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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00863681
Recruitment Status : Completed
First Posted : March 18, 2009
Results First Posted : October 22, 2020
Last Update Posted : October 22, 2020
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hypertension, Pulmonary
Intervention Drug: Riociguat (BAY63-2521)
Enrollment 396
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 Details 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
Hide 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 [1] 66 [1] 38 [1]
Not Completed 91 43 18
Reason Not Completed
Other             2             0             0
Missing             1             0             0
Death             40             23             6
Withdrawal by Subject             12             5             2
Protocol Violation             2             0             0
Lost to Follow-up             3             0             3
Adverse Event             28             10             6
Lack of Efficacy             2             2             1
Non-compliance with study drug             1             3             0
[1]
Completed treatment
Arm/Group Title Riociguat-Former Riociguat 1.0-2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0-1.5 mg Total
Hide 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 Number of Baseline Participants 231 109 56 396
Hide Baseline Analysis Population Description
All 396 participants who received 1 of 3 blinded treatments for 12 weeks in the double blind PATENT-1 study entered long term extension PATENT-2 study. Baseline of PATENT-2 was Week 0 of PATENT-1. All 396 participants were included in the long term safety set.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 109 participants 56 participants 396 participants
<=18 years
0
   0.0%
0
   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, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 231 participants 109 participants 56 participants 396 participants
50.4  (16.4) 48.8  (15.9) 48.2  (16.3) 49.7  (16.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 109 participants 56 participants 396 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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 109 participants 56 participants 396 participants
White
148
  64.1%
66
  60.6%
28
  50.0%
242
  61.1%
Black or African American
2
   0.9%
1
   0.9%
1
   1.8%
4
   1.0%
Asian
74
  32.0%
33
  30.3%
20
  35.7%
127
  32.1%
Hispanic or Latino
7
   3.0%
8
   7.3%
7
  12.5%
22
   5.6%
Multiple
0
   0.0%
1
   0.9%
0
   0.0%
1
   0.3%
1.Primary Outcome
Title Number of Participants With Treatment-emergent Adverse Events (TEAE)
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Measure Type: Count of Participants
Unit of Measure: Participants
Any TEAE
229
  99.1%
108
  99.1%
56
 100.0%
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Measure Type: Count of Participants
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 209 93 49
Measure Type: Number
Unit of Measure: Percentage of participants
aPTT (Sec) Number Analyzed 94 participants 40 participants 24 participants
68.1 80.0 79.2
Basophils (Giga/L) Number Analyzed 209 participants 91 participants 49 participants
1.0 1.1 2.0
Basophils/Leukocytes (%) Number Analyzed 207 participants 91 participants 49 participants
16.4 12.1 10.4
Eosinophils (Giga/L) Number Analyzed 208 participants 91 participants 49 participants
1.9 2.2 2.0
Eosinophils/Leukocytes (%) Number Analyzed 206 participants 89 participants 48 participants
8.7 3.4 10.4
Erythrocytes (T/L) Number Analyzed 190 participants 87 participants 40 participants
13.7 21.8 35.0
Hematocrit (%) Number Analyzed 163 participants 69 participants 35 participants
35.6 37.7 48.6
Hemoglobin (g/dL) Number Analyzed 202 participants 85 participants 45 participants
8.9 16.5 24.4
Leukocytes (Giga/L) Number Analyzed 202 participants 88 participants 45 participants
10.9 13.6 22.2
Lymphocytes (Giga/L) Number Analyzed 209 participants 89 participants 49 participants
1.4 3.4 0.0
Lymphocytes/Leukocytes (%) Number Analyzed 201 participants 87 participants 46 participants
11.4 19.5 6.5
Monocytes (Giga/L) Number Analyzed 205 participants 91 participants 48 participants
6.3 3.3 0.0
Monocytes/Leukocytes (%) Number Analyzed 205 participants 89 participants 45 participants
20.0 18.0 22.2
Neutrophils (Giga/L) Number Analyzed 197 participants 85 participants 46 participants
14.2 18.8 28.3
Neutrophils/Leukocytes (%) Number Analyzed 186 participants 81 participants 44 participants
42.5 38.3 52.3
Platelets (Giga/L) Number Analyzed 201 participants 93 participants 45 participants
14.9 9.7 15.6
Prothrombin INR Number Analyzed 112 participants 50 participants 29 participants
56.3 74.0 58.6
4.Secondary Outcome
Title Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Hematology and Coagulation
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 211 96 49
Measure Type: Number
Unit of Measure: Percentage of participants
aPTT (Sec) Number Analyzed 211 participants 96 participants 47 participants
12.8 13.5 8.5
Erythrocytes (T/L) Number Analyzed 174 participants 79 participants 44 participants
31.0 22.8 25.0
Hematocrit (%) Number Analyzed 195 participants 90 participants 45 participants
22.1 23.3 26.7
Hemoglobin (g/dL) Number Analyzed 170 participants 79 participants 39 participants
48.2 38.0 46.2
Leukocytes (Giga/L) Number Analyzed 191 participants 89 participants 43 participants
25.7 23.6 25.6
Lymphocytes (Giga/L) Number Analyzed 184 participants 82 participants 46 participants
29.3 29.3 32.6
Lymphocytes/Leukocytes (%) Number Analyzed 169 participants 74 participants 42 participants
50.3 44.6 64.3
Monocytes (Giga/L) Number Analyzed 209 participants 91 participants 49 participants
0.5 1.1 2.0
Monocytes/Leukocytes (%) Number Analyzed 209 participants 91 participants 49 participants
2.4 3.3 14.3
Neutrophils (Giga/L) Number Analyzed 203 participants 90 participants 47 participants
9.4 4.4 8.5
Neutrophils/Leukocytes (%) Number Analyzed 204 participants 88 participants 46 participants
6.9 4.5 6.5
Platelets (Giga/L) Number Analyzed 168 participants 78 participants 41 participants
23.8 29.5 26.8
Prothrombin INR Number Analyzed 205 participants 96 participants 46 participants
0.0 0.0 0.0
5.Secondary Outcome
Title Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Clinical Chemistry
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 222 103 52
Measure Type: Number
Unit of Measure: Percentage of participants
Alanine Aminotransferase (U/L) Number Analyzed 202 participants 92 participants 46 participants
13.4 12.0 8.7
Albumin (g/dL) Number Analyzed 222 participants 102 participants 52 participants
0.5 1.0 0.0
Alkaline Phosphatase (U/L) Number Analyzed 197 participants 94 participants 45 participants
15.7 23.4 15.6
Aspartate Aminotransferase (U/L) Number Analyzed 199 participants 96 participants 47 participants
11.6 11.5 10.6
Bilirubin (mg/dL) Number Analyzed 193 participants 93 participants 45 participants
14.5 11.8 28.9
Calcium(mg/dL) Number Analyzed 40 participants 15 participants 6 participants
2.5 0.0 0.0
Creatine Kinase (U/L) Number Analyzed 214 participants 97 participants 47 participants
23.8 24.7 19.1
Creatinine (mg/dL) Number Analyzed 160 participants 78 participants 33 participants
29.4 39.7 45.5
Gamma Glutamyl Transferase(U/L) Number Analyzed 176 participants 76 participants 40 participants
18.2 17.1 25.0
Glutamate Dehydrogenase (U/L) Number Analyzed 160 participants 69 participants 37 participants
40.0 37.7 56.8
Phosphate (mg/dL) Number Analyzed 38 participants 14 participants 6 participants
2.6 0.0 0.0
Potassium (mmol/L) Number Analyzed 218 participants 102 participants 50 participants
4.6 4.9 8.0
Protein (g/dL) Number Analyzed 216 participants 102 participants 52 participants
2.3 4.9 3.8
Pseudocholinesterase (U/mL) Number Analyzed 220 participants 102 participants 52 participants
0.5 0.0 0.0
Sodium (mmol/L) Number Analyzed 222 participants 103 participants 52 participants
0.5 1.9 3.8
Triacylglycerol Lipase (U/L) Number Analyzed 199 participants 88 participants 49 participants
22.6 19.3 12.2
Urate (mg/dL) Number Analyzed 173 participants 75 participants 41 participants
24.3 25.3 29.3
Urea (mg/dL) Number Analyzed 199 participants 90 participants 46 participants
20.1 18.9 30.4
eGFR - MDRD Method (mL/min/1.73 m*2) Number Analyzed 222 participants 103 participants 52 participants
0.0 0.0 0.0
Creatinine Clearance (mL/min) Number Analyzed 198 participants 91 participants 45 participants
12.1 15.4 13.3
6.Secondary Outcome
Title Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Clinical Chemistry
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 223 103 52
Measure Type: Number
Unit of Measure: Percentage of participants
Alanine Aminotransferase (U/L) Number Analyzed 1 participants 1 participants 1 participants
0.0 0.0 0.0
Albumin (g/dL) Number Analyzed 221 participants 101 participants 51 participants
4.1 4.0 0.0
Alkaline Phosphatase (U/L) Number Analyzed 215 participants 101 participants 51 participants
3.3 4.0 0.0
Bilirubin (mg/dL) Number Analyzed 223 participants 103 participants 52 participants
0.0 1.0 0.0
Calcium (mg/dL) Number Analyzed 40 participants 10 participants 5 participants
25.0 10.0 20.0
Creatine Kinase (U/L) Number Analyzed 207 participants 99 participants 49 participants
8.7 5.1 12.2
Creatinine (mg/dL) Number Analyzed 221 participants 102 participants 52 participants
4.5 6.9 5.8
Gamma Glutamyl Transferase (U/L) Number Analyzed 222 participants 103 participants 52 participants
0.0 0.0 0.0
Phosphate (mg/dL) Number Analyzed 38 participants 13 participants 6 participants
5.3 15.4 33.3
Potassium (mmol/L) Number Analyzed 213 participants 95 participants 47 participants
24.9 32.6 29.8
Protein (g/dL) Number Analyzed 211 participants 97 participants 47 participants
9.0 10.3 8.5
Pseudocholinesterase (U/mL) Number Analyzed 209 participants 99 participants 50 participants
11.0 11.1 8.0
Sodium (mmol/L) Number Analyzed 213 participants 100 participants 51 participants
8.5 13.0 11.8
Triacylglycerol Lipase (U/L) Number Analyzed 222 participants 103 participants 52 participants
0.0 0.0 0.0
Urate (mg/dL) Number Analyzed 222 participants 101 participants 52 participants
3.6 5.0 3.8
Urea (mg/dL) Number Analyzed 222 participants 103 participants 52 participants
0.9 1.0 0.0
eGFR - MDRD Method(mL/min/1.73 m*2) Number Analyzed 179 participants 86 participants 43 participants
19.0 17.4 23.3
Creatinine Clearance (mL/min) Number Analyzed 127 participants 66 participants 31 participants
45.7 30.3 48.4
7.Other Pre-specified Outcome
Title Change of Systolic Blood Pressure (SBP)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Mean (Standard Deviation)
Unit of Measure: millimetre(s) of mercury (mmHg)
Baseline (Week 0) Number Analyzed 231 participants 109 participants 56 participants
114.36  (14.78) 113.75  (12.76) 110.88  (12.49)
Change from baseline to Termination visit Number Analyzed 169 participants 80 participants 41 participants
-0.88  (15.82) -1.30  (15.62) -0.99  (16.12)
8.Other Pre-specified Outcome
Title Change of Diastolic Blood Pressure (DBP)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Mean (Standard Deviation)
Unit of Measure: mmHg
Baseline (Week 0) Number Analyzed 231 participants 109 participants 56 participants
72.03  (10.53) 71.84  (9.06) 69.61  (9.89)
Change from baseline to Termination visit Number Analyzed 169 participants 80 participants 41 participants
-3.33  (12.90) -4.00  (11.72) -2.13  (9.65)
9.Other Pre-specified Outcome
Title Change of Heart Rate
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Mean (Standard Deviation)
Unit of Measure: beats/minute (BPM)
Baseline (Week 0) Number Analyzed 231 participants 109 participants 56 participants
76.47  (11.04) 77.30  (12.53) 76.04  (10.83)
Change from baseline to Termination visit Number Analyzed 169 participants 80 participants 41 participants
0.75  (13.92) 0.18  (14.07) -1.10  (14.74)
10.Other Pre-specified Outcome
Title Change of Weight
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Mean (Standard Deviation)
Unit of Measure: kilogram (kg)
Baseline (Week 0) Number Analyzed 231 participants 109 participants 56 participants
68.24  (18.25) 69.03  (16.94) 69.57  (14.69)
Change from baseline to Termination visit Number Analyzed 169 participants 81 participants 41 participants
-1.67  (6.45) 0.04  (6.04) -1.79  (8.08)
11.Other Pre-specified Outcome
Title Change of Oxygen Saturation (SaO2)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 227 109 56
Mean (Standard Deviation)
Unit of Measure: Percentage
Baseline (Week 0) Number Analyzed 227 participants 109 participants 56 participants
95.10  (2.61) 94.32  (3.18) 94.00  (2.95)
Change from baseline to Termination visit Number Analyzed 15 participants 9 participants 2 participants
-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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 227 109 56
Mean (Standard Deviation)
Unit of Measure: mmHg
Baseline (Week 0) Number Analyzed 227 participants 109 participants 56 participants
76.99  (17.60) 74.54  (17.84) 72.12  (13.63)
Change from baseline to Termination visit Number Analyzed 15 participants 9 participants 2 participants
-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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 227 109 56
Mean (Standard Deviation)
Unit of Measure: mmHg
Baseline (Week 0) Number Analyzed 227 participants 109 participants 56 participants
32.94  (4.62) 32.46  (4.63) 33.40  (4.41)
Change from baseline to Termination visit Number Analyzed 15 participants 9 participants 2 participants
-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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 218 103 53
Mean (Standard Deviation)
Unit of Measure: millisecond (msec)
Baseline (Week 0) Number Analyzed 218 participants 103 participants 53 participants
817.69  (125.61) 828.96  (146.32) 822.33  (130.27)
Change from baseline to Month 48 Number Analyzed 15 participants 7 participants 6 participants
59.07  (109.89) 75.69  (181.94) 89.61  (113.25)
15.Other Pre-specified Outcome
Title Change of PR Duration From ECG
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 211 102 53
Mean (Standard Deviation)
Unit of Measure: msec
Baseline (Week 0) Number Analyzed 211 participants 102 participants 53 participants
171.07  (27.76) 173.97  (32.90) 171.74  (25.77)
Change from baseline to Month 48 Number Analyzed 15 participants 6 participants 6 participants
7.51  (16.29) 16.50  (19.41) -3.22  (17.18)
16.Other Pre-specified Outcome
Title Change of QRS Duration From ECG
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 213 103 53
Mean (Standard Deviation)
Unit of Measure: msec
Baseline (Week 0) Number Analyzed 213 participants 103 participants 53 participants
99.59  (17.38) 100.09  (16.15) 103.22  (19.82)
Change from baseline to Month 48 Number Analyzed 15 participants 7 participants 6 participants
5.07  (8.56) 11.14  (18.69) -0.44  (7.52)
17.Other Pre-specified Outcome
Title Change of QT Duration in ECG
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 177 76 40
Mean (Standard Deviation)
Unit of Measure: msec
Baseline (Week 0) Number Analyzed 177 participants 76 participants 40 participants
401.56  (31.35) 406.67  (35.44) 405.10  (30.52)
Change from baseline to Month 48 Number Analyzed 9 participants 3 participants 4 participants
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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Median (Full Range)
Unit of Measure: meters
Baseline (Week 0)
375.0
(160 to 468)
395.0
(174 to 450)
376.0
(158 to 448)
Change from baseline to End of study visit
19.0
(-448 to 309)
9.0
(-446 to 275)
1.5
(-448 to 492)
19.Other Pre-specified Outcome
Title Change in Pulmonary Vascular Resistance (PVR)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 228 103 56
Mean (Standard Deviation)
Unit of Measure: dyn*s*cm^-5
Baseline (Week 0) Number Analyzed 228 participants 103 participants 56 participants
802.40  (452.97) 835.45  (476.52) 855.70  (552.92)
Change from baseline to Termination visit Number Analyzed 2 participants 0 participants 0 participants
34.25  (104.83)
20.Other Pre-specified Outcome
Title Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 210 97 47
Mean (Standard Deviation)
Unit of Measure: picograms/millilitre (pg/mL)
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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline (Week 0)-class I Number Analyzed 231 participants 109 participants 56 participants
5
   2.2%
3
   2.8%
4
   7.1%
Baseline (Week 0)-class II Number Analyzed 231 participants 109 participants 56 participants
98
  42.4%
54
  49.5%
17
  30.4%
Baseline (Week 0)-class III Number Analyzed 231 participants 109 participants 56 participants
128
  55.4%
49
  45.0%
35
  62.5%
Baseline (Week 0)-class IV Number Analyzed 231 participants 109 participants 56 participants
0
   0.0%
2
   1.8%
0
   0.0%
Baseline (Week 0)-Missing Number Analyzed 231 participants 109 participants 56 participants
0
   0.0%
1
   0.9%
0
   0.0%
Change from baseline to EOS visit- -2 Number Analyzed 231 participants 108 participants 56 participants
5
   2.2%
0
   0.0%
1
   1.8%
Change from baseline to EOS visit- -1 Number Analyzed 231 participants 108 participants 56 participants
50
  21.6%
16
  14.8%
13
  23.2%
Change from baseline to EOS visit- 0 Number Analyzed 231 participants 108 participants 56 participants
101
  43.7%
52
  48.1%
28
  50.0%
Change from baseline to EOS visit- +1 Number Analyzed 231 participants 108 participants 56 participants
23
  10.0%
15
  13.9%
6
  10.7%
Change from baseline to EOS visit- +2 Number Analyzed 231 participants 108 participants 56 participants
33
  14.3%
17
  15.7%
5
   8.9%
Change from baseline to EOS visit- +3 Number Analyzed 231 participants 108 participants 56 participants
19
   8.2%
8
   7.4%
3
   5.4%
22.Other Pre-specified Outcome
Title Number of Participants With Clinical Worsening
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Measure Type: Count of Participants
Unit of Measure: Participants
Any clinical worsening
87
  37.7%
41
  37.6%
18
  32.1%
Heart/lung transplantation
3
   1.3%
0
   0.0%
2
   3.6%
Atrial septostomy
1
   0.4%
1
   0.9%
0
   0.0%
Hospitalization due to pulmonary hypertension
29
  12.6%
12
  11.0%
8
  14.3%
Start of new pulmonary hypertension treatment
52
  22.5%
20
  18.3%
14
  25.0%
Decrease in 6MWD due to pulmonary hypertension
7
   3.0%
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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Measure Type: Number
Unit of Measure: Percentage per 100 person-years
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 231 109 56
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
Baseline (Week 0) Number Analyzed 231 participants 109 participants 56 participants
3.87  (2.24) 3.80  (2.26) 3.41  (1.77)
Change from baseline to Week 12 Number Analyzed 216 participants 101 participants 54 participants
-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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 230 107 55
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 225 105 55
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
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)
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.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Former Riociguat 1.0- 2.5 mg Former Riociguat 1.0 - 1.5 mg Former Placebo
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   48/231 (20.78%)      7/56 (12.50%)      30/109 (27.52%)    
Hide 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 (69.70%)      39/56 (69.64%)      76/109 (69.72%)    
Blood and lymphatic system disorders       
Anaemia * 1  5/231 (2.16%)  5 1/56 (1.79%)  1 6/109 (5.50%)  7
Iron deficiency anaemia * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Pancytopenia * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Spontaneous haematoma * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Immune thrombocytopenic purpura * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cardiac disorders       
Acute myocardial infarction * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Angina pectoris * 1  3/231 (1.30%)  3 1/56 (1.79%)  1 1/109 (0.92%)  1
Aortic valve stenosis * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Arrhythmia * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Atrial fibrillation * 1  2/231 (0.87%)  2 2/56 (3.57%)  2 2/109 (1.83%)  2
Atrial flutter * 1  5/231 (2.16%)  5 0/56 (0.00%)  0 1/109 (0.92%)  1
Atrioventricular block * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cardiac failure * 1  8/231 (3.46%)  13 1/56 (1.79%)  3 7/109 (6.42%)  8
Cardiac failure acute * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Cardiac failure chronic * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cardiac failure congestive * 1  1/231 (0.43%)  4 0/56 (0.00%)  0 0/109 (0.00%)  0
Cardiogenic shock * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cor pulmonale * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cor pulmonale chronic * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Palpitations * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pericardial effusion * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Right ventricular failure * 1  26/231 (11.26%)  47 7/56 (12.50%)  9 6/109 (5.50%)  8
Supraventricular extrasystoles * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Supraventricular tachycardia * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Tachycardia * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 1/109 (0.92%)  1
Ventricular extrasystoles * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Cardiopulmonary failure * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Acute coronary syndrome * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cardiac ventricular thrombosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pulseless electrical activity * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Acute right ventricular failure * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 2/109 (1.83%)  2
Cardiac dysfunction * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  2
Congenital, familial and genetic disorders       
Heart disease congenital * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Eye disorders       
Cataract * 1  1/231 (0.43%)  1 1/56 (1.79%)  2 0/109 (0.00%)  0
Retinal haemorrhage * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Vitreous haemorrhage * 1  1/231 (0.43%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Choroidal neovascularisation * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Optic nerve disorder * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Gastrointestinal disorders       
Abdominal discomfort * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Abdominal pain * 1  3/231 (1.30%)  3 0/56 (0.00%)  0 0/109 (0.00%)  0
Abdominal pain upper * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 2/109 (1.83%)  2
Anal fissure * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Ascites * 1  1/231 (0.43%)  5 1/56 (1.79%)  1 1/109 (0.92%)  2
Colitis * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Diarrhoea * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Diverticulum intestinal * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Gastric ulcer * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Gastritis * 1  3/231 (1.30%)  3 0/56 (0.00%)  0 1/109 (0.92%)  1
Gastritis erosive * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 2/109 (1.83%)  2
Gastritis haemorrhagic * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Gastrooesophageal reflux disease * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Gastrointestinal haemorrhage * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 2/109 (1.83%)  2
Haemorrhoids * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Hiatus hernia * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Ileus * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 2/109 (1.83%)  2
Inguinal hernia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Melaena * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Oesophageal varices haemorrhage * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Rectal haemorrhage * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 2/109 (1.83%)  2
Rectal polyp * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Toothache * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Upper gastrointestinal haemorrhage * 1  2/231 (0.87%)  3 0/56 (0.00%)  0 3/109 (2.75%)  3
Vomiting * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Subileus * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Lower gastrointestinal haemorrhage * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Intra-abdominal haemorrhage * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
General disorders       
Asthenia * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Chest pain * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 2/109 (1.83%)  2
Death * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 3/109 (2.75%)  3
Injection site pain * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Malaise * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Oedema * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Oedema peripheral * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 2/109 (1.83%)  3
Sudden death * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 1/109 (0.92%)  1
Sudden cardiac death * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 1/109 (0.92%)  1
General physical health deterioration * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 2/109 (1.83%)  2
Exercise tolerance decreased * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Drug intolerance * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Vascular stent stenosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Multiple organ dysfunction syndrome * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Hepatobiliary disorders       
Bile duct stone * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cholecystitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cholelithiasis * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Hepatic cirrhosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Hepatic congestion * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Liver disorder * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Infections and infestations       
Abscess * 1  0/231 (0.00%)  0 1/56 (1.79%)  2 0/109 (0.00%)  0
Acute sinusitis * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Appendicitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Bronchitis * 1  5/231 (2.16%)  5 2/56 (3.57%)  3 2/109 (1.83%)  4
Bronchopulmonary aspergillosis * 1  1/231 (0.43%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Cellulitis * 1  2/231 (0.87%)  2 1/56 (1.79%)  3 0/109 (0.00%)  0
Cervicitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Clostridium difficile colitis * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Endometritis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Erysipelas * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 3/109 (2.75%)  4
Gastroenteritis * 1  7/231 (3.03%)  7 0/56 (0.00%)  0 0/109 (0.00%)  0
Gastroenteritis viral * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Gastrointestinal infection * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Herpes zoster * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 1/109 (0.92%)  1
Infected skin ulcer * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Infection * 1  0/231 (0.00%)  0 2/56 (3.57%)  2 0/109 (0.00%)  0
Localised infection * 1  0/231 (0.00%)  0 1/56 (1.79%)  2 0/109 (0.00%)  0
Lower respiratory tract infection * 1  2/231 (0.87%)  2 2/56 (3.57%)  2 1/109 (0.92%)  1
Periodontitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pneumonia * 1  4/231 (1.73%)  4 6/56 (10.71%)  7 7/109 (6.42%)  9
Pneumonia viral * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Pyelonephritis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Salmonellosis * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Sepsis * 1  4/231 (1.73%)  5 2/56 (3.57%)  2 1/109 (0.92%)  1
Tonsillitis * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Tracheobronchitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Urinary tract infection * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 2/109 (1.83%)  2
Viral infection * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Urosepsis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Anal abscess * 1  0/231 (0.00%)  0 1/56 (1.79%)  2 0/109 (0.00%)  0
Appendiceal abscess * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Campylobacter infection * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Ureteritis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Haematoma infection * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Escherichia urinary tract infection * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Clostridium difficile infection * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Gastric infection * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Lung infection pseudomonal * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Lung infection * 1  2/231 (0.87%)  2 3/56 (5.36%)  3 2/109 (1.83%)  2
Serratia infection * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Bronchitis bacterial * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Respiratory tract infection * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 2/109 (1.83%)  2
Gastroenteritis norovirus * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Pneumocystis jirovecii pneumonia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Bacterial colitis * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Systemic infection * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Vascular device infection * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 2/109 (1.83%)  4
Injury, poisoning and procedural complications       
Brain herniation * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Facial bones fracture * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Fall * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Femur fracture * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 1/109 (0.92%)  1
Fibula fracture * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Joint dislocation * 1  0/231 (0.00%)  0 1/56 (1.79%)  3 0/109 (0.00%)  0
Overdose * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Rib fracture * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Road traffic accident * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Snake bite * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Spinal fracture * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Subcutaneous haematoma * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Subdural haematoma * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Subdural haemorrhage * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Wrist fracture * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Vascular pseudoaneurysm * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Traumatic fracture * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Contusion * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Postoperative hypotension * 1  0/231 (0.00%)  0 1/56 (1.79%)  2 0/109 (0.00%)  0
Post procedural haemorrhage * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Chest injury * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Upper limb fracture * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Procedural pain * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Periprosthetic fracture * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Toxicity to various agents * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Craniocerebral injury * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Investigations       
Biopsy * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Catheterisation cardiac * 1  18/231 (7.79%)  24 3/56 (5.36%)  3 4/109 (3.67%)  4
Chest X-ray abnormal * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Endoscopy * 1  1/231 (0.43%)  1 2/56 (3.57%)  2 0/109 (0.00%)  0
Endoscopy upper gastrointestinal tract * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Haemoglobin decreased * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Intraocular pressure increased * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Oxygen saturation decreased * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Transplant evaluation * 1  1/231 (0.43%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Troponin increased * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Metabolism and nutrition disorders       
Acidosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Electrolyte imbalance * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Fluid overload * 1  2/231 (0.87%)  5 1/56 (1.79%)  1 0/109 (0.00%)  0
Fluid retention * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Gout * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Hyperkalaemia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Hyponatraemia * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Back pain * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Bursitis * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Flank pain * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Fracture delayed union * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Haemarthrosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Joint effusion * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Neck pain * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Osteoarthritis * 1  3/231 (1.30%)  4 0/56 (0.00%)  0 0/109 (0.00%)  0
Rheumatoid arthritis * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Scleroderma * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Sjogren's syndrome * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Spinal osteoarthritis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Systemic lupus erythematosus * 1  3/231 (1.30%)  4 1/56 (1.79%)  1 0/109 (0.00%)  0
Intervertebral disc protrusion * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Haematoma muscle * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Connective tissue disorder * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Joint instability * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Spinal pain * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Systemic scleroderma * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Bladder neoplasm * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Breast neoplasm * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Gastrointestinal carcinoma * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Lung adenocarcinoma * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Malignant melanoma * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Metastases to liver * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Metastases to lung * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Papillary thyroid cancer * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Rectal cancer * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Uterine leiomyoma * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Colorectal cancer metastatic * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cancer pain * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Lung neoplasm malignant * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Renal neoplasm * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Non-small cell lung cancer * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Lymphatic system neoplasm * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Hepatocellular carcinoma * 1  1/231 (0.43%)  3 0/56 (0.00%)  0 0/109 (0.00%)  0
Nervous system disorders       
Cerebral haemorrhage * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Cerebral infarction * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Coma hepatic * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Dizziness * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Epilepsy * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Facial paralysis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Headache * 1  2/231 (0.87%)  2 1/56 (1.79%)  1 0/109 (0.00%)  0
Neuropathy peripheral * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Presyncope * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Seizure * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Somnolence * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Subarachnoid haemorrhage * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Syncope * 1  26/231 (11.26%)  43 5/56 (8.93%)  5 15/109 (13.76%)  23
Transient ischaemic attack * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 1/109 (0.92%)  1
Brain stem syndrome * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Central nervous system vasculitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pregnancy, puerperium and perinatal conditions       
Abortion * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Product Issues       
Device dislocation * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Lead dislodgement * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Psychiatric disorders       
Anxiety * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Completed suicide * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Delirium * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Depression * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Mental status changes * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Renal and urinary disorders       
Haematuria * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Proteinuria * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Renal colic * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Renal failure * 1  4/231 (1.73%)  4 0/56 (0.00%)  0 2/109 (1.83%)  2
Renal impairment * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Chronic kidney disease * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Acute kidney injury * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Reproductive system and breast disorders       
Cervical dysplasia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Endometriosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Menorrhagia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Metrorrhagia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Ovarian cyst * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 1/109 (0.92%)  1
Ovarian cyst ruptured * 1  1/231 (0.43%)  1 1/56 (1.79%)  2 0/109 (0.00%)  0
Scrotal oedema * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Uterine polyp * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Endometrial dysplasia * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Haemorrhagic ovarian cyst * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Asthma * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Chronic obstructive pulmonary disease * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Chronic respiratory failure * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Diaphragm muscle weakness * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Dyspnoea * 1  11/231 (4.76%)  12 1/56 (1.79%)  1 2/109 (1.83%)  2
Epistaxis * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Haemoptysis * 1  8/231 (3.46%)  12 2/56 (3.57%)  2 4/109 (3.67%)  5
Hypoxia * 1  3/231 (1.30%)  3 1/56 (1.79%)  1 0/109 (0.00%)  0
Interstitial lung disease * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Nasal obstruction * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Pharyngeal oedema * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Pneumonia aspiration * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Pneumothorax * 1  2/231 (0.87%)  4 0/56 (0.00%)  0 0/109 (0.00%)  0
Pneumothorax spontaneous * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pulmonary artery thrombosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pulmonary embolism * 1  2/231 (0.87%)  2 1/56 (1.79%)  1 1/109 (0.92%)  1
Pulmonary fibrosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pulmonary haemorrhage * 1  3/231 (1.30%)  5 0/56 (0.00%)  0 0/109 (0.00%)  0
Pulmonary hypertension * 1  17/231 (7.36%)  21 6/56 (10.71%)  8 6/109 (5.50%)  8
Pulmonary thrombosis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pulmonary veno-occlusive disease * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Respiratory arrest * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Respiratory failure * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 2/109 (1.83%)  2
Sleep apnoea syndrome * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 1/109 (0.92%)  1
Pulmonary mass * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Nasal cavity mass * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Pulmonary arterial hypertension * 1  31/231 (13.42%)  50 11/56 (19.64%)  13 14/109 (12.84%)  28
Acute interstitial pneumonitis * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Hypersensitivity pneumonitis * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Skin and subcutaneous tissue disorders       
Dermatitis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Fixed eruption * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Pyoderma gangrenosum * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Skin ulcer * 1  2/231 (0.87%)  3 0/56 (0.00%)  0 0/109 (0.00%)  0
Social circumstances       
Homicide * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Surgical and medical procedures       
Abortion induced * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Atrial septal defect repair * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Cardiac pacemaker insertion * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Carpal tunnel decompression * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Cholecystectomy * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Gastric polypectomy * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Hysterectomy * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Lung transplant * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Osteotomy * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Prophylaxis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Central venous catheterisation * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  1
Swan ganz catheter placement * 1  2/231 (0.87%)  3 0/56 (0.00%)  0 0/109 (0.00%)  0
Skin neoplasm excision * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Dental operation * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Varicose vein operation * 1  0/231 (0.00%)  0 0/56 (0.00%)  0 1/109 (0.92%)  2
Bladder polypectomy * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Cataract operation * 1  1/231 (0.43%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Balloon atrial septostomy * 1  1/231 (0.43%)  2 1/56 (1.79%)  1 0/109 (0.00%)  0
Trapeziectomy * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Vascular disorders       
Arteriovenous fistula * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Circulatory collapse * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Haematoma * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Hypertensive crisis * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Hypotension * 1  5/231 (2.16%)  5 1/56 (1.79%)  1 0/109 (0.00%)  0
Raynaud's phenomenon * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
Shock * 1  2/231 (0.87%)  2 0/56 (0.00%)  0 0/109 (0.00%)  0
Vasculitis * 1  1/231 (0.43%)  1 1/56 (1.79%)  1 0/109 (0.00%)  0
Lymphocele * 1  0/231 (0.00%)  0 1/56 (1.79%)  1 0/109 (0.00%)  0
Shock haemorrhagic * 1  1/231 (0.43%)  1 0/56 (0.00%)  0 0/109 (0.00%)  0
1
Term from vocabulary, MedDRA (22.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (94.37%)      54/56 (96.43%)      106/109 (97.25%)    
Blood and lymphatic system disorders       
Anaemia * 1  30/231 (12.99%)  35 6/56 (10.71%)  6 14/109 (12.84%)  29
Cardiac disorders       
Atrioventricular block first degree * 1  3/231 (1.30%)  3 3/56 (5.36%)  3 3/109 (2.75%)  3
Cardiac failure * 1  6/231 (2.60%)  6 4/56 (7.14%)  4 2/109 (1.83%)  2
Palpitations * 1  22/231 (9.52%)  27 5/56 (8.93%)  9 14/109 (12.84%)  14
Right ventricular failure * 1  7/231 (3.03%)  10 3/56 (5.36%)  3 6/109 (5.50%)  6
Tachycardia * 1  9/231 (3.90%)  10 4/56 (7.14%)  7 4/109 (3.67%)  6
Ear and labyrinth disorders       
Vertigo * 1  6/231 (2.60%)  6 1/56 (1.79%)  1 6/109 (5.50%)  7
Gastrointestinal disorders       
Abdominal distension * 1  14/231 (6.06%)  20 0/56 (0.00%)  0 6/109 (5.50%)  7
Abdominal pain * 1  17/231 (7.36%)  24 4/56 (7.14%)  4 9/109 (8.26%)  11
Abdominal pain upper * 1  18/231 (7.79%)  19 2/56 (3.57%)  2 7/109 (6.42%)  8
Constipation * 1  22/231 (9.52%)  26 2/56 (3.57%)  2 10/109 (9.17%)  11
Diarrhoea * 1  50/231 (21.65%)  81 11/56 (19.64%)  22 34/109 (31.19%)  62
Dyspepsia * 1  34/231 (14.72%)  68 8/56 (14.29%)  9 14/109 (12.84%)  22
Gastritis * 1  7/231 (3.03%)  8 3/56 (5.36%)  3 10/109 (9.17%)  12
Gastrooesophageal reflux disease * 1  16/231 (6.93%)  19 6/56 (10.71%)  6 13/109 (11.93%)  16
Nausea * 1  46/231 (19.91%)  63 8/56 (14.29%)  10 26/109 (23.85%)  41
Vomiting * 1  36/231 (15.58%)  47 9/56 (16.07%)  19 23/109 (21.10%)  34
General disorders       
Asthenia * 1  17/231 (7.36%)  23 3/56 (5.36%)  4 6/109 (5.50%)  8
Chest discomfort * 1  15/231 (6.49%)  26 6/56 (10.71%)  7 6/109 (5.50%)  6
Chest pain * 1  32/231 (13.85%)  44 7/56 (12.50%)  7 16/109 (14.68%)  25
Fatigue * 1  20/231 (8.66%)  23 4/56 (7.14%)  6 12/109 (11.01%)  20
Oedema * 1  9/231 (3.90%)  11 4/56 (7.14%)  6 9/109 (8.26%)  11
Oedema peripheral * 1  64/231 (27.71%)  108 17/56 (30.36%)  26 31/109 (28.44%)  51
Pyrexia * 1  24/231 (10.39%)  45 3/56 (5.36%)  3 7/109 (6.42%)  8
Peripheral swelling * 1  7/231 (3.03%)  7 5/56 (8.93%)  7 4/109 (3.67%)  5
Infections and infestations       
Bronchitis * 1  24/231 (10.39%)  35 11/56 (19.64%)  13 14/109 (12.84%)  19
Conjunctivitis * 1  8/231 (3.46%)  10 3/56 (5.36%)  5 4/109 (3.67%)  4
Gastroenteritis * 1  14/231 (6.06%)  15 6/56 (10.71%)  6 6/109 (5.50%)  7
Gastrointestinal infection * 1  9/231 (3.90%)  11 3/56 (5.36%)  5 3/109 (2.75%)  3
Influenza * 1  14/231 (6.06%)  21 7/56 (12.50%)  7 4/109 (3.67%)  5
Lower respiratory tract infection * 1  8/231 (3.46%)  11 3/56 (5.36%)  5 6/109 (5.50%)  17
Nasopharyngitis * 1  76/231 (32.90%)  160 21/56 (37.50%)  44 31/109 (28.44%)  81
Oral candidiasis * 1  2/231 (0.87%)  2 3/56 (5.36%)  3 0/109 (0.00%)  0
Pharyngitis * 1  9/231 (3.90%)  13 4/56 (7.14%)  8 4/109 (3.67%)  4
Pneumonia * 1  9/231 (3.90%)  9 7/56 (12.50%)  7 8/109 (7.34%)  10
Sinusitis * 1  13/231 (5.63%)  25 1/56 (1.79%)  1 9/109 (8.26%)  11
Upper respiratory tract infection * 1  39/231 (16.88%)  64 10/56 (17.86%)  20 24/109 (22.02%)  49
Urinary tract infection * 1  12/231 (5.19%)  21 9/56 (16.07%)  12 12/109 (11.01%)  17
Lung infection * 1  4/231 (1.73%)  5 3/56 (5.36%)  4 4/109 (3.67%)  4
Respiratory tract infection * 1  24/231 (10.39%)  53 5/56 (8.93%)  10 13/109 (11.93%)  19
Injury, poisoning and procedural complications       
Fall * 1  12/231 (5.19%)  13 1/56 (1.79%)  1 2/109 (1.83%)  3
Contusion * 1  17/231 (7.36%)  24 1/56 (1.79%)  1 3/109 (2.75%)  4
Investigations       
Blood potassium decreased * 1  8/231 (3.46%)  10 3/56 (5.36%)  3 4/109 (3.67%)  6
International normalised ratio increased * 1  9/231 (3.90%)  11 4/56 (7.14%)  5 4/109 (3.67%)  4
Weight decreased * 1  8/231 (3.46%)  9 0/56 (0.00%)  0 6/109 (5.50%)  7
Weight increased * 1  6/231 (2.60%)  8 5/56 (8.93%)  7 1/109 (0.92%)  1
Metabolism and nutrition disorders       
Hypokalaemia * 1  26/231 (11.26%)  34 9/56 (16.07%)  14 12/109 (11.01%)  16
Iron deficiency * 1  11/231 (4.76%)  13 4/56 (7.14%)  4 7/109 (6.42%)  9
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  28/231 (12.12%)  34 6/56 (10.71%)  7 10/109 (9.17%)  15
Arthritis * 1  2/231 (0.87%)  2 4/56 (7.14%)  5 3/109 (2.75%)  4
Back pain * 1  36/231 (15.58%)  48 5/56 (8.93%)  7 11/109 (10.09%)  17
Joint swelling * 1  4/231 (1.73%)  5 3/56 (5.36%)  4 2/109 (1.83%)  2
Muscle spasms * 1  6/231 (2.60%)  8 3/56 (5.36%)  4 9/109 (8.26%)