Trial Outcomes & Findings for A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH. (NCT NCT00855465)

Last Updated: 2023-11-21

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

262 participants

Primary outcome timeframe

Baseline and week 16

Results posted on

2023-11-21

Participant Flow

Only subjects with symptomatic chronic thromboembolic pulmonary hypertension (CTEPH) could participate in this study. CTEPH was defined either as inoperable or as persisting or recurrent PH after pulmonary endarterectomy.

446 subjects were screened in 89 study centers in 26 countries worldwide. 184 of the 446 screened subjects were not randomized (adverse event \[1\], death \[4\], protocol violation \[164\], withdrawal by subject \[15\]). 262 of the 446 subjects were randomized. 261 of the 262 randomized subjects received study medication.

Participant milestones

Participant milestones
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration 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 16 weeks	Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Treatment Period STARTED	174	88
Treatment Period Participants Received Treatment	173	88
Treatment Period COMPLETED	160	83
Treatment Period NOT COMPLETED	14	5
Follow-up Period (FUP) STARTED	17	4
Follow-up Period (FUP) COMPLETED	9	2
Follow-up Period (FUP) NOT COMPLETED	8	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration 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 16 weeks	Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Treatment Period Adverse Event	4	2
Treatment Period Death	2	2
Treatment Period Lack of Efficacy	2	1
Treatment Period Non-compliance	1	0
Treatment Period Protocol Violation	2	0
Treatment Period Withdrawal by Subject	2	0
Treatment Period Not treated	1	0
Follow-up Period (FUP) Adverse Event	0	1
Follow-up Period (FUP) Death	0	1
Follow-up Period (FUP) Lost to Follow-up	3	0
Follow-up Period (FUP) Withdrawal by Subject	4	0
Follow-up Period (FUP) Missing	1	0

Baseline Characteristics

A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks	Total n=261 Participants Total of all reporting groups
Age, Continuous	59.3 Years STANDARD_DEVIATION 13.9 • n=5 Participants	59.2 Years STANDARD_DEVIATION 12.7 • n=7 Participants	59.3 Years STANDARD_DEVIATION 13.5 • n=5 Participants
Sex: Female, Male Female	118 Participants n=5 Participants	54 Participants n=7 Participants	172 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants	34 Participants n=7 Participants	89 Participants n=5 Participants
Race/Ethnicity, Customized White	120 Participants n=5 Participants	65 Participants n=7 Participants	185 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=5 Participants	1 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized Asian	37 Participants n=5 Participants	20 Participants n=7 Participants	57 Participants n=5 Participants
Race/Ethnicity, Customized Mixed	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Not reported	8 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants
Operability Inoperable CTEPH	121 Participants n=5 Participants	68 Participants n=7 Participants	189 Participants n=5 Participants
Operability Postoperative CTEPH	52 Participants n=5 Participants	20 Participants n=7 Participants	72 Participants n=5 Participants
Body Mass Index	27.13 kg/m^2 STANDARD_DEVIATION 5.75 • n=5 Participants	27.73 kg/m^2 STANDARD_DEVIATION 5.30 • n=7 Participants	27.33 kg/m^2 STANDARD_DEVIATION 5.60 • n=5 Participants
6-minute walking distance	342.3 Meters STANDARD_DEVIATION 81.9 • n=5 Participants	356.0 Meters STANDARD_DEVIATION 74.7 • n=7 Participants	346.9 Meters STANDARD_DEVIATION 79.7 • n=5 Participants
WHO (World Health Organization) functional class missing	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
WHO (World Health Organization) functional class I	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
WHO (World Health Organization) functional class II	55 Participants n=5 Participants	25 Participants n=7 Participants	80 Participants n=5 Participants
WHO (World Health Organization) functional class III	107 Participants n=5 Participants	60 Participants n=7 Participants	167 Participants n=5 Participants
WHO (World Health Organization) functional class IV	8 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants
Pulmonary vascular resistance	790.68 dynscm^-5 STANDARD_DEVIATION 431.57 • n=5 Participants	779.32 dynscm^-5 STANDARD_DEVIATION 400.94 • n=7 Participants	786.68 dynscm^-5 STANDARD_DEVIATION 420.21 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and week 16

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 participant's functional exercise capacity.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16	38.9 Meters Standard Deviation 79.3	-5.5 Meters Standard Deviation 84.3

SECONDARY outcome

Timeframe: Baseline and week 16

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)_individual Dose Titration n=151 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16	-225.68 dynscm^-5 Standard Deviation 247.52	23.07 dynscm^-5 Standard Deviation 273.53

SECONDARY outcome

Timeframe: Baseline and week 16

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)_individual Dose Titration n=150 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 16 weeks	Placebo n=73 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16	-290.69 pg/mL Standard Deviation 1716.90	76.35 pg/mL Standard Deviation 1446.63

SECONDARY outcome

Timeframe: Baseline and week 16

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 (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)_individual Dose Titration n=173 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 16 weeks	Placebo n=87 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 2	0.6 Percentage of Participants	3.4 Percentage of Participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 -2	2.3 Percentage of Participants	0 Percentage of Participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 -1	30.6 Percentage of Participants	14.9 Percentage of Participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 0	61.8 Percentage of Participants	78.2 Percentage of Participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 1	4.0 Percentage of Participants	3.4 Percentage of Participants
World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 3	0.6 Percentage of Participants	0 Percentage of Participants

SECONDARY outcome

Timeframe: At week 16

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; rescue endarterectomy; 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)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Percentage of Participants With Clinical Worsening Any Event	2.3 Percentage of participants	5.7 Percentage of participants
Percentage of Participants With Clinical Worsening Hospitalization due to pulmonary hypertension	0 Percentage of participants	1.1 Percentage of participants
Percentage of Participants With Clinical Worsening Start of new pulmonary hypertension	1.2 Percentage of participants	1.1 Percentage of participants
Percentage of Participants With Clinical Worsening Decrease in 6MWT due to pulmonary hypertension	0.6 Percentage of participants	2.3 Percentage of participants
Percentage of Participants With Clinical Worsening Persistant worsening of functional class due to PH	0 Percentage of participants	1.1 Percentage of participants
Percentage of Participants With Clinical Worsening Death	1.2 Percentage of participants	3.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and week 16

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)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Borg CR 10 Scale - Change From Baseline to Week 16	-0.83 Scores on a scale Standard Deviation 2.39	0.17 Scores on a scale Standard Deviation 2.42

SECONDARY outcome

Timeframe: Baseline and week 16

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)_individual Dose Titration n=172 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 16 weeks	Placebo n=87 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
EQ-5D Utility Score - Change From Baseline to Week 16	0.0615 Scores on a scale Standard Deviation 0.2768	-0.0819 Scores on a scale Standard Deviation 0.3446

SECONDARY outcome

Timeframe: Baseline and week 16

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)_individual Dose Titration n=170 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 16 weeks	Placebo n=86 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16	-6.72 Scores on a scale Standard Deviation 18.62	-2.09 Scores on a scale Standard Deviation 19.31

OTHER_PRE_SPECIFIED outcome

Timeframe: At visit 6 (week 16)

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

All cause mortality (including cardiovascular mortality) was one component of the composite endpoint "time to clinical worsening".

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
All Caused Mortality	2 Participants	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

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)_individual Dose Titration n=156 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 16 weeks	Placebo n=84 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16	-4.31 mmHg Standard Deviation 6.70	0.76 mmHg Standard Deviation 7.26

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

The cardiac index (CI) is a calculated hemodynamic parameter. CI is derived from the directly measured parameters cardiac output (CO), divided by the body surface area (BSA). BSA is a calculated parameter, using the subject's height and weight in the DuBois formula. Formula: BSA = (W \[kg\]\*0.425)\*(H \[cm\]\*0.725)\*0.007184 (m\^2)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=155 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 16 weeks	Placebo n=83 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Cardiac Index (CI) - Change From Baseline to Week 16	0.45 L/min/m^2 Standard Deviation 0.56	-0.01 L/min/m^2 Standard Deviation 0.58

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.

Systolic systemic arterial blood pressure (SBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 95 - 180 mmHg.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Systolic Blood Pressure (SBP) - Change From Baseline to Week 16	-10.49 mmHg Standard Deviation 14.17	-5.28 mmHg Standard Deviation 14.61

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.

Diastolic systemic arterial blood pressure (DBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: \<= 110 mmHg.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16	-8.17 mmHg Standard Deviation 10.81	-3.40 mmHg Standard Deviation 10.38

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.

Heart rate (HR) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 50 -105 beats per minute (bpm) at rest.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Heart Rate (HR) - Change From Baseline to Week 16	0.83 Beats/min Standard Deviation 11.74	1.67 Beats/min Standard Deviation 12.37

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Population: Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Alanine Aminotransferase (ALT) is a standard clinical chemistry parameter. Normal range: 0 to 45 U/L.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=161 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Alanine Aminotransferase (ALT) - Change From Baseline to Week 16	-1.2 U/L Standard Deviation 16.2	2.2 U/L Standard Deviation 13.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Aspartate Aminotransferase (AST) is a standard clinical chemistry parameter. Normal range: 0 to 41 U/L.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=160 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Aspartate Aminotransferase (AST) - Change From Baseline to Week 16	0.3 U/L Standard Deviation 14.4	2.8 U/L Standard Deviation 12.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Alkaline phosphatase (AP) is a standard clinical chemistry parameter. Normal range: 40 to 129 U/L (males), 35 to 104 U/L (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Alkaline Phosphatase (AP) - Change From Baseline to Week 16	-3.8 U/L Standard Deviation 19.4	2.5 U/L Standard Deviation 20.2

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Bilirubin is a standard clinical chemistry parameter. Normal range: 0.1 to 1.2 mg/dL

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Bilirubin - Change From Baseline to Week 16	0.010 mg/dL Standard Deviation 0.483	0.189 mg/dL Standard Deviation 0.453

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Creatinine is a standard clinical chemistry parameter. Normal range: 0.25 to 1.20 mg/dL (males), 0.46 to 1.00 mg/dL (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Creatinine - Change From Baseline to Week 16	0.003 mg/dL Standard Deviation 0.338	0.032 mg/dL Standard Deviation 0.178

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Creatinine clearance is a standard clinical chemistry parameter. Normal range: 90 to 140 mL/min (males), 80 to 125 mL/min (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Creatinine Clearance - Change From Baseline to Week 16	2.25 mL/min Standard Deviation 15.53	-0.93 mL/min Standard Deviation 11.36

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Creatine Kinase is a standard clinical chemistry parameter. Normal range: 35 to 232 U/L (males), 26 to 145 U/L (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Creatine Kinase (CK) - Change From Baseline to Week 16	7.9 U/L Standard Deviation 64.9	5.6 U/L Standard Deviation 65.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Erythrocytes (red blood cells, RBC) is a standard clinical hematology parameter. Normal range: 4.6 to 5.8\*10\^12 cells/L (males), 4.1 to 5.2\*10\^12 cells/L (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=155 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 16 weeks	Placebo n=81 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Erythrocytes (RBC) - Change From Baseline to Week 16	-0.14 *10^12 cells/L Standard Deviation 0.39	0.04 *10^12 cells/L Standard Deviation 0.31

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Leukocytes (white blood cells, WBC) is a standard clinical hematology parameter. Normal range: 4.0 to 10.7\*10\^9 cells/L

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=155 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 16 weeks	Placebo n=81 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Leukocytes (WBC) - Change From Baseline to Week 16	-0.55 *10^9 cells/L Standard Deviation 1.77	0.23 *10^9 cells/L Standard Deviation 1.69

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Total lymphocytes is a standard clinical hematology parameter. Normal range: 1.0 to 4.0\*10\^9 cells/L

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=154 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 16 weeks	Placebo n=79 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Lymphocytes - Change From Baseline to Week 16	-0.16 *10^9 cells/L Standard Deviation 0.48	0.00 *10^9 cells/L Standard Deviation 0.53

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Neutrophils is a standard clinical hematology parameter. Normal range: 1.6 to 7.4\*10\^9 cells/L

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=154 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 16 weeks	Placebo n=79 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Neutrophils - Change From Baseline to Week 16	-0.31 *10^9 cells/L Standard Deviation 1.55	0.26 *10^9 cells/L Standard Deviation 1.57

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Hemoglobin is a standard clinical hematology parameter. Normal range: 13.5 to 17.5 g/dL (males), 12.0 to 16.0 g/dL (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=155 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 16 weeks	Placebo n=81 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Hemoglobin - Change From Baseline to Week 16	-0.69 g/dL Standard Deviation 1.17	0.02 g/dL Standard Deviation 0.88

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Hematocrit is a standard clinical hematology parameter. Normal range: 40 to 52% (males), 36 to 46% (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=155 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 16 weeks	Placebo n=81 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Hematocrit - Change From Baseline to Week 16	-2.0 Volume percentage of red blood cells Standard Deviation 4.1	0.5 Volume percentage of red blood cells Standard Deviation 3.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Potassium is a standard clinical chemistry parameter. Normal range: 3.5 to 5.3 mmol/L

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=161 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Potassium - Change From Baseline to Week 16	-0.08 mmol/L Standard Deviation 0.48	-0.02 mmol/L Standard Deviation 0.56

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Urate is a standard clinical chemistry parameter. Normal range: 4.0 to 8.5 mg/dL (males, 16-59 years), 3.4 to 8.7 mg/dL (males, \>60 years) 2.5 to 7.5 mg/dL (females)

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Urate - Change From Baseline to Week 16	-0.405 mg/dL Standard Deviation 1.415	0.209 mg/dL Standard Deviation 1.577

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Urea (blood urea nitrogen, BUN) is a standard clinical chemistry parameter. Normal range: 4 to 25 mg/dL

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Urea (BUN) - Change From Baseline to Week 16	-0.60 mg/dL Standard Deviation 15.26	0.99 mg/dL Standard Deviation 13.62

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Cystatin C is a biomarker. Normal range: 0.53 to 1.01 ng/mL

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=139 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 16 weeks	Placebo n=66 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Cystatin C - Change From Baseline to Week 16	16.1 ng/ml Standard Deviation 241.1	62.9 ng/ml Standard Deviation 198.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Triacylglycerol lipase is a standard clinical chemistry parameter. Normal range: 7 to 60 U/L

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=82 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Triacylglycerol Lipase - Change From Baseline to Week 16	-4.2 U/L Standard Deviation 12.9	0.1 U/L Standard Deviation 17.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Arterial partial pressure of carbon dioxide (PaCO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=151 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 16 weeks	Placebo n=80 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16	0.34 mmHg Standard Deviation 4.05	0.56 mmHg Standard Deviation 4.52

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Arterial partial pressure of oxygen (PaO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=151 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 16 weeks	Placebo n=80 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16	-3.01 mmHg Standard Deviation 14.71	-4.95 mmHg Standard Deviation 12.05

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Oxygen saturation (SaO2) is measured as part of the capillary or arterial blood gas analysis. Normal blood oxygen saturation is considered 95-100 percent. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=151 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 16 weeks	Placebo n=79 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Oxygen Saturation (SaO2) - Change From Baseline to Week 16	-1.5 Percentage of oxygen saturation Standard Deviation 4.4	-3.1 Percentage of oxygen saturation Standard Deviation 8.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

PR duration was evaluated as part of the 12-lead electrocardiogram. electrocardiograms (ECGs) were recorded after the participant had been at rest for 15 minutes in a supine position.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=162 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 16 weeks	Placebo n=78 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean PR Duration (PRmean) - Change From Baseline to Week 16	-0.32 ms Standard Deviation 14.21	0.87 ms Standard Deviation 11.16

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

QRS duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=165 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 16 weeks	Placebo n=80 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean QRS Duration (QRSmean) - Change From Baseline to Week 16	-0.19 ms Standard Deviation 4.49	-0.05 ms Standard Deviation 4.30

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

QT duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=123 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 16 weeks	Placebo n=53 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean QT Duration (QTmean) - Change From Baseline to Week 16	1.19 ms Standard Deviation 24.89	-2.00 ms Standard Deviation 25.56

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Bazett-corrected QTcB duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=123 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 16 weeks	Placebo n=53 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16	-4.30 ms Standard Deviation 14.44	-0.51 ms Standard Deviation 15.58

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Fridericia-corrected QTcF duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=123 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 16 weeks	Placebo n=53 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16	-2.34 ms Standard Deviation 13.71	-1.02 ms Standard Deviation 13.29

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

RR duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=166 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 16 weeks	Placebo n=81 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean RR Duration (RRmean) - Change From Baseline to Week 16	3.89 ms Standard Deviation 132.02	-14.00 ms Standard Deviation 131.93

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and week 16

Ventricular rate was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position

Outcome measures

Outcome measures
Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=166 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 16 weeks	Placebo n=81 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16	-0.70 beats per minute (bpm) Standard Deviation 11.96	1.60 beats per minute (bpm) Standard Deviation 11.68

Adverse Events

Riociguat (Adempas, BAY63-2521)_individual Dose Titration

Serious events: 34 serious events

Other events: 146 other events

Deaths: 0 deaths

Placebo

Serious events: 14 serious events

Other events: 67 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

Measure	Riociguat (Adempas, BAY63-2521)_individual Dose Titration n=173 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 16 weeks	Placebo n=88 participants at risk Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Blood and lymphatic system disorders Anaemia	0.58% 1/173 • 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.	1.1% 1/88 • 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 Atrial fibrillation	0.58% 1/173 • 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% 0/88 • 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 Atrial flutter	0.58% 1/173 • 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.	1.1% 1/88 • 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 Atrial tachycardia	0.58% 1/173 • 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% 0/88 • 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 arrest	0.00% 0/173 • 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.	2.3% 2/88 • 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	0.58% 1/173 • 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% 0/88 • 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	3.5% 6/173 • 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.	3.4% 3/88 • 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 Sick sinus syndrome	0.58% 1/173 • 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% 0/88 • 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 Cardiopulmonary failure	0.00% 0/173 • 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.	1.1% 1/88 • 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 Chronic right ventricular failure	0.58% 1/173 • 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% 0/88 • 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 Duodenal ulcer	0.58% 1/173 • 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% 0/88 • 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 ulcer	0.00% 0/173 • 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.	1.1% 1/88 • 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% 2/173 • 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% 0/88 • 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 Intestinal obstruction	0.58% 1/173 • 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% 0/88 • 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	0.58% 1/173 • 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% 0/88 • 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 General physical health deterioration	0.58% 1/173 • 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% 0/88 • 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 due to cardiac disease	0.58% 1/173 • 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% 0/88 • 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 Catheter site haemorrhage	1.2% 2/173 • 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% 0/88 • 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	0.58% 1/173 • 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.	1.1% 1/88 • 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 Erysipelas	0.58% 1/173 • 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% 0/88 • 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	0.58% 1/173 • 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% 0/88 • 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% 0/173 • 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.	1.1% 1/88 • 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	0.58% 1/173 • 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% 0/88 • 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 Anal abscess	0.58% 1/173 • 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% 0/88 • 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 Fall	0.58% 1/173 • 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% 0/88 • 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 Head injury	0.58% 1/173 • 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% 0/88 • 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 Injury	0.00% 0/173 • 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.	1.1% 1/88 • 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	0.58% 1/173 • 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% 0/88 • 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 Light chain analysis increased	0.00% 0/173 • 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.	1.1% 1/88 • 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) Lung neoplasm malignant	0.58% 1/173 • 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% 0/88 • 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 Syncope	2.3% 4/173 • 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.	3.4% 3/88 • 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.
Psychiatric disorders Bipolar I disorder	0.00% 0/173 • 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.	1.1% 1/88 • 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.
Renal and urinary disorders Renal failure	0.58% 1/173 • 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% 0/88 • 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.
Renal and urinary disorders Renal failure acute	0.58% 1/173 • 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% 0/88 • 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.
Renal and urinary disorders Renal failure chronic	1.2% 2/173 • 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% 0/88 • 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.
Renal and urinary disorders Renal impairment	0.00% 0/173 • 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.	1.1% 1/88 • 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.
Reproductive system and breast disorders Vaginal haemorrhage	0.58% 1/173 • 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% 0/88 • 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.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.58% 1/173 • 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% 0/88 • 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.58% 1/173 • 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.	1.1% 1/88 • 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.
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.58% 1/173 • 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% 0/88 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.58% 1/173 • 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.	1.1% 1/88 • 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.
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.7% 3/173 • 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% 0/88 • 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.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.58% 1/173 • 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% 0/88 • 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.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	1.2% 2/173 • 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% 0/88 • 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.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.2% 2/173 • 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% 0/88 • 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.
Vascular disorders Hypotension	0.58% 1/173 • 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% 0/88 • 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.
Vascular disorders Deep vein thrombosis	0.00% 0/173 • 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.	1.1% 1/88 • 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.