PATENT-2: BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00863681
• Collaborator: (none)
• Enrollment: 396
• Locations: 99
• Arm: 1
• Actual Duration (Months): 125.2
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Patients who have completed the 12 weeks treatment of the PATENT-1 trial (study number 12934) will be asked to participate in this long term extension study with BAY63-2521.

Condition or Disease	Intervention/Treatment	Phase
Hypertension, Pulmonary	Drug: Riociguat (BAY63-2521)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 396 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-term Extension, Multicentre, Multi-national Study to Evaluate the Safety and Tolerability of Oral BAY63-2521 (1mg,1.5 mg, 2.0 mg, 2.5 mg Tid) in Patients With Symptomatic Pulmonary Arterial Hypertension (PAH)
• Actual Study Start Date: Mar 12, 2009
• Actual Primary Completion Date: Aug 19, 2019
• Actual Study Completion Date: Aug 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1	Drug: Riociguat (BAY63-2521); BAY63-2521: 1mg tid -2.5 mg tid oral until end of study

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (TEAE) [From administration of first dose of study medication in PATENT-2 up to 2 days after end of treatment with study medication, up to 10 years and 5 months.]

   Analyses of drug-related TEAEs were based on the assessment of causal relationship to study medication.

2. Number of Participant With Death [From baseline to end of safety follow-up visit, up to 10 years and 6 months (1 month more than End of study visit)]

   Analyses of deaths were based on the assessment of causal relationship to study medication. The safety follow-up visit was to be performed 30 days after the last dose of riociguat.

Secondary Outcome Measures

1. Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Hematology and Coagulation [From baseline to termination visit, up to 10 years]

   Percentage of participants only with a treatment-emergent shift in hematology and coagulation parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or low value at baseline who had at least one high value after the start of treatment with the number of participants with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

2. Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Hematology and Coagulation [From baseline to termination visit, up to 10 years]

   Percentage of participants only with a treatment-emergent shift in hematology and coagulation parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or high value at baseline who had at least one low value after the start of treatment with the number of participants with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

3. Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Clinical Chemistry [From baseline to termination visit, up to 10 years]

   Percentage of participants per treatment group only with a treatment-emergent shift in clinical chemistry parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or low value at baseline who had at least one high value after the start of treatment with the number of participants with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

4. Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Clinical Chemistry [From baseline to termination visit, up to 10 years]

   Percentage of participants per treatment group only with a treatment-emergent shift in clinical chemistry parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or high value at baseline who had at least one low value after the start of treatment with the number of participants with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

Other Outcome Measures

1. Change of Systolic Blood Pressure (SBP) [From baseline to termination visit, up to 10 years]

   SBP was measured after the participant had been at rest for 10 minutes in a supine position. Low SBP was defined as SBP <95 mmHg, normal SBP as SBP 95-140mmHg, and high SBP as SBP >140 mmHg. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

2. Change of Diastolic Blood Pressure (DBP) [From baseline to termination visit, up to 10 years]

   DBP was measured after the participants had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

3. Change of Heart Rate [From baseline to termination visit, up to 10 years]

   Heart rate was measured after the participant had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

4. Change of Weight [From baseline to termination visit, up to 10 years]

   Weight was evaluated for safety. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

5. Change of Oxygen Saturation (SaO2) [From baseline to termination visit, up to 10 years]

   SaO2 is one parameters of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

6. Change of Arterial Partial Oxygen Pressure (PaO2) [From baseline to termination visit, up to 10 years]

   PaO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

7. Change of Arterial Partial Pressure of Carbon Dioxide (PaCO2) [From baseline to termination visit, up to 10 years]

   PaCO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

8. Change of RR Duration From Electrocardiogram (ECG) [From baseline to Month 48]

   Heart rate from ECG is derived from the RR duration, unless arrhythmias such as atrial fibrillation or ventricular extra beats require additional calculations. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.

9. Change of PR Duration From ECG [From baseline to Month 48]

   PR duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.

10. Change of QRS Duration From ECG [From baseline to Month 48]

    QRS duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.

11. Change of QT Duration in ECG [From baseline to Month 48]

    QT duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.

12. Change in Six-minute Walking Distance (6MWD) Test [From baseline to End of study visit, up to 10 years and 5 months.]

    6MWD is exercise testing and is one of efficacy evaluation

13. Change in Pulmonary Vascular Resistance (PVR) [From baseline to Termination visit, up to 10 years 5 months]

    Pulmonary vascular resistance (PVR) was measured only if right-heart catheterization was performed as part of a regular diagnostic work-up. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.

14. Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) [From baseline to End of study visit, up to 10 year and 5 months]

    NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure

15. Change in World Health Organization (WHO) Functional Class [From baseline to End of study visit, up to 10 years and 5 months.]

    WHO classification: I: Participants with PH. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. II: Participants with PH are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. III: Participants with PH are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. IV: Participants with PH with inability to carry out any physical activity. They manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. For class change from baseline, minus indicates a participant's functional class decreased compared with baseline (e.g. "-1" indicates a participant changed from class IV to class III, or from class II to class I), plus indicates a participant's functional class increased compared with baseline (e.g. "+1" indicates a participant changed from class I to class II, or from class III to class IV).

16. Number of Participants With Clinical Worsening [From baseline to End of study visit, up to 10 years and 5 months.]

    Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)

17. Incidence of Clinical Worsening Events Per 100 Person Years [From baseline to End of study visit, up to 10 years and 5 months.]

    Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)

18. Change From Baseline in Borg CR 10 Scale [From baseline to Week 12]

    The Borg CR10 Scale was measured in conjunction with the 6MWD test. The test was explained to the participant before starting the 6MWD test. Participants were asked to rank their exertion at the end of the 6MWD test. Low values indicate low levels of exertion; high values indicate more intense exertion reported by the participant. The score ranges from 0 ("Nothing at all") to 10 ("Extremely strong - Maximal")

19. Change in Score of EQ-5D Questionnaire [From baseline to End of study visit, up to 10 years and 5 months.]

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

20. Change in Score of Living With Pulmonary Hypertension (LPH) Questionnaire [From baseline to End of study visit, up to 10 years and 5 months.]

    The LPH questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The LPH is a self-report questionnaire and was completed by the participant. The LPH total score can range from 0 (best) to 105 (worst).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients who have completed 12 weeks of treatment in the double blind trial PATENT 1

Exclusion Criteria:

• Patients who have an ongoing serious adverse event from PATENT 1 that is assessed as related to BAY63-2521 are not allowed to participate in the extension trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90073
2		Sacramento	California	United States	95817
3		Aurora	Colorado	United States	80045
4		Boston	Massachusetts	United States	02111
5		Boston	Massachusetts	United States	02114
6		Omaha	Nebraska	United States	68131
7		Cleveland	Ohio	United States	44195
8		Columbus	Ohio	United States	43221
9		Fairfield	Ohio	United States	45014
10		Dallas	Texas	United States	75390-9252
11		El Paso	Texas	United States	79902
12		Capital Federal		Argentina
13		Darlinghurst	New South Wales	Australia	2010
14		Auchenflower	Queensland	Australia	4066
15		Chermside	Queensland	Australia	4032
16		Hobart	Tasmania	Australia	7000
17		Prahran	Victoria	Australia	3181
18		Linz	Oberösterreich	Austria	4020
19		Innsbruck		Austria	6020
20		Wien		Austria	1090
21		Bruxelles - Brussel		Belgium	1070
22		Leuven		Belgium	3000
23		Porto Alegre	Rio Grande Do Sul	Brazil	90020 090
24		São Paulo	Sao Paulo	Brazil	04012 180
25		São Paulo	Sao Paulo	Brazil	04020-050
26		Rio de Janeiro		Brazil	21941-913
27		Calgary	Alberta	Canada	T1Y 6J4
28		Montreal	Quebec	Canada	H3T 1E2
29		Guangzhou	Guangdong	China	510100
30		Beijing		China	100020
31		Beijing		China	100037
32		Shanghai		China	200032
33		Shanghai		China	200433
34		Praha 2		Czechia	12808
35		Aarhus N		Denmark	8200
36		Besancon		France	25030
37		Brest		France	F-29609
38		GRENOBLE Cedex 09		France	38043
39		Lille Cedex		France	59037
40		Montpellier		France	34059
41		Pessac		France	33604
42		Rouen		France	76031
43		Heidelberg	Baden-Württemberg	Germany	69126
44		München	Bayern	Germany	81377
45		Gießen	Hessen	Germany	35392
46		Greifswald	Mecklenburg-Vorpommern	Germany	17475
47		Hannover	Niedersachsen	Germany	30625
48		Köln	Nordrhein-Westfalen	Germany	50924
49		Homburg	Saarland	Germany	66421
50		Dresden	Sachsen	Germany	01307
51		Leipzig	Sachsen	Germany	04103
52		Chaidari		Greece	124 62
53		Trieste	Friuli-Venezia Giulia	Italy	34149
54		Roma	Lazio	Italy	00161
55		Milano	Lombardia	Italy	20123
56		Pavia	Lombardia	Italy	27100
57		Nagoya	Aichi	Japan	467-8602
58		Kobe	Hyogo	Japan	650-0017
59		Toride	Ibaraki	Japan	302-0022
60		Tsukuba	Ibaraki	Japan	305-8576
61		Kanazawa	Ishikawa	Japan	920-8641
62		Sendai	Miyagi	Japan	980-8574
63		Tomigusuku	Okinawa	Japan	901-0243
64		Bunkyo-ku	Tokyo	Japan	113-8655
65		Mitaka	Tokyo	Japan	181-8611
66		Ota-ku	Tokyo	Japan	143-8541
67		Shinjuku-ku	Tokyo	Japan	160-8582
68		Hiroshima		Japan	734-8511
69		Okayama		Japan	701-1192
70		Seoul		Korea, Republic of	03722
71		Seoul		Korea, Republic of	05505
72		Seoul		Korea, Republic of	06351
73	Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde"	Guadalajara	Jalisco	Mexico	44280
74	Pulmocritic	Guadalajara	Jalisco	Mexico	44670
75		Monterrey	Nuevo Leon	Mexico	64020
76		Culiacan	Sinaloa	Mexico	80020
77		Mexico D.F.		Mexico	14080
78		Querétaro		Mexico	38000
79		Otwock		Poland	05-400
80		Coimbra		Portugal	3000-075
81		Lisboa		Portugal	1169-024
82	Centro Hospitalar de Lisboa Norte - Hospital Santa Maria	Lisboa		Portugal	1649-035
83		Moscow		Russian Federation	121552
84		St. Petersburg		Russian Federation	197341
85		Singapore		Singapore	119228
86		Singapore		Singapore	168752
87		Umeå		Sweden	901 85
88		Zürich		Switzerland	8091
89		Kaoshiung		Taiwan	81346
90		Taipei		Taiwan	10016
91		Taipei		Taiwan	11217
92		Bangkok		Thailand	10330
93		Chiang Mai		Thailand	50200
94		Ankara		Turkey
95		Istanbul		Turkey	34098
96		Izmir		Turkey	35-100
97		Cambridge	Cambridgeshire	United Kingdom	CB23 3RE
98		Clydebank	West Dunbartonshire	United Kingdom	G81 4DY
99		London		United Kingdom	NW3 2QG

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

• Study Protocol - Dec 13, 2012
• Statistical Analysis Plan - Jul 25, 2019

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe
• Click here to find results for studies related to Bayer products

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00863681
• Other Study ID Numbers: 12935; 2008-003610-94
• First Posted: Mar 18, 2009
• Last Update Posted: Oct 22, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Pulmonary arterial hypertension; PH; Stimulator
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension; Riociguat

Study Results

Participant Flow

Recruitment Details	Study was conducted at 97 centers in 27 countries between 12-MAR-2009 (first participant first visit) and 19-AUG-2019 (last participant last visit);
Pre-assignment Detail	Of the 405 participants who completed PATENT-1(NCT00810693) study, 396 participants entered PATENT-2 study. 231 participants were from the former riociguat 1.0-2.5mg group, 109 were from the former placebo group and 56 were from the former riociguat 1.0-1.5mg group.

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Period Title: Overall Study
STARTED	231	109	56
COMPLETED	140	66	38
NOT COMPLETED	91	43	18

Baseline Characteristics

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg	Total
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Total of all reporting groups
Overall Participants	231	109	56	396
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	174 75.3%	87 79.8%	45 80.4%	306 77.3%
>=65 years	57 24.7%	22 20.2%	11 19.6%	90 22.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.4 (16.4)	48.8 (15.9)	48.2 (16.3)	49.7 (16.2)
Sex: Female, Male (Count of Participants)
Female	186 80.5%	87 79.8%	44 78.6%	317 80.1%
Male	45 19.5%	22 20.2%	12 21.4%	79 19.9%
Race/Ethnicity, Customized (Count of Participants)
White	148 64.1%	66 60.6%	28 50%	242 61.1%
Black or African American	2 0.9%	1 0.9%	1 1.8%	4 1%
Asian	74 32%	33 30.3%	20 35.7%	127 32.1%
Hispanic or Latino	7 3%	8 7.3%	7 12.5%	22 5.6%
Multiple	0 0%	1 0.9%	0 0%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAE)
Description	Analyses of drug-related TEAEs were based on the assessment of causal relationship to study medication.
Time Frame	From administration of first dose of study medication in PATENT-2 up to 2 days after end of treatment with study medication, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Any TEAE	229 99.1%	108 99.1%	56 100%
Any drug-related TEAE	138 59.7%	74 67.9%	30 53.6%
Any serious TEAE	161 69.7%	76 69.7%	39 69.6%
Any drug-related serious TEAE	25 10.8%	16 14.7%	3 5.4%
Any TEAE leading to death	42 18.2%	25 22.9%	6 10.7%

2. Primary Outcome

Title	Number of Participant With Death
Description	Analyses of deaths were based on the assessment of causal relationship to study medication. The safety follow-up visit was to be performed 30 days after the last dose of riociguat.
Time Frame	From baseline to end of safety follow-up visit, up to 10 years and 6 months (1 month more than End of study visit)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Count of Participants [Participants]	48 20.8%	30 27.5%	7 12.5%

3. Secondary Outcome

Title	Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Hematology and Coagulation
Description	Percentage of participants only with a treatment-emergent shift in hematology and coagulation parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or low value at baseline who had at least one high value after the start of treatment with the number of participants with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit, and for each parameter.

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	209	93	49
aPTT (Sec)	68.1 29.5%	80.0 73.4%	79.2 141.4%
Basophils (Giga/L)	1.0 0.4%	1.1 1%	2.0 3.6%
Basophils/Leukocytes (%)	16.4 7.1%	12.1 11.1%	10.4 18.6%
Eosinophils (Giga/L)	1.9 0.8%	2.2 2%	2.0 3.6%
Eosinophils/Leukocytes (%)	8.7 3.8%	3.4 3.1%	10.4 18.6%
Erythrocytes (T/L)	13.7 5.9%	21.8 20%	35.0 62.5%
Hematocrit (%)	35.6 15.4%	37.7 34.6%	48.6 86.8%
Hemoglobin (g/dL)	8.9 3.9%	16.5 15.1%	24.4 43.6%
Leukocytes (Giga/L)	10.9 4.7%	13.6 12.5%	22.2 39.6%
Lymphocytes (Giga/L)	1.4 0.6%	3.4 3.1%	0.0 0%
Lymphocytes/Leukocytes (%)	11.4 4.9%	19.5 17.9%	6.5 11.6%
Monocytes (Giga/L)	6.3 2.7%	3.3 3%	0.0 0%
Monocytes/Leukocytes (%)	20.0 8.7%	18.0 16.5%	22.2 39.6%
Neutrophils (Giga/L)	14.2 6.1%	18.8 17.2%	28.3 50.5%
Neutrophils/Leukocytes (%)	42.5 18.4%	38.3 35.1%	52.3 93.4%
Platelets (Giga/L)	14.9 6.5%	9.7 8.9%	15.6 27.9%
Prothrombin INR	56.3 24.4%	74.0 67.9%	58.6 104.6%

4. Secondary Outcome

Title	Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Hematology and Coagulation
Description	Percentage of participants only with a treatment-emergent shift in hematology and coagulation parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or high value at baseline who had at least one low value after the start of treatment with the number of participants with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit, and for each parameter.

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	211	96	49
aPTT (Sec)	12.8 5.5%	13.5 12.4%	8.5 15.2%
Erythrocytes (T/L)	31.0 13.4%	22.8 20.9%	25.0 44.6%
Hematocrit (%)	22.1 9.6%	23.3 21.4%	26.7 47.7%
Hemoglobin (g/dL)	48.2 20.9%	38.0 34.9%	46.2 82.5%
Leukocytes (Giga/L)	25.7 11.1%	23.6 21.7%	25.6 45.7%
Lymphocytes (Giga/L)	29.3 12.7%	29.3 26.9%	32.6 58.2%
Lymphocytes/Leukocytes (%)	50.3 21.8%	44.6 40.9%	64.3 114.8%
Monocytes (Giga/L)	0.5 0.2%	1.1 1%	2.0 3.6%
Monocytes/Leukocytes (%)	2.4 1%	3.3 3%	14.3 25.5%
Neutrophils (Giga/L)	9.4 4.1%	4.4 4%	8.5 15.2%
Neutrophils/Leukocytes (%)	6.9 3%	4.5 4.1%	6.5 11.6%
Platelets (Giga/L)	23.8 10.3%	29.5 27.1%	26.8 47.9%
Prothrombin INR	0.0 0%	0.0 0%	0.0 0%

5. Secondary Outcome

Title	Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Clinical Chemistry
Description	Percentage of participants per treatment group only with a treatment-emergent shift in clinical chemistry parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or low value at baseline who had at least one high value after the start of treatment with the number of participants with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit, and for each parameter.

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	222	103	52
Alanine Aminotransferase (U/L)	13.4 5.8%	12.0 11%	8.7 15.5%
Albumin (g/dL)	0.5 0.2%	1.0 0.9%	0.0 0%
Alkaline Phosphatase (U/L)	15.7 6.8%	23.4 21.5%	15.6 27.9%
Aspartate Aminotransferase (U/L)	11.6 5%	11.5 10.6%	10.6 18.9%
Bilirubin (mg/dL)	14.5 6.3%	11.8 10.8%	28.9 51.6%
Calcium(mg/dL)	2.5 1.1%	0.0 0%	0.0 0%
Creatine Kinase (U/L)	23.8 10.3%	24.7 22.7%	19.1 34.1%
Creatinine (mg/dL)	29.4 12.7%	39.7 36.4%	45.5 81.3%
Gamma Glutamyl Transferase(U/L)	18.2 7.9%	17.1 15.7%	25.0 44.6%
Glutamate Dehydrogenase (U/L)	40.0 17.3%	37.7 34.6%	56.8 101.4%
Phosphate (mg/dL)	2.6 1.1%	0.0 0%	0.0 0%
Potassium (mmol/L)	4.6 2%	4.9 4.5%	8.0 14.3%
Protein (g/dL)	2.3 1%	4.9 4.5%	3.8 6.8%
Pseudocholinesterase (U/mL)	0.5 0.2%	0.0 0%	0.0 0%
Sodium (mmol/L)	0.5 0.2%	1.9 1.7%	3.8 6.8%
Triacylglycerol Lipase (U/L)	22.6 9.8%	19.3 17.7%	12.2 21.8%
Urate (mg/dL)	24.3 10.5%	25.3 23.2%	29.3 52.3%
Urea (mg/dL)	20.1 8.7%	18.9 17.3%	30.4 54.3%
eGFR - MDRD Method (mL/min/1.73 m*2)	0.0 0%	0.0 0%	0.0 0%
Creatinine Clearance (mL/min)	12.1 5.2%	15.4 14.1%	13.3 23.8%

6. Secondary Outcome

Title	Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Clinical Chemistry
Description	Percentage of participants per treatment group only with a treatment-emergent shift in clinical chemistry parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or high value at baseline who had at least one low value after the start of treatment with the number of participants with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit, and for each parameter.

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	223	103	52
Alanine Aminotransferase (U/L)	0.0 0%	0.0 0%	0.0 0%
Albumin (g/dL)	4.1 1.8%	4.0 3.7%	0.0 0%
Alkaline Phosphatase (U/L)	3.3 1.4%	4.0 3.7%	0.0 0%
Bilirubin (mg/dL)	0.0 0%	1.0 0.9%	0.0 0%
Calcium (mg/dL)	25.0 10.8%	10.0 9.2%	20.0 35.7%
Creatine Kinase (U/L)	8.7 3.8%	5.1 4.7%	12.2 21.8%
Creatinine (mg/dL)	4.5 1.9%	6.9 6.3%	5.8 10.4%
Gamma Glutamyl Transferase (U/L)	0.0 0%	0.0 0%	0.0 0%
Phosphate (mg/dL)	5.3 2.3%	15.4 14.1%	33.3 59.5%
Potassium (mmol/L)	24.9 10.8%	32.6 29.9%	29.8 53.2%
Protein (g/dL)	9.0 3.9%	10.3 9.4%	8.5 15.2%
Pseudocholinesterase (U/mL)	11.0 4.8%	11.1 10.2%	8.0 14.3%
Sodium (mmol/L)	8.5 3.7%	13.0 11.9%	11.8 21.1%
Triacylglycerol Lipase (U/L)	0.0 0%	0.0 0%	0.0 0%
Urate (mg/dL)	3.6 1.6%	5.0 4.6%	3.8 6.8%
Urea (mg/dL)	0.9 0.4%	1.0 0.9%	0.0 0%
eGFR - MDRD Method(mL/min/1.73 m*2)	19.0 8.2%	17.4 16%	23.3 41.6%
Creatinine Clearance (mL/min)	45.7 19.8%	30.3 27.8%	48.4 86.4%

7. Other Pre-specified Outcome

Title	Change of Systolic Blood Pressure (SBP)
Description	SBP was measured after the participant had been at rest for 10 minutes in a supine position. Low SBP was defined as SBP <95 mmHg, normal SBP as SBP 95-140mmHg, and high SBP as SBP >140 mmHg. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)	114.36 (14.78)	113.75 (12.76)	110.88 (12.49)
Change from baseline to Termination visit	-0.88 (15.82)	-1.30 (15.62)	-0.99 (16.12)

8. Other Pre-specified Outcome

Title	Change of Diastolic Blood Pressure (DBP)
Description	DBP was measured after the participants had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)	72.03 (10.53)	71.84 (9.06)	69.61 (9.89)
Change from baseline to Termination visit	-3.33 (12.90)	-4.00 (11.72)	-2.13 (9.65)

9. Other Pre-specified Outcome

Title	Change of Heart Rate
Description	Heart rate was measured after the participant had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)	76.47 (11.04)	77.30 (12.53)	76.04 (10.83)
Change from baseline to Termination visit	0.75 (13.92)	0.18 (14.07)	-1.10 (14.74)

10. Other Pre-specified Outcome

Title	Change of Weight
Description	Weight was evaluated for safety. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)	68.24 (18.25)	69.03 (16.94)	69.57 (14.69)
Change from baseline to Termination visit	-1.67 (6.45)	0.04 (6.04)	-1.79 (8.08)

11. Other Pre-specified Outcome

Title	Change of Oxygen Saturation (SaO2)
Description	SaO2 is one parameters of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	227	109	56
Baseline (Week 0)	95.10 (2.61)	94.32 (3.18)	94.00 (2.95)
Change from baseline to Termination visit	-1.14 (3.48)	-0.56 (4.45)	-4.30 (5.23)

12. Other Pre-specified Outcome

Title	Change of Arterial Partial Oxygen Pressure (PaO2)
Description	PaO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	227	109	56
Baseline (Week 0)	76.99 (17.60)	74.54 (17.84)	72.12 (13.63)
Change from baseline to Termination visit	-4.77 (17.42)	7.14 (58.00)	-8.05 (2.76)

13. Other Pre-specified Outcome

Title	Change of Arterial Partial Pressure of Carbon Dioxide (PaCO2)
Description	PaCO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to termination visit, up to 10 years

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	227	109	56
Baseline (Week 0)	32.94 (4.62)	32.46 (4.63)	33.40 (4.41)
Change from baseline to Termination visit	-1.87 (3.72)	-0.68 (5.70)	2.00 (4.24)

14. Other Pre-specified Outcome

Title	Change of RR Duration From Electrocardiogram (ECG)
Description	Heart rate from ECG is derived from the RR duration, unless arrhythmias such as atrial fibrillation or ventricular extra beats require additional calculations. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
Time Frame	From baseline to Month 48

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	218	103	53
Baseline (Week 0)	817.69 (125.61)	828.96 (146.32)	822.33 (130.27)
Change from baseline to Month 48	59.07 (109.89)	75.69 (181.94)	89.61 (113.25)

15. Other Pre-specified Outcome

Title	Change of PR Duration From ECG
Description	PR duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
Time Frame	From baseline to Month 48

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	211	102	53
Baseline (Week 0)	171.07 (27.76)	173.97 (32.90)	171.74 (25.77)
Change from baseline to Month 48	7.51 (16.29)	16.50 (19.41)	-3.22 (17.18)

16. Other Pre-specified Outcome

Title	Change of QRS Duration From ECG
Description	QRS duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
Time Frame	From baseline to Month 48

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	213	103	53
Baseline (Week 0)	99.59 (17.38)	100.09 (16.15)	103.22 (19.82)
Change from baseline to Month 48	5.07 (8.56)	11.14 (18.69)	-0.44 (7.52)

17. Other Pre-specified Outcome

Title	Change of QT Duration in ECG
Description	QT duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
Time Frame	From baseline to Month 48

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	177	76	40
Baseline (Week 0)	401.56 (31.35)	406.67 (35.44)	405.10 (30.52)
Change from baseline to Month 48	10.93 (27.58)	16.89 (16.78)	27.34 (28.61)

18. Other Pre-specified Outcome

Title	Change in Six-minute Walking Distance (6MWD) Test
Description	6MWD is exercise testing and is one of efficacy evaluation
Time Frame	From baseline to End of study visit, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)	375.0 (160)	395.0 (174)	376.0 (158)
Change from baseline to End of study visit	19.0 (-448)	9.0 (-446)	1.5 (-448)

19. Other Pre-specified Outcome

Title	Change in Pulmonary Vascular Resistance (PVR)
Description	Pulmonary vascular resistance (PVR) was measured only if right-heart catheterization was performed as part of a regular diagnostic work-up. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
Time Frame	From baseline to Termination visit, up to 10 years 5 months

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	228	103	56
Baseline (Week 0)	802.40 (452.97)	835.45 (476.52)	855.70 (552.92)
Change from baseline to Termination visit	34.25 (104.83)

20. Other Pre-specified Outcome

Title	Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP)
Description	NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure
Time Frame	From baseline to End of study visit, up to 10 year and 5 months

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	210	97	47
Baseline (Week 0)	996.30 (1627.48)	1135.68 (1533.20)	1220.11 (1457.90)
Change from baseline to End of study visit	82.52 (2253.30)	202.42 (3466.94)	115.77 (1918.81)

21. Other Pre-specified Outcome

Title	Change in World Health Organization (WHO) Functional Class
Description	WHO classification: I: Participants with PH. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. II: Participants with PH are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. III: Participants with PH are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. IV: Participants with PH with inability to carry out any physical activity. They manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. For class change from baseline, minus indicates a participant's functional class decreased compared with baseline (e.g. "-1" indicates a participant changed from class IV to class III, or from class II to class I), plus indicates a participant's functional class increased compared with baseline (e.g. "+1" indicates a participant changed from class I to class II, or from class III to class IV).
Time Frame	From baseline to End of study visit, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)-class I	5 2.2%	3 2.8%	4 7.1%
Baseline (Week 0)-class II	98 42.4%	54 49.5%	17 30.4%
Baseline (Week 0)-class III	128 55.4%	49 45%	35 62.5%
Baseline (Week 0)-class IV	0 0%	2 1.8%	0 0%
Baseline (Week 0)-Missing	0 0%	1 0.9%	0 0%
Change from baseline to EOS visit- -2	5 2.2%	0 0%	1 1.8%
Change from baseline to EOS visit- -1	50 21.6%	16 14.7%	13 23.2%
Change from baseline to EOS visit- 0	101 43.7%	52 47.7%	28 50%
Change from baseline to EOS visit- +1	23 10%	15 13.8%	6 10.7%
Change from baseline to EOS visit- +2	33 14.3%	17 15.6%	5 8.9%
Change from baseline to EOS visit- +3	19 8.2%	8 7.3%	3 5.4%

22. Other Pre-specified Outcome

Title	Number of Participants With Clinical Worsening
Description	Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)
Time Frame	From baseline to End of study visit, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Any clinical worsening	87 37.7%	41 37.6%	18 32.1%
Heart/lung transplantation	3 1.3%	0 0%	2 3.6%
Atrial septostomy	1 0.4%	1 0.9%	0 0%
Hospitalization due to pulmonary hypertension	29 12.6%	12 11%	8 14.3%
Start of new pulmonary hypertension treatment	52 22.5%	20 18.3%	14 25%
Decrease in 6MWD due to pulmonary hypertension	7 3%	6 5.5%	2 3.6%
Persistent worsening of functional class due to PH	8 3.5%	2 1.8%	1 1.8%
Death	48 20.8%	30 27.5%	7 12.5%

23. Other Pre-specified Outcome

Title	Incidence of Clinical Worsening Events Per 100 Person Years
Description	Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)
Time Frame	From baseline to End of study visit, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Any clinical worsening event	22.09	22.10	19.20
Heart/Lung Transplantation	0.34	0	0.89
Atrial Septostomy	0.11	0.25	0
Hospitalization due to PH	4.46	3.81	5.80
Start of new PH treatment	9.73	8.13	7.59
Decrease in 6MWD due to PH	1.03	1.78	0.89
Persistent worsening of functional class due to PH	0.92	0.51	0.89
Death	5.49	7.62	3.13

24. Other Pre-specified Outcome

Title	Change From Baseline in Borg CR 10 Scale
Description	The Borg CR10 Scale was measured in conjunction with the 6MWD test. The test was explained to the participant before starting the 6MWD test. Participants were asked to rank their exertion at the end of the 6MWD test. Low values indicate low levels of exertion; high values indicate more intense exertion reported by the participant. The score ranges from 0 ("Nothing at all") to 10 ("Extremely strong - Maximal")
Time Frame	From baseline to Week 12

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	231	109	56
Baseline (Week 0)	3.87 (2.24)	3.80 (2.26)	3.41 (1.77)
Change from baseline to Week 12	-0.58 (1.84)	-0.54 (1.91)	-0.52 (1.64)

25. Other Pre-specified Outcome

Title	Change in Score of EQ-5D Questionnaire
Description	The EQ-5D is a standardized instrument for use as a measure of health outcome. The EQ-5D is a self report questionnaire. The utility score is calculated based on five questions concerning problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression. An increase in the utility score represents an improvement in quality of life. The score ranges from -0.594 (worst answer in all five questions) to 1 (best answer in all five questions).
Time Frame	From baseline to End of study visit, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	230	107	55
Baseline (Week 0)	0.6883 (0.2339)	0.6929 (0.2302)	0.6338 (0.2744)
Change from baseline to EOS Visit	-0.2452 (0.5894)	-0.2812 (0.5944)	-0.0925 (0.4376)

26. Other Pre-specified Outcome

Title	Change in Score of Living With Pulmonary Hypertension (LPH) Questionnaire
Description	The LPH questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The LPH is a self-report questionnaire and was completed by the participant. The LPH total score can range from 0 (best) to 105 (worst).
Time Frame	From baseline to End of study visit, up to 10 years and 5 months.

Outcome Measure Data

Analysis Population Description

Participants in SAF with evaluable data for each visit

Arm/Group Title	Riociguat-Former Riociguat 1.0-2.5 mg	Riociguat-Former Placebo	Riociguat-Former Riociguat 1.0-1.5 mg
Arm/Group Description	Participants from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.	Participants were from the former placebo group of PATENT-1. The starting dose in PATENT-2 was 1.0 mg riociguat three times one day.	Participants from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1 on the same dose as they received on the last day of PATENT-1.
Measure Participants	225	105	55
Baseline (Week 0)	41.77 (22.18)	41.94 (23.34)	45.10 (22.08)
Change from baseline to EOS Visit	4.99 (34.04)	12.28 (32.76)	-4.07 (31.40)

Adverse Events

Time Frame	From administration of first dose of study medication in PATENT-2 up to 2 days after end of treatment with study medication, up to 10 years and 5 months.
Arm/Group Title	Former Riociguat 1.0- 2.5 mg		Former Riociguat 1.0 - 1.5 mg		Former Placebo
Arm/Group Description	Patients from the PATENT-1 1.0 - 2.5 mg Dose Arm will enter the extension trial (PATENT-2)with the same dose which they have received on the last day of PATENT-1 (Visit 6).		Patients from the PATENT-1 1.0 - 1.5 mg Dose Arm will enter the extension trial (PATENT-2)with the same dose which they have received on the last day of PATENT-1 (Visit 6).		Patients from the PATENT-1 Placebo Arm will enter the extension trial (PATENT-2)with the starting dose 1 mg Riociguat tid.
All Cause Mortality
	Former Riociguat 1.0- 2.5 mg		Former Riociguat 1.0 - 1.5 mg		Former Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/231 (20.8%)		7/56 (12.5%)		30/109 (27.5%)
Serious Adverse Events
	Former Riociguat 1.0- 2.5 mg		Former Riociguat 1.0 - 1.5 mg		Former Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	161/231 (69.7%)		39/56 (69.6%)		76/109 (69.7%)
Blood and lymphatic system disorders
Anaemia	5/231 (2.2%)	5	1/56 (1.8%)	1	6/109 (5.5%)	7
Iron deficiency anaemia	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Pancytopenia	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Spontaneous haematoma	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Immune thrombocytopenic purpura	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cardiac disorders
Acute myocardial infarction	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Angina pectoris	3/231 (1.3%)	3	1/56 (1.8%)	1	1/109 (0.9%)	1
Aortic valve stenosis	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Arrhythmia	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Atrial fibrillation	2/231 (0.9%)	2	2/56 (3.6%)	2	2/109 (1.8%)	2
Atrial flutter	5/231 (2.2%)	5	0/56 (0%)	0	1/109 (0.9%)	1
Atrioventricular block	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cardiac failure	8/231 (3.5%)	13	1/56 (1.8%)	3	7/109 (6.4%)	8
Cardiac failure acute	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Cardiac failure chronic	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cardiac failure congestive	1/231 (0.4%)	4	0/56 (0%)	0	0/109 (0%)	0
Cardiogenic shock	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cor pulmonale	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cor pulmonale chronic	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Palpitations	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pericardial effusion	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Right ventricular failure	26/231 (11.3%)	47	7/56 (12.5%)	9	6/109 (5.5%)	8
Supraventricular extrasystoles	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Supraventricular tachycardia	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Tachycardia	0/231 (0%)	0	1/56 (1.8%)	1	1/109 (0.9%)	1
Ventricular extrasystoles	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Cardiopulmonary failure	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Acute coronary syndrome	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cardiac ventricular thrombosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pulseless electrical activity	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Acute right ventricular failure	1/231 (0.4%)	1	0/56 (0%)	0	2/109 (1.8%)	2
Cardiac dysfunction	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	2
Congenital, familial and genetic disorders
Heart disease congenital	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Eye disorders
Cataract	1/231 (0.4%)	1	1/56 (1.8%)	2	0/109 (0%)	0
Retinal haemorrhage	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Vitreous haemorrhage	1/231 (0.4%)	2	0/56 (0%)	0	0/109 (0%)	0
Choroidal neovascularisation	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Optic nerve disorder	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Abdominal pain	3/231 (1.3%)	3	0/56 (0%)	0	0/109 (0%)	0
Abdominal pain upper	0/231 (0%)	0	0/56 (0%)	0	2/109 (1.8%)	2
Anal fissure	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Ascites	1/231 (0.4%)	5	1/56 (1.8%)	1	1/109 (0.9%)	2
Colitis	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Diarrhoea	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Diverticulum intestinal	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Gastric ulcer	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Gastritis	3/231 (1.3%)	3	0/56 (0%)	0	1/109 (0.9%)	1
Gastritis erosive	0/231 (0%)	0	0/56 (0%)	0	2/109 (1.8%)	2
Gastritis haemorrhagic	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Gastrooesophageal reflux disease	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Gastrointestinal haemorrhage	2/231 (0.9%)	2	0/56 (0%)	0	2/109 (1.8%)	2
Haemorrhoids	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Hiatus hernia	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Ileus	1/231 (0.4%)	1	0/56 (0%)	0	2/109 (1.8%)	2
Inguinal hernia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Melaena	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Oesophageal varices haemorrhage	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Rectal haemorrhage	0/231 (0%)	0	0/56 (0%)	0	2/109 (1.8%)	2
Rectal polyp	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Toothache	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Upper gastrointestinal haemorrhage	2/231 (0.9%)	3	0/56 (0%)	0	3/109 (2.8%)	3
Vomiting	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Subileus	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Lower gastrointestinal haemorrhage	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Intra-abdominal haemorrhage	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
General disorders
Asthenia	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Chest pain	1/231 (0.4%)	1	1/56 (1.8%)	1	2/109 (1.8%)	2
Death	2/231 (0.9%)	2	0/56 (0%)	0	3/109 (2.8%)	3
Injection site pain	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Malaise	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Oedema	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Oedema peripheral	2/231 (0.9%)	2	0/56 (0%)	0	2/109 (1.8%)	3
Sudden death	2/231 (0.9%)	2	0/56 (0%)	0	1/109 (0.9%)	1
Sudden cardiac death	1/231 (0.4%)	1	1/56 (1.8%)	1	1/109 (0.9%)	1
General physical health deterioration	1/231 (0.4%)	1	0/56 (0%)	0	2/109 (1.8%)	2
Exercise tolerance decreased	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Drug intolerance	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Vascular stent stenosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Multiple organ dysfunction syndrome	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Hepatobiliary disorders
Bile duct stone	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cholecystitis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cholelithiasis	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Hepatic cirrhosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Hepatic congestion	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Liver disorder	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Infections and infestations
Abscess	0/231 (0%)	0	1/56 (1.8%)	2	0/109 (0%)	0
Acute sinusitis	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Appendicitis	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Bronchitis	5/231 (2.2%)	5	2/56 (3.6%)	3	2/109 (1.8%)	4
Bronchopulmonary aspergillosis	1/231 (0.4%)	2	0/56 (0%)	0	0/109 (0%)	0
Cellulitis	2/231 (0.9%)	2	1/56 (1.8%)	3	0/109 (0%)	0
Cervicitis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Clostridium difficile colitis	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Endometritis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Erysipelas	0/231 (0%)	0	0/56 (0%)	0	3/109 (2.8%)	4
Gastroenteritis	7/231 (3%)	7	0/56 (0%)	0	0/109 (0%)	0
Gastroenteritis viral	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Gastrointestinal infection	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Herpes zoster	1/231 (0.4%)	1	1/56 (1.8%)	1	1/109 (0.9%)	1
Infected skin ulcer	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Infection	0/231 (0%)	0	2/56 (3.6%)	2	0/109 (0%)	0
Localised infection	0/231 (0%)	0	1/56 (1.8%)	2	0/109 (0%)	0
Lower respiratory tract infection	2/231 (0.9%)	2	2/56 (3.6%)	2	1/109 (0.9%)	1
Periodontitis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pneumonia	4/231 (1.7%)	4	6/56 (10.7%)	7	7/109 (6.4%)	9
Pneumonia viral	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Pyelonephritis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Salmonellosis	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Sepsis	4/231 (1.7%)	5	2/56 (3.6%)	2	1/109 (0.9%)	1
Tonsillitis	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Tracheobronchitis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Urinary tract infection	1/231 (0.4%)	1	0/56 (0%)	0	2/109 (1.8%)	2
Viral infection	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Urosepsis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Anal abscess	0/231 (0%)	0	1/56 (1.8%)	2	0/109 (0%)	0
Appendiceal abscess	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Campylobacter infection	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Ureteritis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Haematoma infection	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Escherichia urinary tract infection	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Clostridium difficile infection	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Gastric infection	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Lung infection pseudomonal	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Lung infection	2/231 (0.9%)	2	3/56 (5.4%)	3	2/109 (1.8%)	2
Serratia infection	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Bronchitis bacterial	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Respiratory tract infection	2/231 (0.9%)	2	0/56 (0%)	0	2/109 (1.8%)	2
Gastroenteritis norovirus	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Pneumocystis jirovecii pneumonia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Bacterial colitis	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Systemic infection	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Vascular device infection	0/231 (0%)	0	0/56 (0%)	0	2/109 (1.8%)	4
Injury, poisoning and procedural complications
Brain herniation	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Facial bones fracture	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Fall	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Femur fracture	0/231 (0%)	0	1/56 (1.8%)	1	1/109 (0.9%)	1
Fibula fracture	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Joint dislocation	0/231 (0%)	0	1/56 (1.8%)	3	0/109 (0%)	0
Overdose	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Rib fracture	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Road traffic accident	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Snake bite	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Spinal fracture	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Subcutaneous haematoma	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Subdural haematoma	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Subdural haemorrhage	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Wrist fracture	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Vascular pseudoaneurysm	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Traumatic fracture	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Contusion	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Postoperative hypotension	0/231 (0%)	0	1/56 (1.8%)	2	0/109 (0%)	0
Post procedural haemorrhage	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Chest injury	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Upper limb fracture	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Procedural pain	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Periprosthetic fracture	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Toxicity to various agents	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Craniocerebral injury	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Investigations
Biopsy	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Catheterisation cardiac	18/231 (7.8%)	24	3/56 (5.4%)	3	4/109 (3.7%)	4
Chest X-ray abnormal	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Endoscopy	1/231 (0.4%)	1	2/56 (3.6%)	2	0/109 (0%)	0
Endoscopy upper gastrointestinal tract	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Haemoglobin decreased	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Intraocular pressure increased	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Oxygen saturation decreased	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Transplant evaluation	1/231 (0.4%)	2	0/56 (0%)	0	0/109 (0%)	0
Troponin increased	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Metabolism and nutrition disorders
Acidosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Electrolyte imbalance	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Fluid overload	2/231 (0.9%)	5	1/56 (1.8%)	1	0/109 (0%)	0
Fluid retention	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Gout	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Hyperkalaemia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Hyponatraemia	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Back pain	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Bursitis	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Flank pain	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Fracture delayed union	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Haemarthrosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Joint effusion	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Neck pain	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Osteoarthritis	3/231 (1.3%)	4	0/56 (0%)	0	0/109 (0%)	0
Rheumatoid arthritis	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Scleroderma	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Sjogren's syndrome	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Spinal osteoarthritis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Systemic lupus erythematosus	3/231 (1.3%)	4	1/56 (1.8%)	1	0/109 (0%)	0
Intervertebral disc protrusion	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Haematoma muscle	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Connective tissue disorder	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Joint instability	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Spinal pain	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Systemic scleroderma	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Breast neoplasm	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Gastrointestinal carcinoma	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Lung adenocarcinoma	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Malignant melanoma	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Metastases to liver	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Metastases to lung	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Papillary thyroid cancer	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Rectal cancer	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Uterine leiomyoma	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Colorectal cancer metastatic	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cancer pain	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Lung neoplasm malignant	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Renal neoplasm	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Non-small cell lung cancer	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Lymphatic system neoplasm	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Hepatocellular carcinoma	1/231 (0.4%)	3	0/56 (0%)	0	0/109 (0%)	0
Nervous system disorders
Cerebral haemorrhage	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Cerebral infarction	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Coma hepatic	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Dizziness	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Epilepsy	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Facial paralysis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Headache	2/231 (0.9%)	2	1/56 (1.8%)	1	0/109 (0%)	0
Neuropathy peripheral	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Presyncope	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Seizure	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Somnolence	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Subarachnoid haemorrhage	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Syncope	26/231 (11.3%)	43	5/56 (8.9%)	5	15/109 (13.8%)	23
Transient ischaemic attack	0/231 (0%)	0	1/56 (1.8%)	1	1/109 (0.9%)	1
Brain stem syndrome	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Central nervous system vasculitis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Product Issues
Device dislocation	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Lead dislodgement	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Psychiatric disorders
Anxiety	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Completed suicide	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Delirium	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Depression	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Mental status changes	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Renal and urinary disorders
Haematuria	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Proteinuria	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Renal colic	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Renal failure	4/231 (1.7%)	4	0/56 (0%)	0	2/109 (1.8%)	2
Renal impairment	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Chronic kidney disease	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Acute kidney injury	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Reproductive system and breast disorders
Cervical dysplasia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Endometriosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Menorrhagia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Metrorrhagia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Ovarian cyst	1/231 (0.4%)	1	1/56 (1.8%)	1	1/109 (0.9%)	1
Ovarian cyst ruptured	1/231 (0.4%)	1	1/56 (1.8%)	2	0/109 (0%)	0
Scrotal oedema	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Uterine polyp	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Endometrial dysplasia	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Haemorrhagic ovarian cyst	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Asthma	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Chronic obstructive pulmonary disease	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Chronic respiratory failure	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Diaphragm muscle weakness	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Dyspnoea	11/231 (4.8%)	12	1/56 (1.8%)	1	2/109 (1.8%)	2
Epistaxis	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Haemoptysis	8/231 (3.5%)	12	2/56 (3.6%)	2	4/109 (3.7%)	5
Hypoxia	3/231 (1.3%)	3	1/56 (1.8%)	1	0/109 (0%)	0
Interstitial lung disease	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Nasal obstruction	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Pharyngeal oedema	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Pneumonia aspiration	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Pneumothorax	2/231 (0.9%)	4	0/56 (0%)	0	0/109 (0%)	0
Pneumothorax spontaneous	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pulmonary artery thrombosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pulmonary embolism	2/231 (0.9%)	2	1/56 (1.8%)	1	1/109 (0.9%)	1
Pulmonary fibrosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pulmonary haemorrhage	3/231 (1.3%)	5	0/56 (0%)	0	0/109 (0%)	0
Pulmonary hypertension	17/231 (7.4%)	21	6/56 (10.7%)	8	6/109 (5.5%)	8
Pulmonary thrombosis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pulmonary veno-occlusive disease	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Respiratory arrest	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Respiratory failure	2/231 (0.9%)	2	0/56 (0%)	0	2/109 (1.8%)	2
Sleep apnoea syndrome	1/231 (0.4%)	1	0/56 (0%)	0	1/109 (0.9%)	1
Pulmonary mass	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Nasal cavity mass	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Pulmonary arterial hypertension	31/231 (13.4%)	50	11/56 (19.6%)	13	14/109 (12.8%)	28
Acute interstitial pneumonitis	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Hypersensitivity pneumonitis	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Skin and subcutaneous tissue disorders
Dermatitis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Fixed eruption	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Pyoderma gangrenosum	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Skin ulcer	2/231 (0.9%)	3	0/56 (0%)	0	0/109 (0%)	0
Social circumstances
Homicide	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Surgical and medical procedures
Abortion induced	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Atrial septal defect repair	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Cardiac pacemaker insertion	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Carpal tunnel decompression	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Cholecystectomy	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Gastric polypectomy	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Hysterectomy	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Lung transplant	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Osteotomy	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Prophylaxis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Central venous catheterisation	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	1
Swan ganz catheter placement	2/231 (0.9%)	3	0/56 (0%)	0	0/109 (0%)	0
Skin neoplasm excision	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Dental operation	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Varicose vein operation	0/231 (0%)	0	0/56 (0%)	0	1/109 (0.9%)	2
Bladder polypectomy	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Cataract operation	1/231 (0.4%)	2	0/56 (0%)	0	0/109 (0%)	0
Balloon atrial septostomy	1/231 (0.4%)	2	1/56 (1.8%)	1	0/109 (0%)	0
Trapeziectomy	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Vascular disorders
Arteriovenous fistula	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Circulatory collapse	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Haematoma	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Hypertensive crisis	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Hypotension	5/231 (2.2%)	5	1/56 (1.8%)	1	0/109 (0%)	0
Raynaud's phenomenon	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Shock	2/231 (0.9%)	2	0/56 (0%)	0	0/109 (0%)	0
Vasculitis	1/231 (0.4%)	1	1/56 (1.8%)	1	0/109 (0%)	0
Lymphocele	0/231 (0%)	0	1/56 (1.8%)	1	0/109 (0%)	0
Shock haemorrhagic	1/231 (0.4%)	1	0/56 (0%)	0	0/109 (0%)	0
Other (Not Including Serious) Adverse Events
	Former Riociguat 1.0- 2.5 mg		Former Riociguat 1.0 - 1.5 mg		Former Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	218/231 (94.4%)		54/56 (96.4%)		106/109 (97.2%)
Blood and lymphatic system disorders
Anaemia	30/231 (13%)	35	6/56 (10.7%)	6	14/109 (12.8%)	29
Cardiac disorders
Atrioventricular block first degree	3/231 (1.3%)	3	3/56 (5.4%)	3	3/109 (2.8%)	3
Cardiac failure	6/231 (2.6%)	6	4/56 (7.1%)	4	2/109 (1.8%)	2
Palpitations	22/231 (9.5%)	27	5/56 (8.9%)	9	14/109 (12.8%)	14
Right ventricular failure	7/231 (3%)	10	3/56 (5.4%)	3	6/109 (5.5%)	6
Tachycardia	9/231 (3.9%)	10	4/56 (7.1%)	7	4/109 (3.7%)	6
Ear and labyrinth disorders
Vertigo	6/231 (2.6%)	6	1/56 (1.8%)	1	6/109 (5.5%)	7
Gastrointestinal disorders
Abdominal distension	14/231 (6.1%)	20	0/56 (0%)	0	6/109 (5.5%)	7
Abdominal pain	17/231 (7.4%)	24	4/56 (7.1%)	4	9/109 (8.3%)	11
Abdominal pain upper	18/231 (7.8%)	19	2/56 (3.6%)	2	7/109 (6.4%)	8
Constipation	22/231 (9.5%)	26	2/56 (3.6%)	2	10/109 (9.2%)	11
Diarrhoea	50/231 (21.6%)	81	11/56 (19.6%)	22	34/109 (31.2%)	62
Dyspepsia	34/231 (14.7%)	68	8/56 (14.3%)	9	14/109 (12.8%)	22
Gastritis	7/231 (3%)	8	3/56 (5.4%)	3	10/109 (9.2%)	12
Gastrooesophageal reflux disease	16/231 (6.9%)	19	6/56 (10.7%)	6	13/109 (11.9%)	16
Nausea	46/231 (19.9%)	63	8/56 (14.3%)	10	26/109 (23.9%)	41
Vomiting	36/231 (15.6%)	47	9/56 (16.1%)	19	23/109 (21.1%)	34
General disorders
Asthenia	17/231 (7.4%)	23	3/56 (5.4%)	4	6/109 (5.5%)	8
Chest discomfort	15/231 (6.5%)	26	6/56 (10.7%)	7	6/109 (5.5%)	6
Chest pain	32/231 (13.9%)	44	7/56 (12.5%)	7	16/109 (14.7%)	25
Fatigue	20/231 (8.7%)	23	4/56 (7.1%)	6	12/109 (11%)	20
Oedema	9/231 (3.9%)	11	4/56 (7.1%)	6	9/109 (8.3%)	11
Oedema peripheral	64/231 (27.7%)	108	17/56 (30.4%)	26	31/109 (28.4%)	51
Pyrexia	24/231 (10.4%)	45	3/56 (5.4%)	3	7/109 (6.4%)	8
Peripheral swelling	7/231 (3%)	7	5/56 (8.9%)	7	4/109 (3.7%)	5
Infections and infestations
Bronchitis	24/231 (10.4%)	35	11/56 (19.6%)	13	14/109 (12.8%)	19
Conjunctivitis	8/231 (3.5%)	10	3/56 (5.4%)	5	4/109 (3.7%)	4
Gastroenteritis	14/231 (6.1%)	15	6/56 (10.7%)	6	6/109 (5.5%)	7
Gastrointestinal infection	9/231 (3.9%)	11	3/56 (5.4%)	5	3/109 (2.8%)	3
Influenza	14/231 (6.1%)	21	7/56 (12.5%)	7	4/109 (3.7%)	5
Lower respiratory tract infection	8/231 (3.5%)	11	3/56 (5.4%)	5	6/109 (5.5%)	17
Nasopharyngitis	76/231 (32.9%)	160	21/56 (37.5%)	44	31/109 (28.4%)	81
Oral candidiasis	2/231 (0.9%)	2	3/56 (5.4%)	3	0/109 (0%)	0
Pharyngitis	9/231 (3.9%)	13	4/56 (7.1%)	8	4/109 (3.7%)	4
Pneumonia	9/231 (3.9%)	9	7/56 (12.5%)	7	8/109 (7.3%)	10
Sinusitis	13/231 (5.6%)	25	1/56 (1.8%)	1	9/109 (8.3%)	11
Upper respiratory tract infection	39/231 (16.9%)	64	10/56 (17.9%)	20	24/109 (22%)	49
Urinary tract infection	12/231 (5.2%)	21	9/56 (16.1%)	12	12/109 (11%)	17
Lung infection	4/231 (1.7%)	5	3/56 (5.4%)	4	4/109 (3.7%)	4
Respiratory tract infection	24/231 (10.4%)	53	5/56 (8.9%)	10	13/109 (11.9%)	19
Injury, poisoning and procedural complications
Fall	12/231 (5.2%)	13	1/56 (1.8%)	1	2/109 (1.8%)	3
Contusion	17/231 (7.4%)	24	1/56 (1.8%)	1	3/109 (2.8%)	4
Investigations
Blood potassium decreased	8/231 (3.5%)	10	3/56 (5.4%)	3	4/109 (3.7%)	6
International normalised ratio increased	9/231 (3.9%)	11	4/56 (7.1%)	5	4/109 (3.7%)	4
Weight decreased	8/231 (3.5%)	9	0/56 (0%)	0	6/109 (5.5%)	7
Weight increased	6/231 (2.6%)	8	5/56 (8.9%)	7	1/109 (0.9%)	1
Metabolism and nutrition disorders
Hypokalaemia	26/231 (11.3%)	34	9/56 (16.1%)	14	12/109 (11%)	16
Iron deficiency	11/231 (4.8%)	13	4/56 (7.1%)	4	7/109 (6.4%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	28/231 (12.1%)	34	6/56 (10.7%)	7	10/109 (9.2%)	15
Arthritis	2/231 (0.9%)	2	4/56 (7.1%)	5	3/109 (2.8%)	4
Back pain	36/231 (15.6%)	48	5/56 (8.9%)	7	11/109 (10.1%)	17
Joint swelling	4/231 (1.7%)	5	3/56 (5.4%)	4	2/109 (1.8%)	2
Muscle spasms	6/231 (2.6%)	8	3/56 (5.4%)	4	9/109 (8.3%)	11
Musculoskeletal pain	10/231 (4.3%)	16	4/56 (7.1%)	4	6/109 (5.5%)	6
Myalgia	5/231 (2.2%)	6	4/56 (7.1%)	4	7/109 (6.4%)	10
Pain in extremity	27/231 (11.7%)	35	7/56 (12.5%)	7	12/109 (11%)	15
Systemic lupus erythematosus	4/231 (1.7%)	4	4/56 (7.1%)	4	0/109 (0%)	0
Spinal pain	5/231 (2.2%)	5	3/56 (5.4%)	3	1/109 (0.9%)	1
Nervous system disorders
Dizziness	67/231 (29%)	118	15/56 (26.8%)	22	31/109 (28.4%)	57
Headache	46/231 (19.9%)	102	10/56 (17.9%)	14	34/109 (31.2%)	61
Hypoaesthesia	9/231 (3.9%)	9	4/56 (7.1%)	4	3/109 (2.8%)	3
Presyncope	5/231 (2.2%)	5	2/56 (3.6%)	4	8/109 (7.3%)	9
Psychiatric disorders
Anxiety	10/231 (4.3%)	10	1/56 (1.8%)	1	8/109 (7.3%)	14
Depression	13/231 (5.6%)	13	3/56 (5.4%)	5	6/109 (5.5%)	7
Insomnia	21/231 (9.1%)	24	5/56 (8.9%)	5	10/109 (9.2%)	13
Respiratory, thoracic and mediastinal disorders
Cough	66/231 (28.6%)	94	13/56 (23.2%)	20	28/109 (25.7%)	42
Dyspnoea	33/231 (14.3%)	54	12/56 (21.4%)	15	15/109 (13.8%)	21
Epistaxis	30/231 (13%)	42	12/56 (21.4%)	18	16/109 (14.7%)	20
Haemoptysis	20/231 (8.7%)	46	2/56 (3.6%)	6	9/109 (8.3%)	10
Nasal congestion	8/231 (3.5%)	9	3/56 (5.4%)	4	6/109 (5.5%)	7
Productive cough	12/231 (5.2%)	16	2/56 (3.6%)	2	8/109 (7.3%)	10
Pulmonary hypertension	6/231 (2.6%)	8	3/56 (5.4%)	4	4/109 (3.7%)	6
Pulmonary arterial hypertension	15/231 (6.5%)	20	2/56 (3.6%)	2	13/109 (11.9%)	20
Skin and subcutaneous tissue disorders
Alopecia	5/231 (2.2%)	5	3/56 (5.4%)	3	3/109 (2.8%)	4
Erythema	1/231 (0.4%)	1	4/56 (7.1%)	4	0/109 (0%)	0
Hyperhidrosis	4/231 (1.7%)	4	4/56 (7.1%)	5	1/109 (0.9%)	1
Pruritus	10/231 (4.3%)	16	3/56 (5.4%)	3	3/109 (2.8%)	3
Rash	13/231 (5.6%)	18	3/56 (5.4%)	3	3/109 (2.8%)	4
Vascular disorders
Haematoma	7/231 (3%)	8	3/56 (5.4%)	3	2/109 (1.8%)	2
Hypotension	32/231 (13.9%)	39	10/56 (17.9%)	13	10/109 (9.2%)	14

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.