.9 Percentage of participants	15.1 Percentage of participants	15.6 Percentage of participants	21.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The Borg CR10 Scale is a patient reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the patient's exertion during a physical test. Low values indicate low levels of exertion, high values indicate more intense exertion reported by the patient. The score ranges from 0 ("Nothing at all") to 10 ("Extremely strong - Maximal").

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=55 Participants Participants received placebo tid.
Borg CR 10 Scale - Change From Baseline to Week 16	0.269 Scores on a scale Standard Deviation 1.900	-0.804 Scores on a scale Standard Deviation 2.319	-0.682 Scores on a scale Standard Deviation 1.516	0.187 Scores on a scale Standard Deviation 2.640

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

EQ-5D utility score is a Quality-of-Life patient reported outcome measure. An increase in the utility score represents an improvement in quality of life. The score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=56 Participants Participants received placebo tid.
EQ-5D Utility Score - Change From Baseline to Week 16	0.073 Scores on a scale Standard Deviation 0.211	0.016 Scores on a scale Standard Deviation 0.242	0.004 Scores on a scale Standard Deviation 0.166	0.018 Scores on a scale Standard Deviation 0.201

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

The self-reported Minnesota Living with Heart Failure questionnaire (MLHF) is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The MLHF total score can range from 0 (best) to 105 (worst).

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=54 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=22 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=55 Participants Participants received placebo tid.
Minnesota Living With Heart Failure Questionnaire (MLHF) Score - Change From Baseline to Week 16	-10.789 Scores on a scale Standard Deviation 22.232	-5.132 Scores on a scale Standard Deviation 14.111	-7.595 Scores on a scale Standard Deviation 18.651	0.211 Scores on a scale Standard Deviation 15.964

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Cystatin C is a biomarker for predicting new onset or deteriorating cardiovascular disease.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=45 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=26 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=17 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=44 Participants Participants received placebo tid.
Cystatin C - Change From Baseline to Week 16	39.3 ng/mL Standard Deviation 232.7	11.2 ng/mL Standard Deviation 218.5	71.2 ng/mL Standard Deviation 140.8	58.6 ng/mL Standard Deviation 242.9

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

N-terminal pro-brain natriuretic peptide (NT-pro BNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=50 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=28 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=21 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=54 Participants Participants received placebo tid.
N-terminal Pro-brain Natriuretic Peptide (NT-pro BNP) - Change From Baseline to Week 16	-168.42 pg/mL Standard Deviation 1585.28	-213.48 pg/mL Standard Deviation 1204.24	-215.71 pg/mL Standard Deviation 769.16	171.51 pg/mL Standard Deviation 2123.55

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Troponin T is a cardiac-specific protein which is released from damaged or injured heart muscle cells.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=34 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=24 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=15 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=44 Participants Participants received placebo tid.
Troponin T - Change From Baseline to Week 16	0.005 µg/L Standard Deviation 0.027	-0.008 µg/L Standard Deviation 0.042	-0.001 µg/L Standard Deviation 0.006	0.003 µg/L Standard Deviation 0.015

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxides. Recent clinical studies have indicated that ADMA may have diagnostic relevance as a novel cardiovascular risk marker.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=49 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=25 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=19 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=51 Participants Participants received placebo tid.
Asymmetric Dimethylarginine (ADMA) - Change From Baseline to Week 16	0.020 µmol/L Standard Deviation 0.115	0.026 µmol/L Standard Deviation 0.118	0.006 µmol/L Standard Deviation 0.098	0.020 µmol/L Standard Deviation 0.090

SECONDARY outcome

Timeframe: Baseline and visit 6 (16 weeks)

Osteopontin is a cytokine-like pro-fibrotic mediator, which is expressed in cardiovascular tissues. Its expression is induced by increased pressure and volume load in the myocardium, kidney and lung. Therefore, osteopontin may be used as a prognostic marker in patients with cardiovascular diseases.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=50 Participants Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=27 Participants Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=18 Participants Participants received riociguat 0.5 mg tid (fixed dose).	Placebo n=51 Participants Participants received placebo tid.
Osteopontin - Change From Baseline to Week 16	-13.400 µg/mL Standard Deviation 44.931	-0.852 µg/mL Standard Deviation 22.396	-2.722 µg/mL Standard Deviation 29.379	-4.588 µg/mL Standard Deviation 77.576

Adverse Events

Riociguat (Adempas, BAY63-2521) up to 2 mg

Serious events: 23 serious events

Other events: 57 other events

Deaths: 0 deaths

Riociguat (Adempas, BAY63-2521) up to 1 mg

Serious events: 7 serious events

Other events: 28 other events

Deaths: 0 deaths

Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg

Serious events: 7 serious events

Other events: 25 other events

Deaths: 0 deaths

Placebo

Serious events: 18 serious events

Other events: 49 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Therapeutic Area Head

Bayer

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Investigative Site, Institution and/or Principal Investigator shall furnish the Sponsor with a copy of any proposed publication of material at least sixty (60) days in advance of the date of submission for publication or presentation.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=67 participants at risk Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=33 participants at risk Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg)	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=32 participants at risk Participants received riociguat 0.5 mg tid (fixed dose)	Placebo n=69 participants at risk Participants received placebo tid
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Surgical and medical procedures Heart transplant	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Surgical and medical procedures Cardiac pacemaker replacement	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Blood and lymphatic system disorders Anaemia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Atrial fibrillation	4.5% 3/67 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac arrest	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac failure	10.4% 7/67 • Number of events 8 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	9.1% 3/33 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	4.3% 3/69 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac failure acute	3.0% 2/67 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	4.3% 3/69 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac failure chronic	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac failure congestive	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac tamponade	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Coronary artery disease	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Right ventricular failure	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Sinus tachycardia	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Ventricular fibrillation	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Ventricular tachycardia	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Gastritis erosive	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Faecaloma	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Cyst	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Hernia	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Pyrexia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders General physical health deterioration	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Medical device complication	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Device malfunction	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Device dislocation	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Hepatobiliary disorders Cholecystitis chronic	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Bronchitis	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Bronchopneumonia	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Gastroenteritis	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Gastroenteritis viral	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Lobar pneumonia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Lower respiratory tract infection	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Osteomyelitis	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Pneumonia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Pneumonia klebsiella	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.

Other adverse events
Measure	Riociguat (Adempas, BAY63-2521) up to 2 mg n=67 participants at risk Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Riociguat (Adempas, BAY63-2521) up to 1 mg n=33 participants at risk Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg)	Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg n=32 participants at risk Participants received riociguat 0.5 mg tid (fixed dose)	Placebo n=69 participants at risk Participants received placebo tid
Blood and lymphatic system disorders Anaemia	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	12.1% 4/33 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Aortic valve incompetence	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Atrial fibrillation	9.0% 6/67 • Number of events 7 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Atrial flutter	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Atrial tachycardia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Bradycardia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac failure	6.0% 4/67 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	5.8% 4/69 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Cardiac failure chronic	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Palpitations	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.2% 2/32 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Pulmonary valve incompetence	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Supraventricular tachycardia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.2% 2/32 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Cardiac disorders Ventricular tachycardia	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Ear and labyrinth disorders Vertigo	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Endocrine disorders Hyperthyroidism	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Eye disorders Vision blurred	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Eye disorders Visual impairment	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Abdominal discomfort	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Abdominal distension	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Abdominal pain upper	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Constipation	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	12.5% 4/32 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Diarrhoea	17.9% 12/67 • Number of events 14 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	15.2% 5/33 • Number of events 11 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	7.2% 5/69 • Number of events 7 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Dyspepsia	9.0% 6/67 • Number of events 8 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	18.2% 6/33 • Number of events 8 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.2% 2/32 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Frequent bowel movements	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Gastrooesophageal reflux disease	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.1% 2/33 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Gastrointestinal pain	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Haematochezia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Haemorrhoids	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Hyperchlorhydria	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Nausea	16.4% 11/67 • Number of events 11 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.1% 2/33 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.2% 2/32 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	7.2% 5/69 • Number of events 7 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Gastrointestinal disorders Vomiting	7.5% 5/67 • Number of events 5 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.1% 2/33 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	5.8% 4/69 • Number of events 6 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Chest discomfort	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	1.4% 1/69 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Chest pain	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	6.2% 2/32 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Fatigue	6.0% 4/67 • Number of events 6 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	9.4% 3/32 • Number of events 3 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	4.3% 3/69 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Oedema peripheral	7.5% 5/67 • Number of events 6 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	12.1% 4/33 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	12.5% 4/32 • Number of events 5 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	7.2% 5/69 • Number of events 6 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Pain	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Pyrexia	3.0% 2/67 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	5.8% 4/69 • Number of events 4 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders General physical health deterioration	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
General disorders Non-cardiac chest pain	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.1% 1/32 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/67 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	3.0% 1/33 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/69 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Infections and infestations Bronchitis	1.5% 1/67 • Number of events 1 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/33 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	0.00% 0/32 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.	2.9% 2/69 • Number of events 2 • All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.