Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction (LEPHT)

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: NCT01065454
Recruitment Status : Active, not recruiting
First Posted : February 9, 2010
Results First Posted : December 25, 2013
Last Update Posted : April 13, 2021
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Hypertension, Pulmonary
Ventricular Dysfunction, Left
Interventions Drug: Riociguat (Adempas, BAY63-2521)
Drug: Placebo
Enrollment 202
Recruitment Details Only subjects with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD) could participate in this study. Subjects must have been pre-treated with optimized CHF therapy.
Pre-assignment Details 301 subjects were screened in 84 study centers in 18 countries worldwide. 99 of the 301 screened subjects were not randomized (adverse event [1], protocol violation [1], screen failure [87], withdrawal by subject [10]). Of the 202 subjects randomized, one subject did not receive any study medication.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg). Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg). Participants received riociguat 0.5 mg tid (fixed dose). Participants received placebo tid.
Period Title: Treatment
Started 67 33 32 69
Completed 54 28 23 57
Not Completed 13 5 9 12
Reason Not Completed
Adverse Event             7             4             3             6
Death             1             0             0             0
Non-compliance             1             0             0             1
Protocol Decision             0             0             3             2
Protocol Violation             1             0             1             0
Withdrawal by Subject             3             1             2             3
Period Title: Follow up
Started 54 28 23 57
Entering Follow-up 49 27 23 51
Completed 15 4 6 13
Not Completed 39 24 17 44
Reason Not Completed
Adverse Event             1             0             0             1
Death             0             1             1             0
Lost to Follow-up             0             0             0             1
Progressive disease             0             0             0             1
Withdrawal by Subject             1             1             1             0
study ongoing             37             22             15             41
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo Total
Hide Arm/Group Description Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg). Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg). Participants received riociguat 0.5 mg tid (fixed dose). Participants received placebo tid. Total of all reporting groups
Overall Number of Baseline Participants 67 33 32 69 201
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
59.3  (10.8) 55.1  (13.2) 57.2  (9.9) 58.9  (11.2) 58.1  (11.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
Female
12
  17.9%
3
   9.1%
6
  18.8%
8
  11.6%
29
  14.4%
Male
55
  82.1%
30
  90.9%
26
  81.3%
61
  88.4%
172
  85.6%
Body mass index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
28.87  (5.27) 28.16  (4.72) 29.20  (5.64) 28.65  (5.89) 28.73  (5.44)
6-minute walking distance   [1] 
Mean (Standard Deviation)
Unit of measure:  Meters
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
380.9  (125.80) 401.9  (101.75) 416.6  (95.77) 382.1  (123.51) 390.5  (116.94)
[1]
Measure Description: 6MWD is a measure for the evaluation of functional exercise capacity.
Left ventricular ejection fraction (LVEF)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
28.4  (5.72) 28.8  (4.54) 27.0  (5.21) 27.1  (5.02) 27.8  (5.24)
[1]
Measure Description: LVEF is a calculated echocardiography parameter.
Etiology  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
Ischemic cardiomyopathy 30 12 14 34 90
Non-ischemic cardiomyopathy 37 20 17 34 108
Data missing 0 1 1 1 3
WHO (World Health Organization) functional class   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
II 35 20 23 42 120
III 31 13 9 23 76
IV 1 0 0 4 5
[1]
Measure Description: The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement, changes to a higher functional class resemble deterioration of pulmonary arterial hypertension (PAH).
Number of participants with diabetes mellitus (including subtypes)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
30 10 13 34 87
Glomerular filtration rate (GFR)  
Mean (Standard Deviation)
Unit of measure:  mL/min/1.73m^2
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
65.1  (19.10) 72.6  (22.70) 72.0  (17.90) 68.7  (19.90) 68.7  (19.91)
Number of participants with atrial fibrillation  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
9 3 3 9 24
Number of participants with atrial flutter  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
0 0 1 1 2
Number of participants with pacemaker rhythm  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
17 9 7 17 50
Baseline drug and device therapy   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 67 participants 33 participants 32 participants 69 participants 201 participants
Cardiac devices 38 17 21 44 120
Angiotensin-converting enzyme inhibitors 50 25 21 46 142
Angiotensin II receptor blockers 20 8 10 19 57
Aldosterone antagonists 51 26 23 53 153
Beta-blockers 31 16 21 32 100
Beta-blockers with alpha-blocking activity 30 15 11 30 86
Loop diuretics 62 31 29 68 188
Thiazide diuretics 12 3 7 10 32
Cardiac glycosides 28 12 6 28 72
Oral anticoagulants 38 16 15 33 102
Amiodarone 9 3 4 8 24
[1]
Measure Description: A single patient could have more than one drug and device therapy.
1.Primary Outcome
Title Pulmonary Artery Mean Pressure (PAPmean) at Rest - Change From Baseline to Week 16
Hide Description Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF [safety analysis set]/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 56
Mean (Standard Deviation)
Unit of Measure: mmHg
-6.1  (9.68) -0.8  (8.41) -4.5  (7.35) -4.0  (9.00)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1044
Comments Baseline value, treatment group and region were used as fixed effects in the ANCOVA model
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -2.71
Confidence Interval (2-Sided) 95%
-5.99 to 0.057
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5292
Comments Baseline value, treatment group and region were used as fixed effects in the ANCOVA model
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMEANS Difference
Estimated Value -1.38
Confidence Interval (2-Sided) 95%
-5.71 to 2.94
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Riociguat (Adempas, BAY63-2521) up to 1 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0278
Comments Baseline value, treatment group and region were used as fixed effects in the ANCOVA model
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -4.51
Confidence Interval (2-Sided) 95%
-8.52 to -0.50
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3821
Comments Baseline value, treatment group and region were used as fixed effects in the ANCOVA model
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 1.80
Confidence Interval (2-Sided) 95%
-2.25 to 5.84
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2084
Comments Baseline value, treatment group and region were used as fixed effects in the ANCOVA model
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 3.13
Confidence Interval (2-Sided) 95%
-1.76 to 8.02
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5442
Comments Baseline value, treatment group and region were used as fixed effects in the ANCOVA model
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -1.33
Confidence Interval (2-Sided) 95%
-5.66 to 3.00
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Venous Oxygen Saturation (SvO2) - Change From Baseline to Week 16
Hide Description The mixed venous oxygen saturation rate (SvO2) is a directly measured hemodynamic parameter. SvO2 is recorded during a right heart catheterization.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 45 23 19 48
Mean (Standard Deviation)
Unit of Measure: Percentage
1.98  (7.084) 0.46  (7.866) -0.21  (5.969) 1.28  (9.259)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 1.87
Confidence Interval (2-Sided) 95%
-0.83 to 4.56
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.20
Confidence Interval (2-Sided) 95%
-3.12 to 3.51
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.23
Confidence Interval (2-Sided) 95%
-3.31 to 3.77
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16
Hide Description The pulmonary vascular resistance (PVR) is a calculated hemodynamic parameter. PVR is derived from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP), divided by the cardiac output (CO). PVR and PAPmean are acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: PVR = 80*(PAPmean - PCWP)/CO
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 53 28 22 56
Mean (Standard Deviation)
Unit of Measure: dyn*s*cm^-5
-78.15  (125.261) -33.05  (99.322) -51.44  (124.107) -36.97  (157.523)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -46.59
Confidence Interval (2-Sided) 95%
-89.4 to -3.8
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -32.26
Confidence Interval (2-Sided) 95%
-84.9 to 20.4
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -26.52
Confidence Interval (2-Sided) 95%
-83.0 to 30.0
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Pulmonary Vascular Resistance Index (PVRi) - Change From Baseline to Week 16
Hide Description The pulmonary vascular resistance index (PVRi) is a calculated hemodynamic parameter. PVRi is derived from the pulmonary vascular resistance (PVR) normalized by the body surface area (BSA). Formula: PVRi = 80*(PAPmean - PCWP)*BSA/CO
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 53 27 22 56
Mean (Standard Deviation)
Unit of Measure: dyn*s*cm^-5*m^2
-152.60  (250.366) -61.763  (202.138) -91.65  (237.256) -76.47  (311.693)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -89.17
Confidence Interval (2-Sided) 95%
-172.9 to 5.5
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -58.22
Confidence Interval (2-Sided) 95%
-162.1 to 45.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -43.22
Confidence Interval (2-Sided) 95%
-153.7 to 67.1
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Systemic Vascular Resistance (SVR) - Change From Baseline to Week 16
Hide Description The systemic vascular resistance (SVR) is a calculated hemodynamic parameter. SVR is derived from the directly measured parameter mean right atrial pressure (RAPmean) and the calculated parameter mean systemic arterial pressure (SAPmean) divided by the cardiac output (CO). RAPmean is acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: SVR = 80*(SAPmean - RAPmean)/CO
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 53 27 22 56
Mean (Standard Deviation)
Unit of Measure: dyn*s*cm^-5
-340.44  (394.87) -118.72  (369.865) -67.46  (315.097) -94.37  (431.049)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -239.31
Confidence Interval (2-Sided) 95%
-363.4 to -115.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -120.89
Confidence Interval (2-Sided) 95%
-274.4 to 32.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -25.54
Confidence Interval (2-Sided) 95%
-189.3 to 138.2
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Systemic Vascular Resistance Index (SVRi) - Change From Baseline to Week 16
Hide Description The systemic vascular resistance index (SVRi) is a calculated hemodynamic parameter. SVRi is derived from the systemic vascular resistance (SVR) normalized by the body surface area (BSA). Formula: SVRi = 80*(SAPmean - RAPmean)*BSA/CO
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 53 27 22 56
Mean (Standard Deviation)
Unit of Measure: dyn*s*cm^-5*m^2
-651.98  (757.617) -217.14  (742.465) -100.31  (612.460) -195.11  (853.927)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -446.49
Confidence Interval (2-Sided) 95%
-687.4 to -205.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -231.57
Confidence Interval (2-Sided) 95%
-530.4 to 67.2
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -34.97
Confidence Interval (2-Sided) 95%
-353.7 to 283.7
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Transpulmonary Pressure Gradient (TPG) - Change From Baseline to Week 16
Hide Description The transpulmonary pressure gradient (TPG) is a calculated hemodynamic parameter. TPG is calculated from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP). These 2 parameters are acquired during a right heart catheterization. Formula: TPG = PAPmean - PCWP
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 53 28 22 56
Mean (Standard Deviation)
Unit of Measure: mmHg
-2.16  (4.795) -1.01  (5.224) -1.65  (4.652) -1.37  (7.001)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -1.27
Confidence Interval (2-Sided) 95%
-3.1 to 0.5
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.88
Confidence Interval (2-Sided) 95%
-3.1 to 1.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.84
Confidence Interval (2-Sided) 95%
-3.2 to 1.5
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Pulmonary Capillary Wedge Pressure (PCWP) - Change From Baseline to Week 16
Hide Description Pulmonary capillary wedge pressure (PCWP) is a directly measured hemodynamic parameter acquired during a right heart catheterization.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 53 28 22 56
Mean (Standard Deviation)
Unit of Measure: mmHg
-3.93  (9.381) 0.25  (9.001) -2.818  (7.842) -2.68  (7.791)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LSS-MEANS Difference
Estimated Value -2.07
Confidence Interval (2-Sided) 95%
-5.0 to 0.8
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS_MEANS
Estimated Value 1.39
Confidence Interval (2-Sided) 95%
-2.1 to 4.9
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS_MEANS Difference
Estimated Value -1.13
Confidence Interval (2-Sided) 95%
-4.9 to 2.7
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Tricuspid Annular Plane Systolic Excursion (TAPSE) - Change From Baseline to Week 16
Hide Description The tricuspid annular plane systolic excursion (TAPSE) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 45 23 21 51
Mean (Standard Deviation)
Unit of Measure: mm
0.584  (2.344) 1.140  (2.986) 0.304  (2.109) 0.393  (1.586)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.28
Confidence Interval (2-Sided) 95%
-0.58 to 1.14
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
-0.23 to 1.87
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.03
Confidence Interval (2-Sided) 95%
-1.11 to 1.06
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Systolic Pulmonary Arterial Pressure (PAPsyst) - Change From Baseline to Week 16
Hide Description Systolic pulmonary arterial pressure (PAPsyst) is a directly measured hemodynamic parameter acquired during a right heart catheterization.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 55
Mean (Standard Deviation)
Unit of Measure: mmHg
-7.69  (14.251) -2.89  (12.333) -5.86  (11.589) -4.49  (13.717)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -3.84
Confidence Interval (2-Sided) 95%
-8.76 to 1.09
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANs Difference
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-6.05 to 6.01
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -2.43
Confidence Interval (2-Sided) 95%
-8.93 to 4.06
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Left Ventricular Ejection Fraction (LVEF) - Change From Baseline to Week 16
Hide Description The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). These 2 parameters are acquired during a non-invasive echocardiography examination. Formula: LEVF = 100*(LVEDV - LVESV)/LVEDV
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 52 27 22 51
Mean (Standard Deviation)
Unit of Measure: Percentage
6.599  (43.187) 12.659  (41.769) 5.529  (48.322) 11.121  (42.989)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.51
Confidence Interval (2-Sided) 95%
-0.21 to 1.24
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS_MEANS Difference
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
-0.07 to 1.69
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.20
Confidence Interval (2-Sided) 95%
-0.74 to 1.15
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Left Ventricular End-systolic Volume (LVESV) - Change From Baseline to Week 16
Hide Description Left ventricular end-systolic volume (LVESV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 52 27 22 51
Mean (Standard Deviation)
Unit of Measure: mL
1.805  (31.735) 6.415  (28.832) 1.507  (34.033) 7.295  (32.311)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -5.06
Confidence Interval (2-Sided) 95%
-17.33 to 7.22
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.28
Confidence Interval (2-Sided) 95%
-14.55 to 15.11
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -5.18
Confidence Interval (2-Sided) 95%
-21.05 to 10.69
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Left Ventricular End-diastolic Volume (LVEDV) - Change From Baseline to Week 16
Hide Description Left ventricular end-diastolic volume (LVEDV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 52 27 22 51
Mean (Standard Deviation)
Unit of Measure: mL
6.599  (43.187) 12.659  (41.769) 5.529  (48.322) 11.121  (42.989)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS_MEANS Difference
Estimated Value -4.27
Confidence Interval (2-Sided) 95%
-21.13 to 12.60
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 2.78
Confidence Interval (2-Sided) 95%
-17.59 to 23.16
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -4.61
Confidence Interval (2-Sided) 95%
-26.43 to 17.20
Estimation Comments [Not Specified]
14.Secondary Outcome
Title E-wave Deceleration Time - Change From Baseline to Week 16
Hide Description E-wave deceleration time is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 49 22 21 53
Mean (Standard Deviation)
Unit of Measure: msec
2.857  (31.470) -0.636  (38.138) 8.000  (39.542) -1.208  (43.937)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 5.29
Confidence Interval (2-Sided) 95%
-7.38 to 17.95
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 6.47
Confidence Interval (2-Sided) 95%
-9.79 to 22.73
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 10.35
Confidence Interval (2-Sided) 95%
-6.14 to 26.84
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Ratio of Mitral Peak Velocity of Early Filling to Mitral Peak Velocity of Late Filling (E/A) - Change From Baseline to Week 16
Hide Description E/A ratio is a measured echocardiography parameter and describes the ratio of mitral peak velocity of early filling to mitral peak velocity of late filling. It is acquired during a non-invasive echocardiography examination.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 44 20 20 48
Mean (Standard Deviation)
Unit of Measure: E/A ratio
-0.247  (0.957) 0.141  (1.261) -0.063  (0.884) -0.175  (1.079)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.15
Confidence Interval (2-Sided) 95%
-0.55 to 0.24
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.17
Confidence Interval (2-Sided) 95%
-0.34 to 0.67
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
-0.45 to 0.56
Estimation Comments [Not Specified]
16.Secondary Outcome
Title 6-minute Walking Distance (6MWD) - Change From Baseline to Week 16
Hide Description 6-minute walking distance (6MWD) is a measure for the objective evaluation of a patient's functional exercise capacity.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 55
Mean (Standard Deviation)
Unit of Measure: m
31.425  (83.386) 25.379  (84.244) -2.784  (90.324) 17.857  (80.851)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 10.17
Confidence Interval (2-Sided) 95%
-18.48 to 38.81
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 7.92
Confidence Interval (2-Sided) 95%
-26.76 to 42.59
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -6.15
Confidence Interval (2-Sided) 95%
-44.08 to 31.78
Estimation Comments [Not Specified]
17.Secondary Outcome
Title WHO (World Health Organization) Functional Class - Change From Baseline to Week 16
Hide Description The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement, changes to a higher functional class resemble deterioration of PAH.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 56
Measure Type: Number
Unit of Measure: Percentage of participants
-1 20.4 21.4 22.7 19.6
0 74.1 75 68.2 71.4
1 5.6 3.6 9.1 8.9
18.Secondary Outcome
Title Percentage of Participants With Clinical Worsening
Hide Description The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all cause mortality, including cardiovascular mortality; first hospitalization for a cardiovascular event, including heart failure, acute myocardial infarction, stroke or ventricular arrhythmia; upgrade of the HTx (heart transplantation) status to next higher level; need for IV diuretics; persistent worsening of WHO functional class due to deterioration of PH or cardiac function.
Time Frame At visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) - a randomized participant was valid for ITT analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one post-baseline measurement were included in the analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 67 33 32 69
Measure Type: Number
Unit of Measure: Percentage of participants
23.9 15.1 15.6 21.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
-13.36 to 14.61
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -9.46
Confidence Interval (2-Sided) 95%
-24.32 to 5.39
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -6.07
Confidence Interval (2-Sided) 95%
-22.26 to 10.13
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Borg CR 10 Scale - Change From Baseline to Week 16
Hide Description The Borg CR10 Scale is a patient reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the patient's exertion during a physical test. Low values indicate low levels of exertion, high values indicate more intense exertion reported by the patient. The score ranges from 0 ("Nothing at all") to 10 ("Extremely strong - Maximal").
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 55
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
0.269  (1.900) -0.804  (2.319) -0.682  (1.516) 0.187  (2.640)
20.Secondary Outcome
Title EQ-5D Utility Score - Change From Baseline to Week 16
Hide Description EQ-5D utility score is a Quality-of-Life patient reported outcome measure. An increase in the utility score represents an improvement in quality of life. The score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 56
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
0.073  (0.211) 0.016  (0.242) 0.004  (0.166) 0.018  (0.201)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-0.04 to 0.10
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.01
Confidence Interval (2-Sided) 95%
-0.07 to 0.09
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.07 to 0.11
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Minnesota Living With Heart Failure Questionnaire (MLHF) Score - Change From Baseline to Week 16
Hide Description The self-reported Minnesota Living with Heart Failure questionnaire (MLHF) is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The MLHF total score can range from 0 (best) to 105 (worst).
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 54 28 22 55
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
-10.789  (22.232) -5.132  (14.111) -7.595  (18.651) 0.211  (15.964)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -6.80
Confidence Interval (2-Sided) 95%
-12.81 to -0.78
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -6.81
Confidence Interval (2-Sided) 95%
-13.96 to 0.35
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -7.50
Confidence Interval (2-Sided) 95%
-15.29 to 0.28
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Cystatin C - Change From Baseline to Week 16
Hide Description Cystatin C is a biomarker for predicting new onset or deteriorating cardiovascular disease.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 45 26 17 44
Mean (Standard Deviation)
Unit of Measure: ng/mL
39.3  (232.7) 11.2  (218.5) 71.2  (140.8) 58.6  (242.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -24.62
Confidence Interval (2-Sided) 95%
-117.58 to 68.33
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -53.29
Confidence Interval (2-Sided) 95%
-162.46 to 55.88
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -8.36
Confidence Interval (2-Sided) 95%
-135.78 to 119.06
Estimation Comments [Not Specified]
23.Secondary Outcome
Title N-terminal Pro-brain Natriuretic Peptide (NT-pro BNP) - Change From Baseline to Week 16
Hide Description N-terminal pro-brain natriuretic peptide (NT-pro BNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 50 28 21 54
Mean (Standard Deviation)
Unit of Measure: pg/mL
-168.42  (1585.28) -213.48  (1204.24) -215.71  (769.16) 171.51  (2123.55)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -407.34
Confidence Interval (2-Sided) 95%
-1055.23 to 240.54
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -447.26
Confidence Interval (2-Sided) 95%
-1212.74 to 318.22
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -517.48
Confidence Interval (2-Sided) 95%
-1369.48 to 334.53
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Troponin T - Change From Baseline to Week 16
Hide Description Troponin T is a cardiac-specific protein which is released from damaged or injured heart muscle cells.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 34 24 15 44
Mean (Standard Deviation)
Unit of Measure: µg/L
0.005  (0.027) -0.008  (0.042) -0.001  (0.006) 0.003  (0.015)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.01 to 0.01
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.02 to 0.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.02 to 0.01
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Asymmetric Dimethylarginine (ADMA) - Change From Baseline to Week 16
Hide Description Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxides. Recent clinical studies have indicated that ADMA may have diagnostic relevance as a novel cardiovascular risk marker.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 49 25 19 51
Mean (Standard Deviation)
Unit of Measure: µmol/L
0.020  (0.115) 0.026  (0.118) 0.006  (0.098) 0.020  (0.090)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.00
Confidence Interval (2-Sided) 95%
-0.04 to 0.03
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.04 to 0.05
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.07 to 0.03
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Osteopontin - Change From Baseline to Week 16
Hide Description Osteopontin is a cytokine-like pro-fibrotic mediator, which is expressed in cardiovascular tissues. Its expression is induced by increased pressure and volume load in the myocardium, kidney and lung. Therefore, osteopontin may be used as a prognostic marker in patients with cardiovascular diseases.
Time Frame Baseline and visit 6 (16 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol set (PPS) - A subject was included in the PPS if he/she was valid for SAF/ITT and showed no major protocol deviations affecting efficacy. Only participants with a baseline and at least one post-baseline measurement were included in this analysis.
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description:
Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).
Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Participants received riociguat 0.5 mg tid (fixed dose).
Participants received placebo tid.
Overall Number of Participants Analyzed 50 27 18 51
Mean (Standard Deviation)
Unit of Measure: µg/mL
-13.400  (44.931) -0.852  (22.396) -2.722  (29.379) -4.588  (77.576)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 2 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANSA Difference
Estimated Value -14.13
Confidence Interval (2-Sided) 95%
-30.79 to 2.53
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) up to 1 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -12.73
Confidence Interval (2-Sided) 95%
-32.89 to 7.43
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS-MEANS Difference
Estimated Value -18.27
Confidence Interval (2-Sided) 95%
-41.53 to 5.00
Estimation Comments [Not Specified]
Time Frame All Adverse Events occurring between the subject has signed the informed consent and 30 days after the definite stop of study medication (over a period approximately 25 months) were reported.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Hide Arm/Group Description Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg). Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg) Participants received riociguat 0.5 mg tid (fixed dose) Participants received placebo tid
All-Cause Mortality
Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/67 (34.33%)      7/33 (21.21%)      7/32 (21.88%)      18/69 (26.09%)    
Blood and lymphatic system disorders         
Anaemia * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Cardiac disorders         
Atrial fibrillation * 1  3/67 (4.48%)  4 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Cardiac arrest * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Cardiac failure * 1  7/67 (10.45%)  8 3/33 (9.09%)  4 1/32 (3.13%)  1 3/69 (4.35%)  3
Cardiac failure acute * 1  2/67 (2.99%)  3 0/33 (0.00%)  0 0/32 (0.00%)  0 3/69 (4.35%)  4
Cardiac failure chronic * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 1/69 (1.45%)  1
Cardiac failure congestive * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 2/69 (2.90%)  2
Cardiac tamponade * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Coronary artery disease * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Right ventricular failure * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 1/69 (1.45%)  1
Sinus tachycardia * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Ventricular fibrillation * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Ventricular tachycardia * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 2/69 (2.90%)  2
Gastrointestinal disorders         
Abdominal pain upper * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Gastritis erosive * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Gastrointestinal haemorrhage * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  3 0/69 (0.00%)  0
Intestinal obstruction * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Faecaloma * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
General disorders         
Cyst * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Hernia * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Pyrexia * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
General physical health deterioration * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Medical device complication * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Device malfunction * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Device dislocation * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Hepatobiliary disorders         
Cholecystitis chronic * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Infections and infestations         
Bronchitis * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Bronchopneumonia * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Gastroenteritis * 1  2/67 (2.99%)  2 1/33 (3.03%)  1 1/32 (3.13%)  1 0/69 (0.00%)  0
Gastroenteritis viral * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Lobar pneumonia * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Lower respiratory tract infection * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Osteomyelitis * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Pneumonia * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Pneumonia klebsiella * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Postoperative wound infection * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Respiratory tract infection * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Injury, poisoning and procedural complications         
Ankle fracture * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Ligament rupture * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Metabolism and nutrition disorders         
Hyperglycaemia * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 1/69 (1.45%)  1
Hyperkalaemia * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Hyperphagia * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Nervous system disorders         
Syncope * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Ischaemic stroke * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Critical illness polyneuropathy * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Hypoxic-ischaemic encephalopathy * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Renal and urinary disorders         
Renal failure * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Renal failure acute * 1  1/67 (1.49%)  1 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Renal failure chronic * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Renal impairment * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Dyspnoea * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Lung disorder * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Respiratory disorder * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Surgical and medical procedures         
Heart transplant * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 1/69 (1.45%)  1
Cardiac pacemaker replacement * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Implantable defibrillator insertion * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Implantable defibrillator replacement * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Vascular disorders         
Circulatory collapse * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Hypotension * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Haemodynamic instability * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Riociguat (Adempas, BAY63-2521) up to 2 mg Riociguat (Adempas, BAY63-2521) up to 1 mg Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   57/67 (85.07%)      28/33 (84.85%)      25/32 (78.13%)      49/69 (71.01%)    
Blood and lymphatic system disorders         
Anaemia * 1  2/67 (2.99%)  2 4/33 (12.12%)  4 0/32 (0.00%)  0 2/69 (2.90%)  3
Cardiac disorders         
Aortic valve incompetence * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Atrial fibrillation * 1  6/67 (8.96%)  7 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Atrial flutter * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Atrial tachycardia * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Bradycardia * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 1/32 (3.13%)  1 1/69 (1.45%)  1
Cardiac failure * 1  4/67 (5.97%)  4 0/33 (0.00%)  0 1/32 (3.13%)  2 4/69 (5.80%)  4
Cardiac failure chronic * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Palpitations * 1  2/67 (2.99%)  2 1/33 (3.03%)  1 2/32 (6.25%)  2 1/69 (1.45%)  1
Pulmonary valve incompetence * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Supraventricular tachycardia * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 2/32 (6.25%)  2 0/69 (0.00%)  0
Ventricular tachycardia * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 1/32 (3.13%)  1 2/69 (2.90%)  2
Ear and labyrinth disorders         
Vertigo * 1  1/67 (1.49%)  1 1/33 (3.03%)  1 1/32 (3.13%)  2 0/69 (0.00%)  0
Endocrine disorders         
Hyperthyroidism * 1  2/67 (2.99%)  2 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Eye disorders         
Vision blurred * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Visual impairment * 1  1/67 (1.49%)  1 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Gastrointestinal disorders         
Abdominal discomfort * 1  1/67 (1.49%)  1 1/33 (3.03%)  1 1/32 (3.13%)  1 0/69 (0.00%)  0
Abdominal distension * 1  1/67 (1.49%)  1 1/33 (3.03%)  3 0/32 (0.00%)  0 0/69 (0.00%)  0
Abdominal pain upper * 1  2/67 (2.99%)  2 1/33 (3.03%)  1 1/32 (3.13%)  1 0/69 (0.00%)  0
Constipation * 1  1/67 (1.49%)  1 1/33 (3.03%)  1 4/32 (12.50%)  4 2/69 (2.90%)  2
Diarrhoea * 1  12/67 (17.91%)  14 5/33 (15.15%)  11 0/32 (0.00%)  0 5/69 (7.25%)  7
Dyspepsia * 1  6/67 (8.96%)  8 6/33 (18.18%)  8 2/32 (6.25%)  4 0/69 (0.00%)  0
Frequent bowel movements * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Gastrooesophageal reflux disease * 1  2/67 (2.99%)  2 2/33 (6.06%)  2 1/32 (3.13%)  1 0/69 (0.00%)  0
Gastrointestinal pain * 1  2/67 (2.99%)  2 0/33 (0.00%)  0 0/32 (0.00%)  0 0/69 (0.00%)  0
Haematochezia * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Haemorrhoids * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Hyperchlorhydria * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Nausea * 1  11/67 (16.42%)  11 2/33 (6.06%)  2 2/32 (6.25%)  2 5/69 (7.25%)  7
Vomiting * 1  5/67 (7.46%)  5 2/33 (6.06%)  2 0/32 (0.00%)  0 4/69 (5.80%)  6
General disorders         
Chest discomfort * 1  2/67 (2.99%)  2 0/33 (0.00%)  0 0/32 (0.00%)  0 1/69 (1.45%)  1
Chest pain * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 2/32 (6.25%)  3 2/69 (2.90%)  4
Fatigue * 1  4/67 (5.97%)  6 0/33 (0.00%)  0 3/32 (9.38%)  3 3/69 (4.35%)  4
Oedema peripheral * 1  5/67 (7.46%)  6 4/33 (12.12%)  4 4/32 (12.50%)  5 5/69 (7.25%)  6
Pain * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Pyrexia * 1  2/67 (2.99%)  2 1/33 (3.03%)  1 0/32 (0.00%)  0 4/69 (5.80%)  4
General physical health deterioration * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Non-cardiac chest pain * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Hepatobiliary disorders         
Hyperbilirubinaemia * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Infections and infestations         
Bronchitis * 1  1/67 (1.49%)  1 0/33 (0.00%)  0 0/32 (0.00%)  0 2/69 (2.90%)  2
Fungal skin infection * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Gastroenteritis * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 3/32 (9.38%)  4 1/69 (1.45%)  1
Herpes zoster * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 1/69 (1.45%)  1
Infection * 1  0/67 (0.00%)  0 1/33 (3.03%)  1 0/32 (0.00%)  0 0/69 (0.00%)  0
Influenza * 1  4/67 (5.97%)  4 0/33 (0.00%)  0 0/32 (0.00%)  0 2/69 (2.90%)  2
Localised infection * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Nasopharyngitis * 1  3/67 (4.48%)  3 3/33 (9.09%)  3 2/32 (6.25%)  3 4/69 (5.80%)  4
Otitis media * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 1/32 (3.13%)  1 0/69 (0.00%)  0
Sinusitis * 1  0/67 (0.00%)  0 0/33 (0.00%)  0 2/32 (6.25%)  2 1/69 (1.45%)  1