Trial Outcomes & Findings for A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PAH) (NCT NCT00810693)

NCT ID: NCT00810693

Last Updated: 2023-11-22

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

445 participants

Primary outcome timeframe

Baseline and week 12

Results posted on

2023-11-22

Participant Flow

Only participants with symptomatic Pulmonary arterial hypertension (PAH) could participate in this study. Both treatment-naïve participants and participants pre-treated with an endothelin receptor antagonist or a non-intravenous prostacyclin analogue could be included.

586 participants were enrolled in 124 study centers in 30 countries worldwide. 141 of the 586 enrolled participants were not randomized (adverse event \[4\], protocol violation \[129\], withdrawal by subject \[8\]). 445 of the 586 participants were randomized. 443 of the 445 randomized participants received study medication.

Participant milestones

Participant milestones
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Treatment Period STARTED	254	64	127
Treatment Period Participants Received Treatment	254	63	126
Treatment Period COMPLETED	237	57	111
Treatment Period NOT COMPLETED	17	7	16
Follow-up Period (FUP) STARTED	23	7	16
Follow-up Period (FUP) COMPLETED	15	4	12
Follow-up Period (FUP) NOT COMPLETED	8	3	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Treatment Period Adverse Event	8	1	7
Treatment Period Death	0	1	2
Treatment Period Lack of Efficacy	0	0	1
Treatment Period Lost to Follow-up	1	0	0
Treatment Period Non-compliance	1	0	0
Treatment Period Protocol Violation	1	2	2
Treatment Period Withdrawal by Subject	6	2	3
Treatment Period Not treated	0	1	1
Follow-up Period (FUP) Adverse Event	3	1	1
Follow-up Period (FUP) Death	2	0	1
Follow-up Period (FUP) Lost to Follow-up	1	0	2
Follow-up Period (FUP) Protocol Violation	0	1	0
Follow-up Period (FUP) Withdrawal by Subject	2	1	0

Baseline Characteristics

A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PAH)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=254 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=126 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks	Total n=443 Participants Total of all reporting groups
Age, Continuous	51.1 Years STANDARD_DEVIATION 16.6 • n=5 Participants	48.8 Years STANDARD_DEVIATION 16.1 • n=7 Participants	50.7 Years STANDARD_DEVIATION 16.5 • n=5 Participants	50.6 Years STANDARD_DEVIATION 16.5 • n=4 Participants
Sex: Female, Male Female	203 Participants n=5 Participants	49 Participants n=7 Participants	98 Participants n=5 Participants	350 Participants n=4 Participants
Sex: Female, Male Male	51 Participants n=5 Participants	14 Participants n=7 Participants	28 Participants n=5 Participants	93 Participants n=4 Participants
Race/Ethnicity, Customized White	161 Participants n=5 Participants	33 Participants n=7 Participants	78 Participants n=5 Participants	272 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	4 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants
Race/Ethnicity, Customized Asian	79 Participants n=5 Participants	22 Participants n=7 Participants	38 Participants n=5 Participants	139 Participants n=4 Participants
Race/Ethnicity, Customized Mixed	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Not reported	9 Participants n=5 Participants	7 Participants n=7 Participants	8 Participants n=5 Participants	24 Participants n=4 Participants
Prior PH therapy Therapy-Naive	123 Participants n=5 Participants	32 Participants n=7 Participants	66 Participants n=5 Participants	221 Participants n=4 Participants
Prior PH therapy Pre-Treated	131 Participants n=5 Participants	31 Participants n=7 Participants	60 Participants n=5 Participants	222 Participants n=4 Participants
pre-treated with endothelin receptor antagonist Yes	113 Participants n=5 Participants	27 Participants n=7 Participants	54 Participants n=5 Participants	194 Participants n=4 Participants
pre-treated with endothelin receptor antagonist No	141 Participants n=5 Participants	36 Participants n=7 Participants	72 Participants n=5 Participants	249 Participants n=4 Participants
pre-treated with prostacyclin analogue Yes	20 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	31 Participants n=4 Participants
pre-treated with prostacyclin analogue No	234 Participants n=5 Participants	59 Participants n=7 Participants	119 Participants n=5 Participants	412 Participants n=4 Participants
PAH subtype Idiopathic PAH	149 Participants n=5 Participants	39 Participants n=7 Participants	84 Participants n=5 Participants	272 Participants n=4 Participants
PAH subtype Familial PAH	7 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	9 Participants n=4 Participants
PAH subtype Connective tissue disease assoc. PAH	71 Participants n=5 Participants	15 Participants n=7 Participants	25 Participants n=5 Participants	111 Participants n=4 Participants
PAH subtype Congenital heart disease (operated) assoc. PAH	15 Participants n=5 Participants	8 Participants n=7 Participants	12 Participants n=5 Participants	35 Participants n=4 Participants
PAH subtype Portal Pulmonary hypertension	11 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	13 Participants n=4 Participants
PAH subtype Anorexigen or Amphtamin assoc: PAH	1 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants
BMI	25.91 kg/m^2 STANDARD_DEVIATION 5.48 • n=5 Participants	26.85 kg/m^2 STANDARD_DEVIATION 5.35 • n=7 Participants	26.26 kg/m^2 STANDARD_DEVIATION 5.92 • n=5 Participants	26.14 kg/m^2 STANDARD_DEVIATION 5.59 • n=4 Participants
Baseline 6MWD	361.4 meters STANDARD_DEVIATION 67.7 • n=5 Participants	363.2 meters STANDARD_DEVIATION 66.6 • n=7 Participants	367.8 meters STANDARD_DEVIATION 74.6 • n=5 Participants	363.5 meters STANDARD_DEVIATION 69.5 • n=4 Participants
WHO (World Health Organization) functional class I	5 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	14 Participants n=4 Participants
WHO (World Health Organization) functional class II	108 Participants n=5 Participants	19 Participants n=7 Participants	60 Participants n=5 Participants	187 Participants n=4 Participants
WHO (World Health Organization) functional class III	140 Participants n=5 Participants	39 Participants n=7 Participants	58 Participants n=5 Participants	237 Participants n=4 Participants
WHO (World Health Organization) functional class IV	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
WHO (World Health Organization) functional class missing	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Pulmonary vascular resistance	790.96 dnscm^-5 STANDARD_DEVIATION 452.60 • n=5 Participants	847.81 dnscm^-5 STANDARD_DEVIATION 548.17 • n=7 Participants	834.06 dnscm^-5 STANDARD_DEVIATION 476.71 • n=5 Participants	810.89 dnscm^-5 STANDARD_DEVIATION 473.45 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline and week 12

Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.

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 2.5 mg_IDT n=254 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=126 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 12	29.6 Meters Standard Deviation 65.8	31.1 Meters Standard Deviation 79.3	-5.6 Meters Standard Deviation 85.5

SECONDARY outcome

Timeframe: Baseline and week 12

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 of PVR.

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 2.5 mg_IDT n=232 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=58 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=107 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 12	-223.29 dynscm^-5 Standard Deviation 260.09	-167.79 dynscm^-5 Standard Deviation 320.22	-8.89 dynscm^-5 Standard Deviation 316.57

SECONDARY outcome

Timeframe: Baseline and week 12

N-terminal pro-brain natriuretic peptide (NT-proBNP) 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 2.5 mg_IDT n=228 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=54 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=106 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 12	-197.89 pg/mL Standard Deviation 1721.29	-471.50 pg/mL Standard Deviation 913.02	232.39 pg/mL Standard Deviation 1011.09

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Participants with a missing baseline were excluded from the analysis of WHO functional class.

The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (participants with PH but without resulting limitation of physical activity) to class IV (participants with PH with inability to carry out any physical activity without symptoms. These participants 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 2.5 mg_IDT n=254 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=125 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
World Health Organization (WHO) Functional Class - Change From Baseline to Week 12 -2	0.4 Percentage of participants	0 Percentage of participants	0 Percentage of participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 12 -1	20.5 Percentage of participants	23.8 Percentage of participants	14.4 Percentage of participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 12 0	75.6 Percentage of participants	68.3 Percentage of participants	71.2 Percentage of participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 12 1	2.8 Percentage of participants	6.3 Percentage of participants	12.0 Percentage of participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 12 2	0.4 Percentage of participants	1.6 Percentage of participants	2.4 Percentage of participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 12 3	0.4 Percentage of participants	0 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: At week 12

Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.

The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all-cause mortality; heart/lung transplantation; atrial septostomy; first hospitalization due to pulmonary hypertension; start of a new pulmonary hypertension treatment; persistent worsening of 6MWD or WHO functional class due to deterioration of PH .

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=254 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=126 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Percentage of Participants With Clinical Worsening Any event	1.2 Percentage of participants	3.2 Percentage of participants	6.3 Percentage of participants
Percentage of Participants With Clinical Worsening Hospitalization due to pulmonary hypertension	0.4 Percentage of participants	0 Percentage of participants	3.2 Percentage of participants
Percentage of Participants With Clinical Worsening Start of new pulmonary hypertension treatment	0.4 Percentage of participants	1.6 Percentage of participants	4.0 Percentage of participants
Percentage of Participants With Clinical Worsening Decrease in 6MWT due to pulmonary hypertension	0.4 Percentage of participants	1.6 Percentage of participants	1.6 Percentage of participants
Percentage of Participants With Clinical Worsening Persistant worsening of functional class due to PH	0 Percentage of participants	0 Percentage of participants	0.8 Percentage of participants
Percentage of Participants With Clinical Worsening Death	0.8 Percentage of participants	1.6 Percentage of participants	2.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered.

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

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=254 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=126 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Borg CR 10 Scale - Change From Baseline to Week 12	-0.44 Scores on a scale Standard Deviation 1.72	-0.33 Scores on a scale Standard Deviation 1.47	0.09 Scores on a scale Standard Deviation 2.05

SECONDARY outcome

Timeframe: Baseline and week 12

EQ-5D utility score is a Quality-of-Life participant reported outcome measure. The utility score is calculated based on five questions concerning problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression. An increase in the utility score represents an improvement in quality of life. The score ranges from -0.594 (worst answer in all five questions) to 1 (best answer in all five questions).

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=253 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=62 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=124 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
EQ-5D Utility Score - Change From Baseline to Week 12	0.0329 Scores on a scale Standard Deviation 0.2350	0.0782 Scores on a scale Standard Deviation 0.3111	-0.0317 Scores on a scale Standard Deviation 0.3044

SECONDARY outcome

Timeframe: Baseline and week 12

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

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=247 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=62 Participants Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=122 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 12	-5.99 Scores on a scale Standard Deviation 17.76	-10.21 Scores on a scale Standard Deviation 21.27	0.36 Scores on a scale Standard Deviation 18.15

Adverse Events

Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT

Serious events: 29 serious events

Other events: 216 other events

Deaths: 0 deaths

Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT

Serious events: 11 serious events

Other events: 57 other events

Deaths: 0 deaths

Placebo

Serious events: 23 serious events

Other events: 96 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 embargo can be up to 6 months (equal to the 180 days), moreover if it is necessary the embargo period can be prolonged to expiry of priority year.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=254 participants at risk Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 participants at risk Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=126 participants at risk Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Blood and lymphatic system disorders Anaemia	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Atrioventricular block	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Cardiac failure	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Cardiomegaly	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Right ventricular failure	0.79% 2/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 3/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Supraventricular tachycardia	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Eye disorders Retinal artery occlusion	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Abdominal pain	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Diarrhoea	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Gastritis	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Haematemesis	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Irritable bowel syndrome	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Intra-abdominal haemorrhage	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Asthenia	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Chest pain	0.79% 2/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Pyrexia	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Bronchitis	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Bronchopneumonia	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Diarrhoea infectious	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Encephalitis herpes	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Gastroenteritis	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Infection	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Influenza	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Pneumonia	0.79% 2/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Sepsis	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Tooth infection	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Enterocolitis infectious	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Mycoplasma infection	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Respiratory tract infection	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Injury, poisoning and procedural complications Muscle rupture	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Injury, poisoning and procedural complications Overdose	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Injury, poisoning and procedural complications Subdural haematoma	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Investigations Catheterisation cardiac	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Investigations Electrocardiogram ST-T segment abnormal	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Investigations Hepatic enzyme increased	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Metabolism and nutrition disorders Dehydration	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic malignant melanoma	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Nervous system disorders Dizziness	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Nervous system disorders Loss of consciousness	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Nervous system disorders Presyncope	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.

Other adverse events
Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=254 participants at risk Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT n=63 participants at risk Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Placebo n=126 participants at risk Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Blood and lymphatic system disorders Anaemia	7.9% 20/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Palpitations	7.9% 20/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	7.9% 5/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 6/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Cardiac disorders Tachycardia	3.5% 9/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	5.6% 7/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Abdominal discomfort	2.8% 7/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Abdominal distension	2.4% 6/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Abdominal pain	3.5% 9/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Abdominal pain upper	3.5% 9/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.0% 5/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Constipation	3.5% 9/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 3/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 2/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Diarrhoea	13.8% 35/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	9.5% 6/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	9.5% 12/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Dyspepsia	18.9% 48/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	12.7% 8/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	7.9% 10/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Gastric polyps	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Gastritis	1.2% 3/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	6.3% 4/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.5% 14/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	6.3% 4/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 4/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Nausea	15.7% 40/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	15.9% 10/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	12.7% 16/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Gastrointestinal disorders Vomiting	10.2% 26/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	11.1% 7/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	8.7% 11/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Asthenia	2.4% 6/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 2/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Chest discomfort	2.4% 6/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	6.3% 4/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	8.7% 11/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Chest pain	6.3% 16/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	6.3% 4/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	7.9% 10/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Face oedema	2.0% 5/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 4/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Fatigue	2.8% 7/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	6.3% 8/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Feeling hot	0.79% 2/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Oedema	3.1% 8/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 2/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Oedema peripheral	17.3% 44/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	22.2% 14/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	11.1% 14/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
General disorders Pyrexia	2.8% 7/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	9.5% 6/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 4/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Bronchitis	3.1% 8/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 3/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Gastroenteritis	2.8% 7/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Nasopharyngitis	10.2% 26/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	9.5% 6/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	11.1% 14/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Oral candidiasis	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Upper respiratory tract infection	2.8% 7/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.0% 5/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Urinary tract infection	1.2% 3/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 4/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Infections and infestations Respiratory tract infection	2.8% 7/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.0% 5/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Investigations Activated partial thromboplastin time prolonged	1.2% 3/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Investigations Haemoglobin decreased	0.00% 0/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 3/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Investigations International normalised ratio increased	2.4% 6/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.0% 5/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Metabolism and nutrition disorders Hyperuricaemia	0.79% 2/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 2/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.79% 1/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Metabolism and nutrition disorders Hypokalaemia	4.7% 12/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 3/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 6/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Metabolism and nutrition disorders Iron deficiency	0.39% 1/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Metabolism and nutrition disorders Decreased appetite	2.0% 5/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	1.6% 1/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Musculoskeletal and connective tissue disorders Arthralgia	3.1% 8/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	0.00% 0/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	2.4% 3/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Musculoskeletal and connective tissue disorders Back pain	3.5% 9/254 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	4.8% 3/63 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.	3.2% 4/126 • Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.