Trial Outcomes & Findings for Efficacy and Safety of Riociguat in Incipient Pulmonary Vascular Disease as an Indicator for Early PAH (NCT NCT05339087)

NCT ID: NCT05339087

Last Updated: 2026-01-21

Results Overview

Change in pulmonary hemodynamics assessed by right heart catheterization

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

35 participants

Primary outcome timeframe

baseline, 24 weeks

Results posted on

2026-01-21

Participant Flow

Participants were recruited at 6 study centres between October 2022 and May 2025. The first participant was enrolled on 24 October 2022, the last on 30 May 2025.

Overall, 35 participants met the eligibility criteria and were randomized to treatment.

Participant milestones

Participant milestones
Measure	Riociguat Riociguat oral tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Overall Study STARTED	17	18
Overall Study Visit 2	13	14
Overall Study Visit 3	16	16
Overall Study COMPLETED	16	16
Overall Study NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Riociguat Riociguat oral tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Overall Study Withdrawal by Subject	1	1
Overall Study Early study termination	0	1

Baseline Characteristics

Systolic blood pressure mesurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Riociguat n=17 Participants Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily) The dose was individually adjusted in accordance with the in-label titration regimen based on the systemic blood pressure of the patient, the subjects and physicians' subjective estimation and occurrence of adverse reactions. At week 8, the maintenance dose was established and continued for the rest of the study treatment phase	Placebo n=18 Participants Placebo oral tablet matching riociguat: Sham titration and adjustment to maintenance dose according to individual tolerability as in the experimental arm.	Total n=35 Participants Total of all reporting groups
Age, Continuous	65.18 years STANDARD_DEVIATION 7.27 • n=17 Participants	65.89 years STANDARD_DEVIATION 6.64 • n=18 Participants	65.54 years STANDARD_DEVIATION 6.86 • n=35 Participants
Sex: Female, Male Female	17 Participants n=17 Participants	17 Participants n=18 Participants	34 Participants n=35 Participants
Sex: Female, Male Male	0 Participants n=17 Participants	1 Participants n=18 Participants	1 Participants n=35 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=17 Participants	0 Participants n=18 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Asian	1 Participants n=17 Participants	0 Participants n=18 Participants	1 Participants n=35 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=17 Participants	0 Participants n=18 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Black or African American	0 Participants n=17 Participants	0 Participants n=18 Participants	0 Participants n=35 Participants
Race (NIH/OMB) White	15 Participants n=17 Participants	18 Participants n=18 Participants	33 Participants n=35 Participants
Race (NIH/OMB) More than one race	0 Participants n=17 Participants	0 Participants n=18 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=17 Participants	0 Participants n=18 Participants	1 Participants n=35 Participants
Height	161.94 cm STANDARD_DEVIATION 7.28 • n=17 Participants	163.33 cm STANDARD_DEVIATION 8.14 • n=18 Participants	162.66 cm STANDARD_DEVIATION 7.67 • n=35 Participants
Weight	69.91 kg STANDARD_DEVIATION 10.9 • n=17 Participants	66.84 kg STANDARD_DEVIATION 11.64 • n=18 Participants	68.37 kg STANDARD_DEVIATION 11.20 • n=35 Participants
Duration of pulmonary hypertension (PH)	0.06 months STANDARD_DEVIATION 0.24 • n=17 Participants	0.56 months STANDARD_DEVIATION 1.65 • n=18 Participants	0.31 months STANDARD_DEVIATION 1.21 • n=35 Participants
Vital signs - Systolic blood pressure	132.25 mmHg STANDARD_DEVIATION 18.88 • n=16 Participants • Systolic blood pressure mesurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	119.50 mmHg STANDARD_DEVIATION 15.27 • n=16 Participants • Systolic blood pressure mesurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	125.88 mmHg STANDARD_DEVIATION 18.09 • n=32 Participants • Systolic blood pressure mesurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.
Vital signs - Diastolic blood pressure	77.13 mmHg STANDARD_DEVIATION 9.56 • n=16 Participants • Diastolic blood pressure measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	73.31 mmHg STANDARD_DEVIATION 9.25 • n=16 Participants • Diastolic blood pressure measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	75.22 mmHg STANDARD_DEVIATION 9.45 • n=32 Participants • Diastolic blood pressure measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.
Vial signs - Heart rate	75.69 beats/min STANDARD_DEVIATION 10.13 • n=16 Participants • Heart rate measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	73.44 beats/min STANDARD_DEVIATION 8.82 • n=16 Participants • Heart rate measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	74.56 beats/min STANDARD_DEVIATION 9.41 • n=32 Participants • Heart rate measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.
Vital signs - Peripheral Oxygen Saturation (SpO2)	97.25 percent STANDARD_DEVIATION 2.05 • n=16 Participants • SpO2 measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	96.56 percent STANDARD_DEVIATION 1.41 • n=16 Participants • SpO2 measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.	96.91 percent STANDARD_DEVIATION 1.77 • n=32 Participants • SpO2 measurements of 16 patients in the riociguat arm and 16 patients in the placebo arm were analysed. Values were missing for 2 patients in the placebo arm and one patient in the riociguat arm.
World Health Organization Functional Class (WHO FC) I	0 Participants n=17 Participants	1 Participants n=18 Participants	1 Participants n=35 Participants
World Health Organization Functional Class (WHO FC) II	16 Participants n=17 Participants	9 Participants n=18 Participants	25 Participants n=35 Participants
World Health Organization Functional Class (WHO FC) III	1 Participants n=17 Participants	8 Participants n=18 Participants	9 Participants n=35 Participants
World Health Organization Functional Class (WHO FC) IV	0 Participants n=17 Participants	0 Participants n=18 Participants	0 Participants n=35 Participants
Pulmonary hypertension (PH) Etiology Idiopathic	2 Participants n=17 Participants	6 Participants n=18 Participants	8 Participants n=35 Participants
Pulmonary hypertension (PH) Etiology Heritable	0 Participants n=17 Participants	0 Participants n=18 Participants	0 Participants n=35 Participants
Pulmonary hypertension (PH) Etiology CTD-associated	15 Participants n=17 Participants	11 Participants n=18 Participants	26 Participants n=35 Participants
Pulmonary hypertension (PH) Etiology other	0 Participants n=17 Participants	1 Participants n=18 Participants	1 Participants n=35 Participants
Concomitant diseases Treated arterial hypertension	12 Participants n=17 Participants	8 Participants n=18 Participants	20 Participants n=35 Participants
Concomitant diseases Dyslipidemia	6 Participants n=17 Participants	5 Participants n=18 Participants	11 Participants n=35 Participants
Concomitant diseases Treated coronary heart disease	1 Participants n=17 Participants	5 Participants n=18 Participants	6 Participants n=35 Participants
Concomitant diseases Diabetes mellitus	0 Participants n=17 Participants	2 Participants n=18 Participants	2 Participants n=35 Participants
Concomitant diseases Mild interstitial lung disease	2 Participants n=17 Participants	7 Participants n=18 Participants	9 Participants n=35 Participants
Concomitant diseases Mild obstructive lung disease	5 Participants n=17 Participants	3 Participants n=18 Participants	8 Participants n=35 Participants
Concomitant diseases Thyroid dysfunction	7 Participants n=17 Participants	5 Participants n=18 Participants	12 Participants n=35 Participants
Concomitant diseases Iron deficiency	5 Participants n=17 Participants	4 Participants n=18 Participants	9 Participants n=35 Participants
Concomitant diseases Oesophagus disease	4 Participants n=17 Participants	0 Participants n=18 Participants	4 Participants n=35 Participants
Concomitant diseases Degenerative bone disease	7 Participants n=17 Participants	5 Participants n=18 Participants	12 Participants n=35 Participants
Concomitant diseases Osteoporosis	2 Participants n=17 Participants	2 Participants n=18 Participants	4 Participants n=35 Participants
Concomitant diseases Autoimmune rheumatic diseases - Systemic Sclerosis (SSc)- limited cutaneous SSc	6 Participants n=17 Participants	4 Participants n=18 Participants	10 Participants n=35 Participants
Concomitant diseases Autoimmune rheumatic diseases - Systemic Sclerosis (SSc) - diffuse cutaneous SSc	0 Participants n=17 Participants	1 Participants n=18 Participants	1 Participants n=35 Participants
Concomitant diseases Autoimmune rheumatic diseases - Systemic Sclerosis (SSc) - other subtypes	6 Participants n=17 Participants	6 Participants n=18 Participants	12 Participants n=35 Participants
Concomitant diseases Autoimmune rheumatic diseases - Sjögren Syndrome	3 Participants n=17 Participants	1 Participants n=18 Participants	4 Participants n=35 Participants
Concomitant diseases Autoimmune rheumatic diseases - Mixed connective tissue disease	0 Participants n=17 Participants	2 Participants n=18 Participants	2 Participants n=35 Participants
Concomitant diseases Autoimmune rheumatic diseases - other	3 Participants n=17 Participants	2 Participants n=18 Participants	5 Participants n=35 Participants
Blood gas analysis - Saturation of Arterial Oxygen (SaO2)	95.70 percent STANDARD_DEVIATION 1.20 • n=12 Participants • SpO2 measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	95.97 percent STANDARD_DEVIATION 1.53 • n=14 Participants • SpO2 measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	95.74 percent STANDARD_DEVIATION 1.56 • n=26 Participants • SpO2 measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.
Blood gas analysis - Partial Pressure of Oxygen (PaO2)	75.57 mmHg STANDARD_DEVIATION 9.60 • n=12 Participants • PaO2 measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	79.02 mmHg STANDARD_DEVIATION 10.44 • n=14 Participants • PaO2 measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	78.88 mmHg STANDARD_DEVIATION 11.14 • n=26 Participants • PaO2 measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.
Blood gas analysis - Partial Pressure of Carbon Dioxide (PaCO2)	34.09 mmHg STANDARD_DEVIATION 4.54 • n=14 Participants • Diastolic blood pressure measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	36.37 mmHg STANDARD_DEVIATION 3.92 • n=12 Participants • Diastolic blood pressure measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	36.02 mmHg STANDARD_DEVIATION 2.92 • n=26 Participants • Diastolic blood pressure measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.
Blood gas analysis - pH	7.41 pH STANDARD_DEVIATION 0.01 • n=12 Participants • pH measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	7.43 pH STANDARD_DEVIATION 0.02 • n=14 Participants • pH measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.	7.42 pH STANDARD_DEVIATION 0.02 • n=26 Participants • pH measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm.
Blood gas analysis - bicarbonates	22.34 mmol/L STANDARD_DEVIATION 1.76 • n=12 Participants • Bicarbonate measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm	24.65 mmol/L STANDARD_DEVIATION 1.25 • n=14 Participants • Bicarbonate measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm	23.36 mmol/L STANDARD_DEVIATION 1.64 • n=26 Participants • Bicarbonate measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and 5 patients in the riociguat arm
Hemodynamics at rest - Right Arterial Pressure (RAP)	6.71 mmHg STANDARD_DEVIATION 3.12 • n=17 Participants	5.28 mmHg STANDARD_DEVIATION 2.85 • n=18 Participants	5.97 mmHg STANDARD_DEVIATION 3.02 • n=35 Participants
Hemodynamics at rest - Systolic Pulmonary Artery Pressure (sPAP)	36.88 mmHg STANDARD_DEVIATION 4.33 • n=17 Participants	36.61 mmHg STANDARD_DEVIATION 3.85 • n=18 Participants	36.74 mmHg STANDARD_DEVIATION 4.03 • n=35 Participants
Hemodynamics at rest - diastolic pulmonary artery pressure (dPAP)	15.47 mmHg STANDARD_DEVIATION 1.94 • n=17 Participants	14.44 mmHg STANDARD_DEVIATION 2.25 • n=18 Participants	14.94 mmHg STANDARD_DEVIATION 2.14 • n=35 Participants
Hemodynamics at rest - mean pulmonary arterial pressure (mPAP)	24.06 mmHg STANDARD_DEVIATION 2.56 • n=17 Participants	23.67 mmHg STANDARD_DEVIATION 2.87 • n=18 Participants	23.86 mmHg STANDARD_DEVIATION 2.69 • n=35 Participants
Hemodynamics at rest - pulmonary artery wedge pressure (PAWP)	9.83 mmHg STANDARD_DEVIATION 3.59 • n=17 Participants	10.18 mmHg STANDARD_DEVIATION 2.27 • n=18 Participants	10.00 mmHg STANDARD_DEVIATION 2.98 • n=35 Participants
Hemodynamics at rest - cardiac output (CO)	4.62 l/min STANDARD_DEVIATION 0.93 • n=17 Participants	4.70 l/min STANDARD_DEVIATION 1.06 • n=18 Participants	4.66 l/min STANDARD_DEVIATION 0.99 • n=35 Participants
Hemodynamics at rest - cardiac index (CI)	2.70 l/min/m2 STANDARD_DEVIATION 0.43 • n=17 Participants	2.74 l/min/m2 STANDARD_DEVIATION 0.64 • n=18 Participants	2.72 l/min/m2 STANDARD_DEVIATION 0.51 • n=35 Participants
Hemodynamics at rest - Pulmonary Vascular Resistance (PVR)	3.09 WU STANDARD_DEVIATION 0.85 • n=17 Participants	2.93 WU STANDARD_DEVIATION 0.59 • n=18 Participants	3.01 WU STANDARD_DEVIATION 0.73 • n=35 Participants
Hemodynamics at rest - Venous Oxygen Saturation (SVO2)	72.53 percent STANDARD_DEVIATION 11.24 • n=17 Participants	59.89 percent STANDARD_DEVIATION 5.9 • n=18 Participants	71.17 percent STANDARD_DEVIATION 8.87 • n=35 Participants
Six-minute walking distance (6MWD) test - 6MWD	431.13 m STANDARD_DEVIATION 53.24 • n=16 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	387.11 m STANDARD_DEVIATION 81.94 • n=18 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	407.82 m STANDARD_DEVIATION 72.42 • n=34 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Six-minute walking distance (6MWD) test - Peripheral Oxygen Saturation (SpO2) (test end)	87.94 percent STANDARD_DEVIATION 9.22 • n=16 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	89.39 percent STANDARD_DEVIATION 11.61 • n=18 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	88.71 percent STANDARD_DEVIATION 10.42 • n=34 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Six-minute walking distance (6MWD) test - Borg dyspnea score	3.53 scores on a scale STANDARD_DEVIATION 2.35 • n=16 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	2.69 scores on a scale STANDARD_DEVIATION 1.83 • n=18 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	3.09 scores on a scale STANDARD_DEVIATION 2.10 • n=34 Participants • 6MWD of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Physical functioning	59.38 scores on a scale STANDARD_DEVIATION 23.66 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	59.17 scores on a scale STANDARD_DEVIATION 23.28 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	59.26 scores on a scale STANDARD_DEVIATION 23.10 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Physical role function	48.44 scores on a scale STANDARD_DEVIATION 41.30 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	31.94 scores on a scale STANDARD_DEVIATION 56.10 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	39.71 scores on a scale STANDARD_DEVIATION 46.66 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Pain	63.56 scores on a scale STANDARD_DEVIATION 25.81 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	62.78 scores on a scale STANDARD_DEVIATION 20.83 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	63.15 scores on a scale STANDARD_DEVIATION 22.94 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Echocardiography at rest - Tricuspid Annular Plane Systolic Excursion (TAPSE)	2.37 cm STANDARD_DEVIATION 0.41 • n=17 Participants	2.30 cm STANDARD_DEVIATION 0.48 • n=18 Participants	2.33 cm STANDARD_DEVIATION 0.44 • n=35 Participants
Short Form-36 Health Survey - General health perception	51.88 scores on a scale STANDARD_DEVIATION 14.89 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	53.06 scores on a scale STANDARD_DEVIATION 23.67 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	52.50 scores on a scale STANDARD_DEVIATION 19.74 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Vitality	40.31 scores on a scale STANDARD_DEVIATION 19.01 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	46.11 scores on a scale STANDARD_DEVIATION 17.62 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	43.38 scores on a scale STANDARD_DEVIATION 18.25 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Social functioning	65.06 scores on a scale STANDARD_DEVIATION 26.59 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	72.39 scores on a scale STANDARD_DEVIATION 22.05 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	68.94 scores on a scale STANDARD_DEVIATION 24.20 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Lung function - Diffusion limited carbon monoxide (DLCO)	62.15 percent predicted STANDARD_DEVIATION 12.47 • n=13 Participants • DLCO measurements of 11 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 6 patients in the riociguat arm.	56.01 percent predicted STANDARD_DEVIATION 7.00 • n=11 Participants • DLCO measurements of 11 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 6 patients in the riociguat arm.	58.83 percent predicted STANDARD_DEVIATION 10.15 • n=24 Participants • DLCO measurements of 11 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 6 patients in the riociguat arm.
Short Form-36 Health Survey - Emotional role function	47.94 scores on a scale STANDARD_DEVIATION 47.12 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	38.89 scores on a scale STANDARD_DEVIATION 53.97 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	43.15 scores on a scale STANDARD_DEVIATION 50.30 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Mental well-being	63.50 scores on a scale STANDARD_DEVIATION 17.64 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	65.33 scores on a scale STANDARD_DEVIATION 15.70 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	64.47 scores on a scale STANDARD_DEVIATION 16.41 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Physical summation score	52.50 scores on a scale STANDARD_DEVIATION 20.19 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	50.56 scores on a scale STANDARD_DEVIATION 23.36 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	51.47 scores on a scale STANDARD_DEVIATION 21.62 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Short Form-36 Health Survey - Mental summation score	53.75 scores on a scale STANDARD_DEVIATION 18.92 • n=16 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	55.22 scores on a scale STANDARD_DEVIATION 19.44 • n=18 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.	54.53 scores on a scale STANDARD_DEVIATION 18.92 • n=34 Participants • The SF-36 survey of 16 patients in the riociguat arm and 18 patients in the placebo arm was analysed. Values were missing for 1 patient in the riociguat arm.
Echocardiography at rest - Estimated Systolic Pulmonary Artery Pressure (sPAP)	35.06 mmHg STANDARD_DEVIATION 7.58 • n=17 Participants • sPAP estimates of 17 patients in the riociguat arm and 16 patients in the placebo arm was analysed. Values were missing for 2 patients in the placebo arm.	31.94 mmHg STANDARD_DEVIATION 7.34 • n=16 Participants • sPAP estimates of 17 patients in the riociguat arm and 16 patients in the placebo arm was analysed. Values were missing for 2 patients in the placebo arm.	33.55 mmHg STANDARD_DEVIATION 7.52 • n=33 Participants • sPAP estimates of 17 patients in the riociguat arm and 16 patients in the placebo arm was analysed. Values were missing for 2 patients in the placebo arm.
Echocardiography at rest - right atrial (RA) area	12.47 cm2 STANDARD_DEVIATION 3.04 • n=17 Participants	13.56 cm2 STANDARD_DEVIATION 2.66 • n=18 Participants	13.03 cm2 STANDARD_DEVIATION 2.86 • n=35 Participants
Echocardiography at rest - right ventricular (RV) area	12.53 cm2 STANDARD_DEVIATION 2.85 • n=15 Participants • RV area measurements of 15 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 2 patients in the riociguat arm.	13.64 cm2 STANDARD_DEVIATION 2.65 • n=14 Participants • RV area measurements of 15 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 2 patients in the riociguat arm.	13.07 cm2 STANDARD_DEVIATION 2.76 • n=29 Participants • RV area measurements of 15 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 2 patients in the riociguat arm.
Echocardiography at rest - left ventricular eccentricity index (LV-EI)	1.64 index STANDARD_DEVIATION 2.41 • n=14 Participants • LV-EI of 15 patients in the riociguat arm and 14 patients in the placebo arm was analysed. Values were missing for 6 patients in the placebo arm and for 3 patients in the riociguat arm.	1.00 index STANDARD_DEVIATION 0.00 • n=12 Participants • LV-EI of 15 patients in the riociguat arm and 14 patients in the placebo arm was analysed. Values were missing for 6 patients in the placebo arm and for 3 patients in the riociguat arm.	1.35 index STANDARD_DEVIATION 1.77 • n=26 Participants • LV-EI of 15 patients in the riociguat arm and 14 patients in the placebo arm was analysed. Values were missing for 6 patients in the placebo arm and for 3 patients in the riociguat arm.
Echocardiography at rest - Left ventricular ejection fraction	62.82 percent STANDARD_DEVIATION 6.65 • n=17 Participants	65.28 percent STANDARD_DEVIATION 5.84 • n=18 Participants	64.09 percent STANDARD_DEVIATION 6.28 • n=35 Participants
Lung function - Forced Vital Capacity (FVC)	92.18 L STANDARD_DEVIATION 12.54 • n=12 Participants • FVC measurements of 12 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 5 patients in the riociguat arm.	88.80 L STANDARD_DEVIATION 16.22 • n=13 Participants • FVC measurements of 12 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 5 patients in the riociguat arm.	90.42 L STANDARD_DEVIATION 14.37 • n=25 Participants • FVC measurements of 12 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 5 patients in the riociguat arm.
Lung function - Forced expiratory volume in the first second (FEV1)	93.87 percent predicted STANDARD_DEVIATION 14.80 • n=12 Participants • FEV1 measurements of 12 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 5 patients in the riociguat arm.	90.90 percent predicted STANDARD_DEVIATION 15.74 • n=13 Participants • FEV1 measurements of 12 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 5 patients in the riociguat arm.	92.32 percent predicted STANDARD_DEVIATION 15.05 • n=25 Participants • FEV1 measurements of 12 patients in the riociguat arm and 13 patients in the placebo arm were analysed. Values were missing for 5 patients in the placebo arm and for 5 patients in the riociguat arm.
Lung function - total lung capacity (TLC)	96.71 percent (predicted) STANDARD_DEVIATION 11.68 • n=12 Participants • TLC measurements of 12 patients in the riociguat arm and 11 patients in the placebo arm were analysed. Values were missing for 7 patients in the placebo arm and for 5 patients in the riociguat arm.	87.45 percent (predicted) STANDARD_DEVIATION 11.97 • n=11 Participants • TLC measurements of 12 patients in the riociguat arm and 11 patients in the placebo arm were analysed. Values were missing for 7 patients in the placebo arm and for 5 patients in the riociguat arm.	92.28 percent (predicted) STANDARD_DEVIATION 12.48 • n=23 Participants • TLC measurements of 12 patients in the riociguat arm and 11 patients in the placebo arm were analysed. Values were missing for 7 patients in the placebo arm and for 5 patients in the riociguat arm.
Lung function - Residual volume	99.48 percent predicted STANDARD_DEVIATION 30.41 • n=11 Participants • Residual Volume measurements of 12 patients in the riociguat arm and 11 patients in the placebo arm were analysed. Values were missing for 7 patients in the placebo arm and for 5 patients in the riociguat arm.	88.54 percent predicted STANDARD_DEVIATION 21.67 • n=12 Participants • Residual Volume measurements of 12 patients in the riociguat arm and 11 patients in the placebo arm were analysed. Values were missing for 7 patients in the placebo arm and for 5 patients in the riociguat arm.	94.25 percent predicted STANDARD_DEVIATION 26.59 • n=23 Participants • Residual Volume measurements of 12 patients in the riociguat arm and 11 patients in the placebo arm were analysed. Values were missing for 7 patients in the placebo arm and for 5 patients in the riociguat arm.
Lung function - Diffusion limited carbon monoxide/alevolar volume (DLCO/VA)	67.15 percent predicted STANDARD_DEVIATION 10.25 • n=2 Participants • DLCO/VA of 2 patients in the riociguat arm and 5 patients in the placebo arm were analysed. Values were missing for 13 patients in the placebo arm and for 15 patients in the riociguat arm.	72.52 percent predicted STANDARD_DEVIATION 17.51 • n=5 Participants • DLCO/VA of 2 patients in the riociguat arm and 5 patients in the placebo arm were analysed. Values were missing for 13 patients in the placebo arm and for 15 patients in the riociguat arm.	70.99 percent predicted STANDARD_DEVIATION 15.12 • n=7 Participants • DLCO/VA of 2 patients in the riociguat arm and 5 patients in the placebo arm were analysed. Values were missing for 13 patients in the placebo arm and for 15 patients in the riociguat arm.
Laboratory - Hemoglobin	13.23 g/dl STANDARD_DEVIATION 1.81 • n=12 Participants • Hemoglobin measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	13.29 g/dl STANDARD_DEVIATION 0.71 • n=15 Participants • Hemoglobin measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	13.26 g/dl STANDARD_DEVIATION 1.29 • n=27 Participants • Hemoglobin measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.
Laboratory - Creatinine	0.73 mg/dl STANDARD_DEVIATION 0.15 • n=12 Participants • Creatinine measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	0.84 mg/dl STANDARD_DEVIATION 0.24 • n=15 Participants • Creatinine measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	0.79 mg/dl STANDARD_DEVIATION 0.21 • n=27 Participants • Creatinine measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.
Laboratory - Urea	25.82 mg/dl STANDARD_DEVIATION 6.68 • n=11 Participants • Urea measurements of 11 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 6 patients in the riociguat arm.	30.53 mg/dl STANDARD_DEVIATION 14.61 • n=15 Participants • Urea measurements of 11 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 6 patients in the riociguat arm.	28.54 mg/dl STANDARD_DEVIATION 11.96 • n=26 Participants • Urea measurements of 11 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 6 patients in the riociguat arm.
Laboratory - Uric acid	4.49 mg/dl STANDARD_DEVIATION 0.81 • n=11 Participants • Uric acid measurements of 11 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 6 patients in the riociguat arm.	4.93 mg/dl STANDARD_DEVIATION 2.10 • n=14 Participants • Uric acid measurements of 11 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 6 patients in the riociguat arm.	4.74 mg/dl STANDARD_DEVIATION 1.65 • n=25 Participants • Uric acid measurements of 11 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 6 patients in the riociguat arm.
Laboratory - Serum Glutamic Pyruvic Transaminase (SGPT)	18.25 U/L STANDARD_DEVIATION 15.22 • n=12 Participants • SGPT measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	22.27 U/L STANDARD_DEVIATION 13.74 • n=15 Participants • SGPT measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	20.48 U/L STANDARD_DEVIATION 14.28 • n=27 Participants • SGPT measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.
Laboratory - C-reactive protein (CRP)	3.27 mg/L STANDARD_DEVIATION 2.23 • n=12 Participants • CRP measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 5 patients in the riociguat arm.	6.15 mg/L STANDARD_DEVIATION 8.50 • n=14 Participants • CRP measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 5 patients in the riociguat arm.	4.82 mg/L STANDARD_DEVIATION 6.48 • n=26 Participants • CRP measurements of 12 patients in the riociguat arm and 14 patients in the placebo arm were analysed. Values were missing for 4 patients in the placebo arm and for 5 patients in the riociguat arm.
Laboratory - N-terminal prohormone of brain natriuretic peptide (NTproBNP)	331.08 pg/ml STANDARD_DEVIATION 361.44 • n=12 Participants • NTproBNP measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	316.73 pg/ml STANDARD_DEVIATION 342.13 • n=15 Participants • NTproBNP measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.	323.11 pg/ml STANDARD_DEVIATION 344.02 • n=27 Participants • NTproBNP measurements of 12 patients in the riociguat arm and 15 patients in the placebo arm were analysed. Values were missing for 3 patients in the placebo arm and for 5 patients in the riociguat arm.

PRIMARY outcome

Timeframe: baseline, 24 weeks

Population: All randomized participants were included in the analysis (intention-to-treat population). The number of analyzed paticipants may vary due to missing data for specific outcome measures. The per-protocol set is identical to the intention-to-treat set, as no major protocol deviations occurred and all participants met the predefined eligibility criteria.

Change in pulmonary hemodynamics assessed by right heart catheterization

Outcome measures

Outcome measures
Measure	Riociguat n=14 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=15 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change of Pulmonary Vascular Resistance (PVR)	-0.69 WU Standard Deviation 0.60	0.89 WU Standard Deviation 3.29

SECONDARY outcome

Timeframe: baseline, 24 weeks

Change in pulmonary hemodynamics assessed by right heart catheterization

Outcome measures

Outcome measures
Measure	Riociguat n=14 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=15 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change of Cardiac Index (CI) at Rest From Baseline at 24 Weeks	0.21 l/min/m2 Standard Deviation 0.54	-0.07 l/min/m2 Standard Deviation 0.40

SECONDARY outcome

Timeframe: baseline, 24 weeks

Change in Pulmonary hemodynamics assessed by right heart catheterization Hierarchical testing of secondary endpoints stopped after first step.

Outcome measures

Outcome measures
Measure	Riociguat n=14 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=15 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change of Total Pulmonary Resistance (TPR) From Baseline at 24 Weeks	0.51 mmHg·min/L Standard Deviation 1.18	-0.21 mmHg·min/L Standard Deviation 0.82

SECONDARY outcome

Timeframe: baseline, 24 weeks

Change assessed by lung function tests. Hierarchical testing of secondary endpoints stopped after first step.

Outcome measures

Outcome measures
Measure	Riociguat n=11 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=13 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change of Diffusion Capacity of the Lung (DLCO) From Baseline at 24 Weeks	1.16 percent predicted Standard Deviation 6.40	0.09 percent predicted Standard Deviation 7.40

SECONDARY outcome

Timeframe: baseline, 24 weeks

Change in exercise capacity assessed by 6-minute walking distance test Hierarchical testing of secondary endpoints stopped after first step.

Outcome measures

Outcome measures
Measure	Riociguat n=16 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=16 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in 6-minute Walking Distance (6MWD)	23 m Standard Deviation 56.41	24 m Standard Deviation 43.58

SECONDARY outcome

Timeframe: baseline, 24 weeks

Change of WHO functional class, change score The World Health Organization (WHO) functional class (FC) describes the severity of pulmonary hypertension (PH) symptoms. FC I is considered the mildest and FC IV the most severe form of PH.

Outcome measures

Outcome measures
Measure	Riociguat n=16 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=16 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 24 Weeks Improvement	2 Participants	3 Participants
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 24 Weeks Worsening	0 Participants	1 Participants
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 24 Weeks Unchanged	14 Participants	12 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 12 weeks

Population: All randomized participants were included in the analysis (intention-to-treat population). The number of analyzed paticipants may vary due to missing data for specific outcome measures.

Outcome measures

Outcome measures
Measure	Riociguat n=13 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=14 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 12 Weeks Improvement (-1)	0 Participants	3 Participants
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 12 Weeks Unchanged	12 Participants	11 Participants
Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 12 Weeks Worsening (+1)	1 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Quality of Life (QoL) was assessed using the Short Form (SF) 36-questionnaire. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale, i.e. a score of 0 is equivalent to maximum disability and a score of 100 is equivalent to no disability. Sections: vitality; physical functioning; bodily pain; general health perceptions; physical role functioning; emotional role functioning; social role functioning; mental health. Two summation scores, physical and mental summation score, were calculated

Outcome measures

Outcome measures
Measure	Riociguat n=15 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=15 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Quality of Life (QoL) From Baseline at 24 Weeks Emotional role function	15.53 scores on a scale Standard Deviation 48.59	40.13 scores on a scale Standard Deviation 58.02
Change in Quality of Life (QoL) From Baseline at 24 Weeks Physical functioning	4.00 scores on a scale Standard Deviation 15.38	2.00 scores on a scale Standard Deviation 21.61
Change in Quality of Life (QoL) From Baseline at 24 Weeks Physical role function	-5.00 scores on a scale Standard Deviation 34.33	31.67 scores on a scale Standard Deviation 53.00
Change in Quality of Life (QoL) From Baseline at 24 Weeks Pain	-1.33 scores on a scale Standard Deviation 19.35	9.53 scores on a scale Standard Deviation 22.51
Change in Quality of Life (QoL) From Baseline at 24 Weeks General health perception	-5.13 scores on a scale Standard Deviation 13.67	0.60 scores on a scale Standard Deviation 15.37
Change in Quality of Life (QoL) From Baseline at 24 Weeks Vitality	-1.67 scores on a scale Standard Deviation 14.47	5.33 scores on a scale Standard Deviation 16.09
Change in Quality of Life (QoL) From Baseline at 24 Weeks Social functioning	1.73 scores on a scale Standard Deviation 23.88	6.67 scores on a scale Standard Deviation 14.78
Change in Quality of Life (QoL) From Baseline at 24 Weeks Mental well-being	2.40 scores on a scale Standard Deviation 12.36	4.53 scores on a scale Standard Deviation 7.84
Change in Quality of Life (QoL) From Baseline at 24 Weeks Physical summation score	-1.67 scores on a scale Standard Deviation 11.89	9.73 scores on a scale Standard Deviation 18.39
Change in Quality of Life (QoL) From Baseline at 24 Weeks Mental summation score	2.60 scores on a scale Standard Deviation 16.97	11.33 scores on a scale Standard Deviation 14.32

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Lung function and lung diffusing capacity

Outcome measures

Outcome measures
Measure	Riociguat n=3 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=5 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Forced Expiratory Volume in 1 Second (FEV1) From Baseline at 24 Weeks	0.37 percent predicted Standard Deviation 2.09	1.04 percent predicted Standard Deviation 5.99

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Lung function and lung diffusing capacity

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=11 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Total Lung Capacity (TLC) From Baseline at 24 Weeks	-4.70 percent predicted Standard Deviation 12.66	-0.91 percent predicted Standard Deviation 8.78

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Lung function and lung diffusing capacity

Outcome measures

Outcome measures
Measure	Riociguat n=11 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=13 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Diffusing Capacity of the Lung (DLCO)	0.09 percent predicted Standard Deviation 7.40	1.16 percent predicted Standard Deviation 6.40

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in systolic pulmonary arterial pressure (sPAP) from baseline at 24 weeks assessed by echocardiography

Outcome measures

Outcome measures
Measure	Riociguat n=15 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=12 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Systolic Pulmonary Arterial Pressure (sPAP) From Baseline at 24 Weeks	-5.20 mmHg Standard Deviation 7.26	-3.42 mmHg Standard Deviation 7.06

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in right ventricular area (RV-area) from baseline at 24 weeks assessed by echocardiography

Outcome measures

Outcome measures
Measure	Riociguat n=15 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=12 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Right Ventricular Area (RV-area) From Baseline at 24 Weeks	0.00 cm2 Standard Deviation 2.51	-1.33 cm2 Standard Deviation 1.97

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in right atrial area (RA-area) from baseline at 24 weeks assessed by echocardiography

Outcome measures

Outcome measures
Measure	Riociguat n=16 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=16 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Right Atrial Area (RA-area) From Baseline at 24 Weeks	0.38 cm2 Standard Deviation 3.34	-0.68 cm2 Standard Deviation 2.27

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in tricuspid annular plane systolic excursion (TAPSE) from baseline at 24 weeks assessed by echocardiography

Outcome measures

Outcome measures
Measure	Riociguat n=16 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=16 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline at 24 Weeks	0.15 cm Standard Deviation 0.34	-0.08 cm Standard Deviation 0.58

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in left ventricular eccentricity index (LV-EI) from baseline at 24 weeks assessed by echocardiography. LV-EI is the ratio of septical-parallel to septical-perdendicular left ventricular diameters in parasternal short-axis view; normal = 1, increased (≥ 1.1) indicates right ventricular pressure/volume overload

Outcome measures

Outcome measures
Measure	Riociguat n=14 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=12 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Left Ventricular Eccentricity Index (LV-EI) From Baseline at 24 Weeks	-0.62 index Standard Deviation 2.41	0.00 index Standard Deviation 0.12

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 12 weeks

blood analysis

Outcome measures

Outcome measures
Measure	Riociguat n=9 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=11 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-pro BNP) From Baseline at 12 Weeks	-116,3333 pg/ml Standard Deviation 229,11951	-8,7273 pg/ml Standard Deviation 212,47545

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

blood analysis

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=14 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-pro BNP) From Baseline at 24 Weeks	-86.50 pg/ml Standard Deviation 246.40	-4.57 pg/ml Standard Deviation 251.30

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in oxygen partial pressure (PaO2) from baseline at 24 weeks assessed by blood gas analysis

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=13 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Oxygen Partial Pressure (PaO2) From Baseline at 24 Weeks	-2.83 mmHg Standard Deviation 7.99	-3.38 mmHg Standard Deviation 12.22

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

blood gas analysis

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=13 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Carbon Dioxide Partial Pressure (PCO2)	0.48 mmHg Standard Deviation 2.73	-0.83 mmHg Standard Deviation 3.75

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change oxygen saturation of the blood (SaO2) assessed by blood gas analysis

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=12 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change Oxygen Saturation of the Blood (SaO2)	-0.36 percent SaO2 Standard Deviation 1.08	-0.87 percent SaO2 Standard Deviation 3.58

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline,24 weeks

blood gas analysis

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=13 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in pH	0.01 pH Standard Deviation 0.03	0.00 pH Standard Deviation 0.03

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Population: All randomized participants were included in the analysis (intention-to-treat population). The number of analyzed paticipants may vary due to missing data for specific outcome measures.

blood gas analysis

Outcome measures

Outcome measures
Measure	Riociguat n=12 Participants Riociguat Oral Tablet: Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily): individually adjusted dose in accordance with the in-label titration regimen (maximum dosage of 2.5mg tid). At week 8, the maintenance dose was established and maintained for the rest of study participation.	Placebo n=13 Participants Placebo oral tablets: Sham titration and adjustment to maintenance dose (tid) according to individual tolerability as in the experimental arm.
Change in Bicarbonates	0.80 mmol/L Standard Deviation 1.63	-0.43 mmol/L Standard Deviation 1.44

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 24 weeks

Change in base excess assessed by blood gas analysis