A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH. (CHEST-1)

• ClinicalTrials.gov Identifier: NCT00855465
• Recruitment Status: Completed
• First Posted: March 4, 2009
• Results First Posted: March 11, 2014
• Last Update Posted: November 28, 2016
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Hypertension
• Interventions: Drug: Riociguat (Adempas, BAY63-2521); Drug: Placebo
• Enrollment: 262

Participant Flow

Recruitment Details	Only subjects with symptomatic chronic thromboembolic pulmonary hypertension (CTEPH) could participate in this study. CTEPH was defined either as inoperable or as persisting or recurrent PH after pulmonary endarterectomy.
Pre-assignment Details	446 subjects were screened in 89 study centers in 26 countries worldwide. 184 of the 446 screened subjects were not randomized (adverse event [1], death [4], protocol violation [164], withdrawal by subject [15]). 262 of the 446 subjects were randomized. 261 of the 262 randomized subjects received study medication.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Period Title: Treatment Period
Started	174	88
Participants Received Treatment	173 [1]	88
Completed	160	83
Not Completed	14	5
Reason Not Completed
Adverse Event	4	2
Death	2	2
Lack of Efficacy	2	1
Non-compliance	1	0
Protocol Violation	2	0
Withdrawal by Subject	2	0
Not treated	1	0
[1] 1 subject randomized but not treated
Period Title: Follow-up Period (FUP)
Started	17 [1]	4 [1]
Completed	9	2
Not Completed	8	2
Reason Not Completed
Adverse Event	0	1
Death	0	1
Lost to Follow-up	3	0
Withdrawal by Subject	4	0
Missing	1	0
[1] Started FUP only if prematurely withdrawn from trt period or if not entering LTE study.

Baseline Characteristics

Arm/Group Title		Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo	Total
Arm/Group Description		Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks	Total of all reporting groups
Overall Number of Baseline Participants		173	88	261
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	173 participants	88 participants	261 participants
		59.3 (13.9)	59.2 (12.7)	59.3 (13.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	173 participants	88 participants	261 participants
	Female	118 68.2%	54 61.4%	172 65.9%
	Male	55 31.8%	34 38.6%	89 34.1%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	173 participants	88 participants	261 participants
White		120	65	185
Black or African American		7	1	8
Asian		37	20	57
Mixed		1	0	1
Not reported		8	2	10
Operability [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	173 participants	88 participants	261 participants
Inoperable CTEPH		121	68	189
Postoperative CTEPH		52	20	72
		[1] Measure Description: CTEPH defined as inoperable or as persisting/recurrent PH after pulmonary endarterectomy (PEA).
Body Mass Index; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	173 participants	88 participants	261 participants
		27.13 (5.75)	27.73 (5.30)	27.33 (5.60)
6-minute walking distance [1]; Mean (Standard Deviation); Unit of measure: Meters
	Number Analyzed	173 participants	88 participants	261 participants
		342.3 (81.9)	356.0 (74.7)	346.9 (79.7)
		[1] Measure Description: 6-minute walking distance (6MWD) is a measure for the objective evaluation of a participant's functional exercise capacity.
WHO (World Health Organization) functional class [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	173 participants	88 participants	261 participants
missing		0	1	1
I		3	0	3
II		55	25	80
III		107	60	167
IV		8	2	10
		[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).
Pulmonary vascular resistance [1]; Mean (Standard Deviation); Unit of measure: Dyn*s*cm^-5
	Number Analyzed	173 participants	88 participants	261 participants
		790.68 (431.57)	779.32 (400.94)	786.68 (420.21)
		[1] Measure 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

Outcome Measures

1. Primary Outcome

Title	6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16
Description	6-minute walking distance (6MWD) is a measure for the objective evaluation of a participant's functional exercise capacity.
Time Frame	Baseline and week 16

Outcome Measure Data

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.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Mean (Standard Deviation); Unit of Measure: Meters
	38.9 (79.3)	-5.5 (84.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values for participants who withdrew/died before 16 weeks were imputed with a worst value of 0m in case of death/clinical worsening without termination visit and with the last observed value otherwise. Comparison was done using analysis of covariance (ANCOVA), with baseline 6MWD as a covariate and treatment group and region as main effects. The primary statistical method was the stratified Wilcoxon test if the Shapiro-Wilk test for normality of residuals was statistically significant.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Prespecified significance level for all significance tests was 5%. Primary analysis, due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Test was stratified by region.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Additional analysis, due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	45.69
	Confidence Interval	(2-Sided) 95%; 24.74 to 66.63
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

2. Secondary Outcome

Title	Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16
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 week 16

Outcome Measure Data

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 of PVR.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	151	82
Mean (Standard Deviation); Unit of Measure: dyn*s*cm^-5
	-225.68 (247.52)	23.07 (273.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis method as for primary efficacy parameter.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO functional class, Time to clinical worsening, Borg scale, EQ5D, LPH. Primary analysis due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Additional analysis due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-246.43
	Confidence Interval	(2-Sided) 95%; -303.33 to -189.53
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

3. Secondary Outcome

Title	N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16
Description	N-terminal pro-brain natriuretic peptide (NT-proBNP) 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 week 16

Outcome Measure Data

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 of NT-proBNP.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	150	73
Mean (Standard Deviation); Unit of Measure: pg/mL
	-290.69 (1716.90)	76.35 (1446.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis method as for primary efficacy parameter.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO functional class, Time to clinical worsening, Borg scale, EQ5D, LPH. Primary analysis due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0293
	Comments	Additional analysis due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-443.99
	Confidence Interval	(2-Sided) 95%; -842.95 to -45.03
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

4. Secondary Outcome

Title	World Health Organization (WHO) Functional Class - Change From Baseline to Week 16
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 week 16

Outcome Measure Data

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. Participants with a missing baseline were excluded from the analysis of WHO functional class.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	87
Measure Type: Number; Unit of Measure: Percentage of Participants
-2	2.3	0
-1	30.6	14.9
0	61.8	78.2
1	4.0	3.4
2	0.6	3.4
3	0.6	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of IV in case of clinical worsening without termination visit or measurement at that termination visit and with a worst value of V in case of death and with the last observed value otherwise.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0026
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO functional class, Time to clinical worsening, Borg scale, EQ5D, LPH.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Test was stratified by region.

5. Secondary Outcome

Title	Percentage of Participants With Clinical Worsening
Description	The combined endpoint “time to clinical worsening”, made up of the following components, defined by the first occurrence: all-cause mortality; heart/lung transplantation; rescue endarterectomy; first hospitalization due to pulmonary hypertension; start of a new pulmonary hypertension treatment; persistent worsening of 6MWD or WHO functional class due to deterioration of PH.
Time Frame	At week 16

Outcome Measure Data

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.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Measure Type: Number; Unit of Measure: Percentage of participants
Any Event	2.3	5.7
Hospitalization due to pulmonary hypertension	0	1.1
Start of new pulmonary hypertension	1.2	1.1
Decrease in 6MWT due to pulmonary hypertension	0.6	2.3
Persistant worsening of functional class due to PH	0	1.1
Death	1.2	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Test for difference of occurence of "Any event".
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1724
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO functional class, Time to clinical worsening, Borg scale, EQ5D, LPH.
	Method	Log Rank
	Comments	Test was stratified by region.
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-3.37
	Confidence Interval	(2-Sided) 95%; -8.72 to 1.99
	Estimation Comments	Based on Mantel-Haenszel estimate stratified by region.

6. Secondary Outcome

Title	Borg CR 10 Scale - Change From Baseline to Week 16
Description	The Borg CR10 Scale is a participant reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the participant's exertion during a physical 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	Baseline and week 16

Outcome Measure Data

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.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-0.83 (2.39)	0.17 (2.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of 10 in case of death or clinical worsening without termination visit and with the last observed value otherwise.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0035
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO functional class, Time to clinical worsening, Borg scale, EQ5D, LPH. Nominally significant only due to hierarchical testing.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Test was stratified by region.

7. Secondary Outcome

Title	EQ-5D Utility Score - Change From Baseline to Week 16
Description	EQ-5D utility score is a Quality-of-Life participant reported outcome measure. 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	Baseline and week 16

Outcome Measure Data

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. Participants with a missing baseline were excluded from the analysis of the EQ5D utility score.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	172	87
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	0.0615 (0.2768)	-0.0819 (0.3446)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values at baseline were imputed using last available observation prior to start of study treatment. Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of -0.594 in case of death or clinical worsening without termination visit and with the last observed value otherwise.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO FC, TTCW, Borg scale, EQ5D, LPH. Primary analysis due to result of Shapiro-Wilk test.Nominally significant only due to hierarchical testing.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Additional analysis due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.21
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

8. Secondary Outcome

Title	Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16
Description	The self-reported Living with Pulmonary Hypertension (LPH) questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual’s quality of life. The LPH total score can range from 0 (best) to 105 (worst).
Time Frame	Baseline and week 16

Outcome Measure Data

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. Participants with a missing baseline were excluded from the analysis of the LPH questionnaire.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	170	86
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-6.72 (18.62)	-2.09 (19.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values at baseline were imputed using last available observation prior to start of study treatment. Missing values for participants who withdrew or died before 16 weeks were imputed with a worst value of 105 in case of death or clinical worsening without termination visit and with the last observed value otherwise.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1220
	Comments	Hierarchical testing for secondary efficacy parameters in the order: PVR, NT-proBNP, WHO functional class, Time to clinical worsening, Borg Dyspnea Score, EQ5D, LPH. Primary analysis due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0165
	Comments	Additional analysis due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.76
	Confidence Interval	(2-Sided) 95%; -10.45 to -1.06
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

9. Other Pre-specified Outcome

Title	All Caused Mortality
Description	All cause mortality (including cardiovascular mortality) was one component of the composite endpoint "time to clinical worsening".
Time Frame	At visit 6 (week 16)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) - a randomized subject was valid for ITT analyses if at least one dose of study medication was administered.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Measure Type: Number; Unit of Measure: Participants
	2	3

10. Other Pre-specified Outcome

Title	Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16
Description	Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.
Time Frame	Baseline and week 16

Outcome Measure Data

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 of PAPmean.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	156	84
Mean (Standard Deviation); Unit of Measure: mmHg
	-4.31 (6.70)	0.76 (7.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis as for primary efficacy parameter.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Exploratory testing. Primary analysis due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Additional analysis due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.96
	Confidence Interval	(2-Sided) 95%; -6.75 to -3.16
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0231
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

11. Other Pre-specified Outcome

Title	Cardiac Index (CI) - Change From Baseline to Week 16
Description	The cardiac index (CI) is a calculated hemodynamic parameter. CI is derived from the directly measured parameters cardiac output (CO), divided by the body surface area (BSA). BSA is a calculated parameter, using the subject’s height and weight in the DuBois formula. Formula: BSA = (W [kg]*0.425)*(H [cm]*0.725)*0.007184 (m^2)
Time Frame	Baseline and week 16

Outcome Measure Data

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 of CI.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	155	83
Mean (Standard Deviation); Unit of Measure: L/min/m^2
	0.45 (0.56)	-0.01 (0.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Missing values at week 16 were imputed using the last available post-baseline observation. Same analysis as for primary efficacy parameter.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Exploratory testing. Primary analysis due to result of Shapiro-Wilk test.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.62
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Additional analysis due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521)_individual Dose Titration, Placebo
	Comments	Shapiro-Wilk test for normality of ANCOVA residuals.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1160
	Comments	[Not Specified]
	Method	Shapiro-Wilk
	Comments	[Not Specified]

12. Other Pre-specified Outcome

Title	Systolic Blood Pressure (SBP) - Change From Baseline to Week 16
Description	Systolic systemic arterial blood pressure (SBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 95 – 180 mmHg.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Mean (Standard Deviation); Unit of Measure: mmHg
	-10.49 (14.17)	-5.28 (14.61)

13. Other Pre-specified Outcome

Title	Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16
Description	Diastolic systemic arterial blood pressure (DBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: <= 110 mmHg.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Mean (Standard Deviation); Unit of Measure: mmHg
	-8.17 (10.81)	-3.40 (10.38)

14. Other Pre-specified Outcome

Title	Heart Rate (HR) - Change From Baseline to Week 16
Description	Heart rate (HR) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 50 -105 beats per minute (bpm) at rest.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	173	88
Mean (Standard Deviation); Unit of Measure: Beats/min
	0.83 (11.74)	1.67 (12.37)

15. Other Pre-specified Outcome

Title	Alanine Aminotransferase (ALT) - Change From Baseline to Week 16
Description	Alanine Aminotransferase (ALT) is a standard clinical chemistry parameter. Normal range: 0 to 45 U/L.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	161	82
Mean (Standard Deviation); Unit of Measure: U/L
	-1.2 (16.2)	2.2 (13.6)

16. Other Pre-specified Outcome

Title	Aspartate Aminotransferase (AST) - Change From Baseline to Week 16
Description	Aspartate Aminotransferase (AST) is a standard clinical chemistry parameter. Normal range: 0 to 41 U/L.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	160	82
Mean (Standard Deviation); Unit of Measure: U/L
	0.3 (14.4)	2.8 (12.0)

17. Other Pre-specified Outcome

Title	Alkaline Phosphatase (AP) - Change From Baseline to Week 16
Description	Alkaline phosphatase (AP) is a standard clinical chemistry parameter. Normal range: 40 to 129 U/L (males), 35 to 104 U/L (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: U/L
	-3.8 (19.4)	2.5 (20.2)

18. Other Pre-specified Outcome

Title	Bilirubin - Change From Baseline to Week 16
Description	Bilirubin is a standard clinical chemistry parameter. Normal range: 0.1 to 1.2 mg/dL
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: mg/dL
	0.010 (0.483)	0.189 (0.453)

19. Other Pre-specified Outcome

Title	Creatinine - Change From Baseline to Week 16
Description	Creatinine is a standard clinical chemistry parameter. Normal range: 0.25 to 1.20 mg/dL (males), 0.46 to 1.00 mg/dL (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: mg/dL
	0.003 (0.338)	0.032 (0.178)

20. Other Pre-specified Outcome

Title	Creatinine Clearance - Change From Baseline to Week 16
Description	Creatinine clearance is a standard clinical chemistry parameter. Normal range: 90 to 140 mL/min (males), 80 to 125 mL/min (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: mL/min
	2.25 (15.53)	-0.93 (11.36)

21. Other Pre-specified Outcome

Title	Creatine Kinase (CK) - Change From Baseline to Week 16
Description	Creatine Kinase is a standard clinical chemistry parameter. Normal range: 35 to 232 U/L (males), 26 to 145 U/L (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: U/L
	7.9 (64.9)	5.6 (65.7)

22. Other Pre-specified Outcome

Title	Erythrocytes (RBC) - Change From Baseline to Week 16
Description	Erythrocytes (red blood cells, RBC) is a standard clinical hematology parameter. Normal range: 4.6 to 5.8*10^12 cells/L (males), 4.1 to 5.2*10^12 cells/L (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	155	81
Mean (Standard Deviation); Unit of Measure: *10^12 cells/L
	-0.14 (0.39)	0.04 (0.31)

23. Other Pre-specified Outcome

Title	Leukocytes (WBC) - Change From Baseline to Week 16
Description	Leukocytes (white blood cells, WBC) is a standard clinical hematology parameter. Normal range: 4.0 to 10.7*10^9 cells/L
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	155	81
Mean (Standard Deviation); Unit of Measure: *10^9 cells/L
	-0.55 (1.77)	0.23 (1.69)

24. Other Pre-specified Outcome

Title	Lymphocytes - Change From Baseline to Week 16
Description	Total lymphocytes is a standard clinical hematology parameter. Normal range: 1.0 to 4.0*10^9 cells/L
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	154	79
Mean (Standard Deviation); Unit of Measure: *10^9 cells/L
	-0.16 (0.48)	0.00 (0.53)

25. Other Pre-specified Outcome

Title	Neutrophils - Change From Baseline to Week 16
Description	Neutrophils is a standard clinical hematology parameter. Normal range: 1.6 to 7.4*10^9 cells/L
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	154	79
Mean (Standard Deviation); Unit of Measure: *10^9 cells/L
	-0.31 (1.55)	0.26 (1.57)

26. Other Pre-specified Outcome

Title	Hemoglobin - Change From Baseline to Week 16
Description	Hemoglobin is a standard clinical hematology parameter. Normal range: 13.5 to 17.5 g/dL (males), 12.0 to 16.0 g/dL (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	155	81
Mean (Standard Deviation); Unit of Measure: g/dL
	-0.69 (1.17)	0.02 (0.88)

27. Other Pre-specified Outcome

Title	Hematocrit - Change From Baseline to Week 16
Description	Hematocrit is a standard clinical hematology parameter. Normal range: 40 to 52% (males), 36 to 46% (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	155	81
Mean (Standard Deviation); Unit of Measure: Volume percentage of red blood cells
	-2.0 (4.1)	0.5 (3.5)

28. Other Pre-specified Outcome

Title	Potassium - Change From Baseline to Week 16
Description	Potassium is a standard clinical chemistry parameter. Normal range: 3.5 to 5.3 mmol/L
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	161	82
Mean (Standard Deviation); Unit of Measure: mmol/L
	-0.08 (0.48)	-0.02 (0.56)

29. Other Pre-specified Outcome

Title	Urate - Change From Baseline to Week 16
Description	Urate is a standard clinical chemistry parameter. Normal range: 4.0 to 8.5 mg/dL (males, 16-59 years), 3.4 to 8.7 mg/dL (males, >60 years) 2.5 to 7.5 mg/dL (females)
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: mg/dL
	-0.405 (1.415)	0.209 (1.577)

30. Other Pre-specified Outcome

Title	Urea (BUN) - Change From Baseline to Week 16
Description	Urea (blood urea nitrogen, BUN) is a standard clinical chemistry parameter. Normal range: 4 to 25 mg/dL
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: mg/dL
	-0.60 (15.26)	0.99 (13.62)

31. Other Pre-specified Outcome

Title	Cystatin C - Change From Baseline to Week 16
Description	Cystatin C is a biomarker. Normal range: 0.53 to 1.01 ng/mL
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	139	66
Mean (Standard Deviation); Unit of Measure: ng/ml
	16.1 (241.1)	62.9 (198.0)

32. Other Pre-specified Outcome

Title	Triacylglycerol Lipase - Change From Baseline to Week 16
Description	Triacylglycerol lipase is a standard clinical chemistry parameter. Normal range: 7 to 60 U/L
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of laboratory parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	82
Mean (Standard Deviation); Unit of Measure: U/L
	-4.2 (12.9)	0.1 (17.5)

33. Other Pre-specified Outcome

Title	Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16
Description	Arterial partial pressure of carbon dioxide (PaCO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of blood gas parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	151	80
Mean (Standard Deviation); Unit of Measure: mmHg
	0.34 (4.05)	0.56 (4.52)

34. Other Pre-specified Outcome

Title	Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16
Description	Arterial partial pressure of oxygen (PaO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of blood gas parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	151	80
Mean (Standard Deviation); Unit of Measure: mmHg
	-3.01 (14.71)	-4.95 (12.05)

35. Other Pre-specified Outcome

Title	Oxygen Saturation (SaO2) - Change From Baseline to Week 16
Description	Oxygen saturation (SaO2) is measured as part of the capillary or arterial blood gas analysis. Normal blood oxygen saturation is considered 95-100 percent. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of blood gas parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	151	79
Mean (Standard Deviation); Unit of Measure: Percentage of oxygen saturation
	-1.5 (4.4)	-3.1 (8.0)

36. Other Pre-specified Outcome

Title	Mean PR Duration (PRmean) - Change From Baseline to Week 16
Description	PR duration was evaluated as part of the 12-lead electrocardiogram. electrocardiograms (ECGs) were recorded after the participant had been at rest for 15 minutes in a supine position.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	162	78
Mean (Standard Deviation); Unit of Measure: ms
	-0.32 (14.21)	0.87 (11.16)

37. Other Pre-specified Outcome

Title	Mean QRS Duration (QRSmean) - Change From Baseline to Week 16
Description	QRS duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	165	80
Mean (Standard Deviation); Unit of Measure: ms
	-0.19 (4.49)	-0.05 (4.30)

38. Other Pre-specified Outcome

Title	Mean QT Duration (QTmean) - Change From Baseline to Week 16
Description	QT duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	123	53
Mean (Standard Deviation); Unit of Measure: ms
	1.19 (24.89)	-2.00 (25.56)

39. Other Pre-specified Outcome

Title	Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16
Description	Bazett-corrected QTcB duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	123	53
Mean (Standard Deviation); Unit of Measure: ms
	-4.30 (14.44)	-0.51 (15.58)

40. Other Pre-specified Outcome

Title	Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16
Description	Fridericia-corrected QTcF duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	123	53
Mean (Standard Deviation); Unit of Measure: ms
	-2.34 (13.71)	-1.02 (13.29)

41. Other Pre-specified Outcome

Title	Mean RR Duration (RRmean) - Change From Baseline to Week 16
Description	RR duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	166	81
Mean (Standard Deviation); Unit of Measure: ms
	3.89 (132.02)	-14.00 (131.93)

42. Other Pre-specified Outcome

Title	Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16
Description	Ventricular rate was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

Safety (SAF) - a randomized participant was valid for safety analyses if at least one dose of study medication was administered. Only participants with a baseline and at least one measurement on treatment (or up to two days after stopping treatment) were included in the analysis of ECG parameters.

Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description:	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
Overall Number of Participants Analyzed	166	81
Mean (Standard Deviation); Unit of Measure: beats per minute (bpm)
	-0.70 (11.96)	1.60 (11.68)

Adverse Events

Time Frame	Adverse event data were collected after signing the informed consent until 2 days after end of study treatment over a period of approximately 30 days.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
Arm/Group Description	Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
All-Cause Mortality
	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	34/173 (19.65%)	14/88 (15.91%)
Blood and lymphatic system disorders
Anaemia * 1	1/173 (0.58%)	1/88 (1.14%)
Cardiac disorders
Atrial fibrillation * 1	1/173 (0.58%)	0/88 (0.00%)
Atrial flutter * 1	1/173 (0.58%)	1/88 (1.14%)
Atrial tachycardia * 1	1/173 (0.58%)	0/88 (0.00%)
Cardiac arrest * 1	0/173 (0.00%)	2/88 (2.27%)
Cardiac failure * 1	1/173 (0.58%)	0/88 (0.00%)
Right ventricular failure * 1	6/173 (3.47%)	3/88 (3.41%)
Sick sinus syndrome * 1	1/173 (0.58%)	0/88 (0.00%)
Cardiopulmonary failure * 1	0/173 (0.00%)	1/88 (1.14%)
Chronic right ventricular failure * 1	1/173 (0.58%)	0/88 (0.00%)
Gastrointestinal disorders
Duodenal ulcer * 1	1/173 (0.58%)	0/88 (0.00%)
Gastric ulcer * 1	0/173 (0.00%)	1/88 (1.14%)
Gastritis * 1	2/173 (1.16%)	0/88 (0.00%)
Intestinal obstruction * 1	1/173 (0.58%)	0/88 (0.00%)
General disorders
Chest pain * 1	1/173 (0.58%)	0/88 (0.00%)
General physical health deterioration * 1	1/173 (0.58%)	0/88 (0.00%)
Oedema due to cardiac disease * 1	1/173 (0.58%)	0/88 (0.00%)
Catheter site haemorrhage * 1	2/173 (1.16%)	0/88 (0.00%)
Infections and infestations
Bronchitis * 1	1/173 (0.58%)	1/88 (1.14%)
Erysipelas * 1	1/173 (0.58%)	0/88 (0.00%)
Gastroenteritis * 1	1/173 (0.58%)	0/88 (0.00%)
Infection * 1	0/173 (0.00%)	1/88 (1.14%)
Pneumonia * 1	1/173 (0.58%)	0/88 (0.00%)
Anal abscess * 1	1/173 (0.58%)	0/88 (0.00%)
Injury, poisoning and procedural complications
Fall * 1	1/173 (0.58%)	0/88 (0.00%)
Head injury * 1	1/173 (0.58%)	0/88 (0.00%)
Injury * 1	0/173 (0.00%)	1/88 (1.14%)
Overdose * 1	1/173 (0.58%)	0/88 (0.00%)
Investigations
Light chain analysis increased * 1	0/173 (0.00%)	1/88 (1.14%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant * 1	1/173 (0.58%)	0/88 (0.00%)
Nervous system disorders
Syncope * 1	4/173 (2.31%)	3/88 (3.41%)
Psychiatric disorders
Bipolar I disorder * 1	0/173 (0.00%)	1/88 (1.14%)
Renal and urinary disorders
Renal failure * 1	1/173 (0.58%)	0/88 (0.00%)
Renal failure acute * 1	1/173 (0.58%)	0/88 (0.00%)
Renal failure chronic * 1	2/173 (1.16%)	0/88 (0.00%)
Renal impairment * 1	0/173 (0.00%)	1/88 (1.14%)
Reproductive system and breast disorders
Vaginal haemorrhage * 1	1/173 (0.58%)	0/88 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure * 1	1/173 (0.58%)	0/88 (0.00%)
Chronic obstructive pulmonary disease * 1	1/173 (0.58%)	1/88 (1.14%)
Chronic respiratory failure * 1	1/173 (0.58%)	0/88 (0.00%)
Dyspnoea * 1	1/173 (0.58%)	1/88 (1.14%)
Haemoptysis * 1	3/173 (1.73%)	0/88 (0.00%)
Pneumonitis * 1	1/173 (0.58%)	0/88 (0.00%)
Pulmonary hypertension * 1	2/173 (1.16%)	0/88 (0.00%)
Respiratory failure * 1	2/173 (1.16%)	0/88 (0.00%)
Vascular disorders
Hypotension * 1	1/173 (0.58%)	0/88 (0.00%)
Deep vein thrombosis * 1	0/173 (0.00%)	1/88 (1.14%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (15.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Riociguat (Adempas, BAY63-2521)_individual Dose Titration	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	146/173 (84.39%)	67/88 (76.14%)
Blood and lymphatic system disorders
Anaemia * 1	5/173 (2.89%)	1/88 (1.14%)
Cardiac disorders
Bradycardia * 1	1/173 (0.58%)	2/88 (2.27%)
Palpitations * 1	6/173 (3.47%)	4/88 (4.55%)
Right ventricular failure * 1	2/173 (1.16%)	2/88 (2.27%)
Ventricular extrasystoles * 1	0/173 (0.00%)	2/88 (2.27%)
Ear and labyrinth disorders
Vertigo * 1	1/173 (0.58%)	4/88 (4.55%)
Gastrointestinal disorders
Abdominal discomfort * 1	6/173 (3.47%)	2/88 (2.27%)
Abdominal pain * 1	4/173 (2.31%)	0/88 (0.00%)
Abdominal pain upper * 1	5/173 (2.89%)	3/88 (3.41%)
Constipation * 1	10/173 (5.78%)	1/88 (1.14%)
Diarrhoea * 1	17/173 (9.83%)	4/88 (4.55%)
Dry mouth * 1	3/173 (1.73%)	2/88 (2.27%)
Dyspepsia * 1	31/173 (17.92%)	7/88 (7.95%)
Dysphagia * 1	6/173 (3.47%)	0/88 (0.00%)
Gastritis * 1	6/173 (3.47%)	0/88 (0.00%)
Gastrooesophageal reflux disease * 1	7/173 (4.05%)	0/88 (0.00%)
Nausea * 1	19/173 (10.98%)	7/88 (7.95%)
Vomiting * 1	17/173 (9.83%)	3/88 (3.41%)
General disorders
Asthenia * 1	3/173 (1.73%)	3/88 (3.41%)
Chest discomfort * 1	5/173 (2.89%)	1/88 (1.14%)
Chest pain * 1	6/173 (3.47%)	4/88 (4.55%)
Fatigue * 1	5/173 (2.89%)	4/88 (4.55%)
Oedema * 1	6/173 (3.47%)	2/88 (2.27%)
Oedema peripheral * 1	27/173 (15.61%)	18/88 (20.45%)
Pyrexia * 1	2/173 (1.16%)	2/88 (2.27%)
Hepatobiliary disorders
Hepatic function abnormal * 1	0/173 (0.00%)	2/88 (2.27%)
Infections and infestations
Bronchitis * 1	5/173 (2.89%)	2/88 (2.27%)
Influenza * 1	0/173 (0.00%)	2/88 (2.27%)
Nasopharyngitis * 1	26/173 (15.03%)	8/88 (9.09%)
Rhinitis * 1	1/173 (0.58%)	2/88 (2.27%)
Upper respiratory tract infection * 1	10/173 (5.78%)	4/88 (4.55%)
Urinary tract infection * 1	7/173 (4.05%)	2/88 (2.27%)
Respiratory tract infection * 1	4/173 (2.31%)	1/88 (1.14%)
Investigations
Activated partial thromboplastin time prolonged * 1	8/173 (4.62%)	2/88 (2.27%)
Blood bilirubin increased * 1	0/173 (0.00%)	2/88 (2.27%)
Blood creatine phosphokinase increased * 1	2/173 (1.16%)	2/88 (2.27%)
Blood creatinine increased * 1	3/173 (1.73%)	5/88 (5.68%)
Blood potassium increased * 1	0/173 (0.00%)	2/88 (2.27%)
Blood urea increased * 1	1/173 (0.58%)	3/88 (3.41%)
Creatinine renal clearance decreased * 1	1/173 (0.58%)	3/88 (3.41%)
Gamma-glutamyltransferase increased * 1	1/173 (0.58%)	2/88 (2.27%)
International normalised ratio increased * 1	10/173 (5.78%)	4/88 (4.55%)
Metabolism and nutrition disorders
Gout * 1	0/173 (0.00%)	3/88 (3.41%)
Hyperkalaemia * 1	3/173 (1.73%)	2/88 (2.27%)
Hypokalaemia * 1	7/173 (4.05%)	2/88 (2.27%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	5/173 (2.89%)	1/88 (1.14%)
Back pain * 1	7/173 (4.05%)	5/88 (5.68%)
Joint swelling * 1	0/173 (0.00%)	2/88 (2.27%)
Muscle spasms * 1	4/173 (2.31%)	2/88 (2.27%)
Musculoskeletal pain * 1	5/173 (2.89%)	2/88 (2.27%)
Myalgia * 1	4/173 (2.31%)	1/88 (1.14%)
Pain in extremity * 1	3/173 (1.73%)	5/88 (5.68%)
Musculoskeletal chest pain * 1	0/173 (0.00%)	2/88 (2.27%)
Nervous system disorders
Dizziness * 1	39/173 (22.54%)	11/88 (12.50%)
Headache * 1	43/173 (24.86%)	12/88 (13.64%)
Hypoaesthesia * 1	4/173 (2.31%)	1/88 (1.14%)
Paraesthesia * 1	3/173 (1.73%)	3/88 (3.41%)
Tremor * 1	2/173 (1.16%)	2/88 (2.27%)
Restless legs syndrome * 1	1/173 (0.58%)	2/88 (2.27%)
Psychiatric disorders
Insomnia * 1	4/173 (2.31%)	6/88 (6.82%)
Respiratory, thoracic and mediastinal disorders
Asthma * 1	1/173 (0.58%)	2/88 (2.27%)
Cough * 1	9/173 (5.20%)	16/88 (18.18%)
Dyspnoea * 1	7/173 (4.05%)	11/88 (12.50%)
Epistaxis * 1	2/173 (1.16%)	2/88 (2.27%)
Nasal congestion * 1	6/173 (3.47%)	3/88 (3.41%)
Productive cough * 1	3/173 (1.73%)	2/88 (2.27%)
Skin and subcutaneous tissue disorders
Eczema * 1	1/173 (0.58%)	2/88 (2.27%)
Erythema * 1	1/173 (0.58%)	3/88 (3.41%)
Hyperhidrosis * 1	1/173 (0.58%)	4/88 (4.55%)
Vascular disorders
Flushing * 1	7/173 (4.05%)	2/88 (2.27%)
Haematoma * 1	2/173 (1.16%)	2/88 (2.27%)
Hypotension * 1	15/173 (8.67%)	3/88 (3.41%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (15.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The embargo can be up to 6 months (equal to the 180 days), moreover if it is necessary the embargo period can be prolonged to expiry of priority year.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: Bayer
• EMail: clinical-trials-contact@bayerhealthcare.com

Publications of Results:

Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657.

Archer SL. Riociguat for pulmonary hypertension--a glass half full. N Engl J Med. 2013 Jul 25;369(4):386-8. doi: 10.1056/NEJMe1306684.

Simonneau G, D'Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, Mayer E, Pulido T, Wang C, Colorado P, Fritsch A, Meier C, Nikkho S, Hoeper MM. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016 May;4(5):372-80. doi: 10.1016/S2213-2600(16)30022-4. Epub 2016 Apr 8.

Wang C, Jing ZC, Huang YG, Zhou DX, Liu ZH, Meier C, Nikkho S, Curram J, Zhang P, He JG. Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison. Heart Asia. 2016 May 17;8(1):74-82. doi: 10.1136/heartasia-2015-010712. eCollection 2016.

Ghofrani HA, Humbert M, Langleben D, Schermuly R, Stasch JP, Wilkins MR, Klinger JR. Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension. Chest. 2017 Feb;151(2):468-480. doi: 10.1016/j.chest.2016.05.024. Epub 2016 Jun 2. Review.

Kim DY, Kim HJ, Han KH, Han SY, Heo J, Woo HY, Um SH, Kim YH, Kweon YO, Lim HY, Yoon JH, Lee WS, Lee BS, Lee HC, Ryoo BY, Yoon SK. Real-Life Experience of Sorafenib Treatment for Hepatocellular Carcinoma in Korea: From GIDEON Data. Cancer Res Treat. 2016 Oct;48(4):1243-1252. Epub 2016 Feb 24.

Kudo M, Ikeda M, Takayama T, Numata K, Izumi N, Furuse J, Okusaka T, Kadoya M, Yamashita S, Ito Y, Kokudo N. Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON. J Gastroenterol. 2016 Dec;51(12):1150-1160. Epub 2016 Apr 22.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kim NH, D'Armini AM, Grimminger F, Grünig E, Hoeper MM, Jansa P, Mayer E, Neurohr C, Simonneau G, Torbicki A, Wang C, Fritsch A, Davie N, Ghofrani HA. Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension. Heart. 2017 Apr;103(8):599-606. doi: 10.1136/heartjnl-2016-309621. Epub 2016 Dec 23.

Saleh S, Becker C, Frey R, Mück W. Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulm Circ. 2016 Mar;6(Suppl 1):S86-96. doi: 10.1086/685404.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00855465 History of Changes
• Other Study ID Numbers: 11348; 2007-000072-16 ( EudraCT Number )
• First Submitted: December 15, 2008
• First Posted: March 4, 2009
• Results First Submitted: November 4, 2013
• Results First Posted: March 11, 2014
• Last Update Posted: November 28, 2016