Trial Outcomes & Findings for Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters. (NCT NCT01179334)

NCT ID: NCT01179334

Last Updated: 2016-08-29

Results Overview

Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: \<= 180 mmHg. In addition, SBP must be \>=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 18 participants
• Primary outcome timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
• Results posted on: 2016-08-29

Participant Flow

Only participants with symptomatic Pulmonary arterial hypertension (PAH) could participate in this study. Subjects must be on pre-treatment with sildenafil at a dose of 20 mg three times daily (tid) (20 or 25 mg tid in New Zealand) for at least 90 days.

24 subjects were enrolled in 11 study centers in 5 European countries. Six of the 24 subjects were screened but not randomized (screen failure [6]). 18 of the 24 participants were randomized. All of the 18 randomized participants received study medication.

Participant milestones

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Treatment Period STARTED	12	6
Treatment Period Participants Received Treatment	12	6
Treatment Period COMPLETED	11	6
Treatment Period NOT COMPLETED	1	0
Long-term Extension (LTE) Period STARTED	11	6
Long-term Extension (LTE) Period COMPLETED	0	0
Long-term Extension (LTE) Period NOT COMPLETED	11	6

Reasons for withdrawal

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Treatment Period Adverse Event	1	0
Long-term Extension (LTE) Period Study terminated by sponsor	6	2
Long-term Extension (LTE) Period Death	3	0
Long-term Extension (LTE) Period Adverse Event	2	4

Baseline Characteristics

Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters.

Baseline characteristics by cohort

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=12 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=6 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Total n=18 Participants Total of all reporting groups
Age, Continuous	58.3 Years STANDARD_DEVIATION 10.7 • n=5 Participants	61.3 Years STANDARD_DEVIATION 10.0 • n=7 Participants	59.3 Years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: pharmacodynamic(s) (PD) analysis set

Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: <= 180 mmHg. In addition, SBP must be >=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Maximum Change From Baseline in Supine Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12)	-20.70 mmHg Standard Deviation 17.97	-20.20 mmHg Standard Deviation 12.91

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: <= 180 mmHg. In addition, SBP must be >=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Maximum Change From Baseline in Standing Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12)	-18.00 mmHg Standard Deviation 16.50	-16.80 mmHg Standard Deviation 10.62

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

Diastolic blood pressure (DBP) was measured as standard vital sign parameter. Range allowed in this study: <= 110 mmHg. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent DBP measurements in that profile) within 4 hours post-dose. Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Maximum Change From Baseline in Supine Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12)	-13.70 mmHg Standard Deviation 11.72	-13.80 mmHg Standard Deviation 12.85

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

Diastolic blood pressure (DBP) was measured as standard vital sign parameter. Range allowed in this study: <= 110 mmHg. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent DBP measurements in that profile) within 4 hours post-dose. Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Maximum Change From Baseline in Standing Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12)	-14.40 mmHg Standard Deviation 10.59	-14.20 mmHg Standard Deviation 10.03

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

Heart rate (HR) was measured as standard vital sign parameter. Range allowed in this study: <= 105 beats per minute (bpm) in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum increase from baseline (or zero if baseline was higher than all subsequent HR measurements in that profile) within 4 hours post-dose. Baseline was the last HR recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Maximum Change From Baseline in Supine Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12)	5.90 Beats/min Standard Deviation 7.14	9.60 Beats/min Standard Deviation 5.50

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

Heart rate (HR) was measured as standard vital sign parameter. Range allowed in this study: <= 105 beats per minute (bpm) in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum increase from baseline (or zero if baseline was higher than all subsequent HR measurements in that profile) within 4 hours post-dose. Baseline was the last HR recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Maximum Change From Baseline in Standing Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12)	6.50 Beats/min Standard Deviation 7.17	10.40 Beats/min Standard Deviation 6.54

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

The area under the effect curve (AUEC) at each visit of supine SBP describes an average within-subject change in SBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Area Under Effect Curve (AUEC) of Supine SBP Within 4 Hours Post-dose at Visit 6 (Week 12)	46.32 mmHg*h Standard Deviation 53.57	42.44 mmHg*h Standard Deviation 28.19

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

The area under effect curve (AUEC) at each visit of standing SBP describes an average within-subject change in SBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Area Under Effect Curve (AUEC) of Standing SBP Within 4 Hours Post-dose at Visit 6 (Week 12)	38.96 mmHg*h Standard Deviation 47.51	30.41 mmHg*h Standard Deviation 33.35

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

The area under effect curve (AUEC) at each visit of supine DBP describes an average within-subject change in DBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Area Under Effect Curve (AUEC) of Supine DBP Within 4 Hours Post-dose at Visit 6 (Week 12)	30.79 mmHg*h Standard Deviation 35.66	32.92 mmHg*h Standard Deviation 35.68

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

The area under effect curve (AUEC) at each visit of standing DBP describes an average within-subject change in DBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Area Under Effect Curve (AUEC) of Standing DBP Within 4 Hours Post-dose at Visit 6 (Week 12)	32.50 mmHg*h Standard Deviation 34.04	24.20 mmHg*h Standard Deviation 22.54

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

The area under effect curve (AUEC) at each visit of supine HR describes an average within-subject change in HR from baseline over a time-period of 4 hours post-dose (Note that the area only takes values above the individual baseline for the respective visit into account. The area that would result from a decrease from baseline is not taken into account for the calculation of the area). Baseline was the last HR recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Area Under Effect Curve (AUEC) of Supine HR Within 4 Hours Post-dose at Visit 6 (Week 12)	9.86 Beats/min*h Standard Deviation 13.08	18.85 Beats/min*h Standard Deviation 14.86

SECONDARY outcome

Timeframe: Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Population: PD analysis set

The area under effect curve (AUEC) at each visit of standing HR describes an average within-subject increase in HR from baseline over a time-period of 4 hours post-dose (Note that the area only takes values above the individual baseline for the respective visit into account. The area that would result from a decrease from baseline is not taken into account for the calculation of the area). Baseline was the last HR recorded at and within 30 minutes before intake of study drug.

Outcome measures

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=10 Participants Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=5 Participants Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Area Under Effect Curve (AUEC) of Standing HR Within 4 Hours Post-dose at Visit 6 (Week 12)	13.18 Beats/min*h Standard Deviation 15.11	15.69 Beats/min*h Standard Deviation 11.81

Adverse Events

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

Serious events: 7 serious events

Other events: 12 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=12 participants at risk Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=6 participants at risk Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Cardiac disorders Angina pectoris	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Atrial fibrillation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Cardiac arrest	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Right ventricular failure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Acute right ventricular failure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Chronic right ventricular failure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Colitis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Constipation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Erysipelas	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Pneumonia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Joint dislocation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Subdural haematoma	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Nervous system disorders Loss of consciousness	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Nervous system disorders Syncope	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Hypoxia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Vascular disorders Hypotension	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.

Other adverse events

Measure	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT n=12 participants at risk Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.	Placebo n=6 participants at risk Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.
Blood and lymphatic system disorders Anaemia	25.0% 3/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Blood and lymphatic system disorders Lymphadenopathy	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Atrial fibrillation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Palpitations	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	33.3% 2/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Cardiac disorders Chronic right ventricular failure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Ear and labyrinth disorders Vertigo	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Endocrine disorders Hypothyroidism	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Eye disorders Eye swelling	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Eye disorders Eyelid oedema	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Eye disorders Vision blurred	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Abdominal pain	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Anal fissure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Constipation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Diarrhoea	25.0% 3/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Dry mouth	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Dyspepsia	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	50.0% 3/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Flatulence	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Gastritis	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Gastrooesophageal reflux disease	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Hiatus hernia	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Mouth ulceration	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Nausea	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Rectal haemorrhage	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Tongue ulceration	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Vomiting	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	33.3% 2/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Epigastric discomfort	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Gastrointestinal disorders Regurgitation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Asthenia	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Chest discomfort	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Chills	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Fatigue	25.0% 3/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Oedema	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Oedema peripheral	58.3% 7/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Pyrexia	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
General disorders Inflammation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Bronchitis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Erysipelas	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Gastroenteritis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Influenza	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Nasopharyngitis	25.0% 3/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Periodontitis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Sialoadenitis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Pharyngotonsillitis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Peritonitis bacterial	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Infections and infestations Oral herpes	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Fall	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Subcutaneous haematoma	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Contusion	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Injury, poisoning and procedural complications Meniscus injury	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Alanine aminotransferase increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Alpha 1 foetoprotein increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Aspartate aminotransferase increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood bilirubin increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood cholinesterase decreased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood creatine phosphokinase increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood creatinine increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood lactate dehydrogenase increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood potassium decreased	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	33.3% 2/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood pressure systolic decreased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Electrocardiogram QT prolonged	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Gamma-glutamyltransferase increased	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Glomerular filtration rate decreased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Lymphocyte count decreased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Neutrophil count increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Weight decreased	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Glutamate dehydrogenase increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Investigations Blood alkaline phosphatase increased	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Metabolism and nutrition disorders Hypoglycaemia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Metabolism and nutrition disorders Hypokalaemia	33.3% 4/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Metabolism and nutrition disorders Hypomagnesaemia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Metabolism and nutrition disorders Hyponatraemia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Metabolism and nutrition disorders Iron deficiency	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Arthralgia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Arthritis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Back pain	16.7% 2/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Joint swelling	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Muscle spasms	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Myalgia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Pain in extremity	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Nervous system disorders Dizziness	33.3% 4/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	33.3% 2/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Nervous system disorders Headache	25.0% 3/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	50.0% 3/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Nervous system disorders Sciatica	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Psychiatric disorders Insomnia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Renal and urinary disorders Renal failure	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Renal and urinary disorders Renal failure chronic	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Reproductive system and breast disorders Menorrhagia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Bronchospasm	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Cough	25.0% 3/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Dyspnoea	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Hypoxia	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Nasal congestion	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Nasal obstruction	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Pleural effusion	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Skin and subcutaneous tissue disorders Night sweats	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Skin and subcutaneous tissue disorders Pruritus	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Skin and subcutaneous tissue disorders Skin ulcer	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Surgical and medical procedures Cataract operation	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Vascular disorders Capillary fragility	0.00% 0/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	16.7% 1/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Vascular disorders Hypertension	8.3% 1/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	0.00% 0/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.
Vascular disorders Hypotension	50.0% 6/12 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.	33.3% 2/6 • Adverse event data were collected after signing the informed consent until 2 days after end of treatment with the study medication. Participants completing the main 12-week study phase were allowed to enter a long-term extension phase receiving individual titrated Riociguat at their optimal dose. Long-term extension phase was planned to last until regulatory approval of riociguat but was prematurely terminated by the sponsor.

Additional Information

Therapeutic Area Head

Bayer

Email: clinical-trials-contact@bayerhealthcare.com

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