A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PAH) (PATENT-1)

• 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	445

Participant Flow

Recruitment Details	Only participants with symptomatic Pulmonary arterial hypertension (PAH) could participate in this study. Both treatment-naïve participants and participants pre-treated with an endothelin receptor antagonist or a non-intravenous prostacyclin analogue could be included.
Pre-assignment Details	586 participants were enrolled in 124 study centers in 30 countries worldwide. 141 of the 586 enrolled participants were not randomized (adverse event [4], protocol violation [129], withdrawal by subject [8]). 445 of the 586 participants were randomized. 443 of the 445 randomized participants received study medication.

Arm/Group Title	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Period Title: Treatment Period
Started	254	64 [1]	127 [1]
Participants Received Treatment	254	63	126
Completed	237	57	111
Not Completed	17	7	16
Reason Not Completed
Adverse Event	8	1	7
Death	0	1	2
Lack of Efficacy	0	0	1
Lost to Follow-up	1	0	0
Non-compliance	1	0	0
Protocol Violation	1	2	2
Withdrawal by Subject	6	2	3
Not treated	0	1	1
[1] 1 randomized but not treated
Period Title: Follow-up Period (FUP)
Started	23 [1]	7 [1]	16 [1]
Completed	15	4	12
Not Completed	8	3	4
Reason Not Completed
Adverse Event	3	1	1
Death	2	0	1
Lost to Follow-up	1	0	2
Protocol Violation	0	1	0
Withdrawal by Subject	2	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[1] Started FUP only if prematurely withdrawn from trt period or if not entering LTE study.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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks	Total of all reporting groups
Overall Number of Baseline Participants		254	63	126	443
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	254 participants	63 participants	126 participants	443 participants
		51.1 (16.6)	48.8 (16.1)	50.7 (16.5)	50.6 (16.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	254 participants	63 participants	126 participants	443 participants
	Female	203 79.9%	49 77.8%	98 77.8%	350 79.0%
	Male	51 20.1%	14 22.2%	28 22.2%	93 21.0%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	254 participants	63 participants	126 participants	443 participants
White		161	33	78	272
Black or African American		4	1	1	6
Asian		79	22	38	139
Mixed		1	0	1	2
Not reported		9	7	8	24
Prior PH therapy; Measure Type: Number; Unit of measure: Participants	Number Analyzed	254 participants	63 participants	126 participants	443 participants
Therapy-Naive		123	32	66	221
Pre-Treated		131	31	60	222
pre-treated with endothelin receptor antagonist [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	254 participants	63 participants	126 participants	443 participants
Yes		113	27	54	194
No		141	36	72	249
		[1] Measure Description: Subjects pre-treated with an endothelin receptor antagonist.
pre-treated with prostacyclin analogue [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	254 participants	63 participants	126 participants	443 participants
Yes		20	4	7	31
No		234	59	119	412
		[1] Measure Description: Subjects pre-treated with a prostacyclin analogue.
PAH subtype [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	254 participants	63 participants	126 participants	443 participants
Idiopathic PAH		149	39	84	272
Familial PAH		7	1	1	9
Connective tissue disease assoc. PAH		71	15	25	111
Congenital heart disease (operated) assoc. PAH		15	8	12	35
Portal Pulmonary hypertension		11	0	2	13
Anorexigen or Amphtamin assoc: PAH		1	0	2	3
		[1] Measure Description: Subtypes acc. to the Venice Clinical Classification of PH, Group 1 (idiopathic PAH, familial PAH, associated PAH due to [1] connective tissue disease, [2] congenital heart disease, [3] portal hypertension with liver cirrhosis, or [4] anorexigen or amphetamine use)
BMI; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	254 participants	63 participants	126 participants	443 participants
		25.91 (5.48)	26.85 (5.35)	26.26 (5.92)	26.14 (5.59)
Baseline 6MWD [1]; Mean (Standard Deviation); Unit of measure: Meters
	Number Analyzed	254 participants	63 participants	126 participants	443 participants
		361.4 (67.7)	363.2 (66.6)	367.8 (74.6)	363.5 (69.5)
		[1] Measure Description: 6-minute walking distance (6MWD) is a measure for the objective evaluation of a patient's functional exercise capacity.
WHO (World Health Organization) functional class [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	254 participants	63 participants	126 participants	443 participants
I		5	5	4	14
II		108	19	60	187
III		140	39	58	237
IV		1	0	3	4
missing		0	0	1	1
		[1] Measure Description: The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (participants with PH but without resulting limitation of physical activity) to class IV (participants with PH with inability to carry out any physical activity without symptoms. These participants 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.
Pulmonary vascular resistance [1]; Mean (Standard Deviation); Unit of measure: Dn*s*cm^-5
	Number Analyzed	254 participants	63 participants	126 participants	443 participants
		790.96 (452.60)	847.81 (548.17)	834.06 (476.71)	810.89 (473.45)
		[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 12
Description	6-minute walking distance (6MWD) is a measure for the objective evaluation of a patient's functional exercise capacity.
Time Frame	Baseline and week 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	254	63	126
Mean (Standard Deviation); Unit of Measure: Meters
	29.6 (65.8)	31.1 (79.3)	-5.6 (85.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	Missing values for participants who withdrew/died before 12 weeks were imputed with worst value of 0m in case of death or clinical worsening without termination visit and with last observed value otherwise. Comparison was done using ANCOVA, with baseline 6MWD as a covariate and treatment group, region and treatment naive/add-on therapy 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 and therapy naive/add-on therapy

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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	35.78
	Confidence Interval	(2-Sided) 95%; 20.06 to 51.51
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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 12
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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	232	58	107
Mean (Standard Deviation); Unit of Measure: dyn*s*cm^-5
	-223.29 (260.09)	-167.79 (320.22)	-8.89 (316.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	Missing values at week 12 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, TTCW, Borg scale, EQ5D, LPH. Primary analysis due to result of Shapiro-Wilk test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Test was stratified by region and therapy naive/add-on therapy

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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	-225.72
	Confidence Interval	(2-Sided) 95%; -281.37 to -170.08
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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 12
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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	228	54	106
Mean (Standard Deviation); Unit of Measure: pg/mL
	-197.89 (1721.29)	-471.50 (913.02)	232.39 (1011.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	Missing values at week 12 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	Test was stratified by region and therapy naive/add-on therapy

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0157
	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	-431.81
	Confidence Interval	(2-Sided) 95%; -781.52 to -82.10
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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 12
Description	The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (participants with PH but without resulting limitation of physical activity) to class IV (participants with PH with inability to carry out any physical activity without symptoms. These participants 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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	254	63	125
Measure Type: Number; Unit of Measure: Percentage of participants
-2	0.4	0	0
-1	20.5	23.8	14.4
0	75.6	68.3	71.2
1	2.8	6.3	12.0
2	0.4	1.6	2.4
3	0.4	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	Missing values for participants who withdrew or died before 12 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	0.0033
	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 and therapy naive/add-on therapy

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; atrial septostomy; 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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	254	63	126
Measure Type: Number; Unit of Measure: Percentage of participants
Any event	1.2	3.2	6.3
Hospitalization due to pulmonary hypertension	0.4	0	3.2
Start of new pulmonary hypertension treatment	0.4	1.6	4.0
Decrease in 6MWT due to pulmonary hypertension	0.4	1.6	1.6
Persistant worsening of functional class due to PH	0	0	0.8
Death	0.8	1.6	2.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	The test is for difference of occurence of "Any event".
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0046
	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 and therapy naive/add-on therapy
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-5.20
	Confidence Interval	(2-Sided) 95%; -9.85 to -0.55
	Estimation Comments	Based on Mantel-Haenszel estimate stratified by region and therapy naive/add-on therapy.

6. Secondary Outcome

Title	Borg CR 10 Scale - Change From Baseline to Week 12
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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	254	63	126
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-0.44 (1.72)	-0.33 (1.47)	0.09 (2.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	Missing values for participants who withdrew or died before 12 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	0.0022
	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 and therapy naive/add-on therapy

7. Secondary Outcome

Title	EQ-5D Utility Score - Change From Baseline to Week 12
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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	253	62	124
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	0.0329 (0.2350)	0.0782 (0.3111)	-0.0317 (0.3044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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 12 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	0.0663
	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	Test was stratified by region and therapy naive/add-on therapy.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0197
	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	0.06
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.11
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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 12
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 12

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
Overall Number of Participants Analyzed	247	62	122
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-5.99 (17.76)	-10.21 (21.27)	0.36 (18.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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 12 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	0.0019
	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	Test was stratified by region and therapy naive/add-on therapy.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	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	-6.17
	Confidence Interval	(2-Sided) 95%; -9.79 to -2.54
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT, 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]

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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	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 12 weeks	Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks	Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
All-Cause Mortality
	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	29/254 (11.42%)	11/63 (17.46%)	23/126 (18.25%)
Blood and lymphatic system disorders
Anaemia * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Cardiac disorders
Atrioventricular block * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Cardiac failure * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Cardiomegaly * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Right ventricular failure * 1	2/254 (0.79%)	3/63 (4.76%)	1/126 (0.79%)
Supraventricular tachycardia * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Eye disorders
Retinal artery occlusion * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Gastrointestinal disorders
Abdominal pain * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Diarrhoea * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Gastritis * 1	1/254 (0.39%)	1/63 (1.59%)	0/126 (0.00%)
Haematemesis * 1	0/254 (0.00%)	1/63 (1.59%)	0/126 (0.00%)
Irritable bowel syndrome * 1	0/254 (0.00%)	1/63 (1.59%)	0/126 (0.00%)
Intra-abdominal haemorrhage * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
General disorders
Asthenia * 1	1/254 (0.39%)	0/63 (0.00%)	1/126 (0.79%)
Chest pain * 1	2/254 (0.79%)	0/63 (0.00%)	1/126 (0.79%)
Pyrexia * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Infections and infestations
Bronchitis * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Bronchopneumonia * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Diarrhoea infectious * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Encephalitis herpes * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Gastroenteritis * 1	1/254 (0.39%)	1/63 (1.59%)	0/126 (0.00%)
Infection * 1	0/254 (0.00%)	1/63 (1.59%)	0/126 (0.00%)
Influenza * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Pneumonia * 1	2/254 (0.79%)	1/63 (1.59%)	0/126 (0.00%)
Sepsis * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Tooth infection * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Enterocolitis infectious * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Mycoplasma infection * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Respiratory tract infection * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Injury, poisoning and procedural complications
Muscle rupture * 1	0/254 (0.00%)	1/63 (1.59%)	0/126 (0.00%)
Overdose * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Subdural haematoma * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Investigations
Catheterisation cardiac * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Electrocardiogram ST-T segment abnormal * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Hepatic enzyme increased * 1	1/254 (0.39%)	0/63 (0.00%)	1/126 (0.79%)
Metabolism and nutrition disorders
Dehydration * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic malignant melanoma * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Nervous system disorders
Dizziness * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Loss of consciousness * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Presyncope * 1	1/254 (0.39%)	0/63 (0.00%)	1/126 (0.79%)
Syncope * 1	3/254 (1.18%)	0/63 (0.00%)	5/126 (3.97%)
Psychiatric disorders
Anxiety * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Renal and urinary disorders
Renal failure acute * 1	2/254 (0.79%)	0/63 (0.00%)	0/126 (0.00%)
Reproductive system and breast disorders
Vaginal haemorrhage * 1	0/254 (0.00%)	1/63 (1.59%)	0/126 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Haemoptysis * 1	2/254 (0.79%)	0/63 (0.00%)	0/126 (0.00%)
Hypoxia * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Interstitial lung disease * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Pneumothorax * 1	1/254 (0.39%)	0/63 (0.00%)	1/126 (0.79%)
Pulmonary congestion * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Pulmonary hypertension * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
Respiratory failure * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Pulmonary arterial hypertension * 1	1/254 (0.39%)	1/63 (1.59%)	2/126 (1.59%)
Vascular disorders
Circulatory collapse * 1	0/254 (0.00%)	0/63 (0.00%)	1/126 (0.79%)
Hypotension * 1	1/254 (0.39%)	0/63 (0.00%)	0/126 (0.00%)
* 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) up to 2.5 mg_IDT	Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	216/254 (85.04%)	57/63 (90.48%)	96/126 (76.19%)
Blood and lymphatic system disorders
Anaemia * 1	20/254 (7.87%)	1/63 (1.59%)	3/126 (2.38%)
Cardiac disorders
Palpitations * 1	20/254 (7.87%)	5/63 (7.94%)	6/126 (4.76%)
Tachycardia * 1	9/254 (3.54%)	0/63 (0.00%)	7/126 (5.56%)
Gastrointestinal disorders
Abdominal discomfort * 1	7/254 (2.76%)	0/63 (0.00%)	1/126 (0.79%)
Abdominal distension * 1	6/254 (2.36%)	2/63 (3.17%)	1/126 (0.79%)
Abdominal pain * 1	9/254 (3.54%)	0/63 (0.00%)	3/126 (2.38%)
Abdominal pain upper * 1	9/254 (3.54%)	2/63 (3.17%)	5/126 (3.97%)
Constipation * 1	9/254 (3.54%)	3/63 (4.76%)	2/126 (1.59%)
Diarrhoea * 1	35/254 (13.78%)	6/63 (9.52%)	12/126 (9.52%)
Dyspepsia * 1	48/254 (18.90%)	8/63 (12.70%)	10/126 (7.94%)
Gastric polyps * 1	0/254 (0.00%)	2/63 (3.17%)	0/126 (0.00%)
Gastritis * 1	3/254 (1.18%)	4/63 (6.35%)	0/126 (0.00%)
Gastrooesophageal reflux disease * 1	14/254 (5.51%)	4/63 (6.35%)	4/126 (3.17%)
Nausea * 1	40/254 (15.75%)	10/63 (15.87%)	16/126 (12.70%)
Vomiting * 1	26/254 (10.24%)	7/63 (11.11%)	11/126 (8.73%)
General disorders
Asthenia * 1	6/254 (2.36%)	2/63 (3.17%)	2/126 (1.59%)
Chest discomfort * 1	6/254 (2.36%)	4/63 (6.35%)	11/126 (8.73%)
Chest pain * 1	16/254 (6.30%)	4/63 (6.35%)	10/126 (7.94%)
Face oedema * 1	5/254 (1.97%)	1/63 (1.59%)	4/126 (3.17%)
Fatigue * 1	7/254 (2.76%)	0/63 (0.00%)	8/126 (6.35%)
Feeling hot * 1	2/254 (0.79%)	0/63 (0.00%)	3/126 (2.38%)
Oedema * 1	8/254 (3.15%)	1/63 (1.59%)	2/126 (1.59%)
Oedema peripheral * 1	44/254 (17.32%)	14/63 (22.22%)	14/126 (11.11%)
Pyrexia * 1	7/254 (2.76%)	6/63 (9.52%)	4/126 (3.17%)
Infections and infestations
Bronchitis * 1	8/254 (3.15%)	3/63 (4.76%)	3/126 (2.38%)
Gastroenteritis * 1	7/254 (2.76%)	0/63 (0.00%)	1/126 (0.79%)
Nasopharyngitis * 1	26/254 (10.24%)	6/63 (9.52%)	14/126 (11.11%)
Oral candidiasis * 1	0/254 (0.00%)	2/63 (3.17%)	0/126 (0.00%)
Upper respiratory tract infection * 1	7/254 (2.76%)	2/63 (3.17%)	5/126 (3.97%)
Urinary tract infection * 1	3/254 (1.18%)	0/63 (0.00%)	4/126 (3.17%)
Respiratory tract infection * 1	7/254 (2.76%)	2/63 (3.17%)	5/126 (3.97%)
Investigations
Activated partial thromboplastin time prolonged * 1	3/254 (1.18%)	0/63 (0.00%)	3/126 (2.38%)
Haemoglobin decreased * 1	0/254 (0.00%)	3/63 (4.76%)	0/126 (0.00%)
International normalised ratio increased * 1	6/254 (2.36%)	0/63 (0.00%)	5/126 (3.97%)
Metabolism and nutrition disorders
Hyperuricaemia * 1	2/254 (0.79%)	2/63 (3.17%)	1/126 (0.79%)
Hypokalaemia * 1	12/254 (4.72%)	3/63 (4.76%)	6/126 (4.76%)
Iron deficiency * 1	1/254 (0.39%)	0/63 (0.00%)	3/126 (2.38%)
Decreased appetite * 1	5/254 (1.97%)	1/63 (1.59%)	3/126 (2.38%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	8/254 (3.15%)	0/63 (0.00%)	3/126 (2.38%)
Back pain * 1	9/254 (3.54%)	3/63 (4.76%)	4/126 (3.17%)
Muscle spasms * 1	3/254 (1.18%)	1/63 (1.59%)	4/126 (3.17%)
Musculoskeletal pain * 1	4/254 (1.57%)	0/63 (0.00%)	3/126 (2.38%)
Myalgia * 1	2/254 (0.79%)	2/63 (3.17%)	1/126 (0.79%)
Pain in extremity * 1	11/254 (4.33%)	0/63 (0.00%)	6/126 (4.76%)
Nervous system disorders
Dizziness * 1	39/254 (15.35%)	15/63 (23.81%)	15/126 (11.90%)
Headache * 1	69/254 (27.17%)	20/63 (31.75%)	25/126 (19.84%)
Presyncope * 1	4/254 (1.57%)	2/63 (3.17%)	0/126 (0.00%)
Psychiatric disorders
Anxiety * 1	2/254 (0.79%)	2/63 (3.17%)	2/126 (1.59%)
Insomnia * 1	9/254 (3.54%)	1/63 (1.59%)	1/126 (0.79%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	12/254 (4.72%)	3/63 (4.76%)	13/126 (10.32%)
Dyspnoea * 1	16/254 (6.30%)	4/63 (6.35%)	14/126 (11.11%)
Epistaxis * 1	11/254 (4.33%)	1/63 (1.59%)	1/126 (0.79%)
Nasal congestion * 1	11/254 (4.33%)	4/63 (6.35%)	3/126 (2.38%)
Pharyngeal inflammation * 1	0/254 (0.00%)	2/63 (3.17%)	0/126 (0.00%)
Oropharyngeal pain * 1	2/254 (0.79%)	0/63 (0.00%)	6/126 (4.76%)
Skin and subcutaneous tissue disorders
Alopecia * 1	2/254 (0.79%)	2/63 (3.17%)	1/126 (0.79%)
Erythema * 1	3/254 (1.18%)	3/63 (4.76%)	0/126 (0.00%)
Pruritus * 1	4/254 (1.57%)	2/63 (3.17%)	2/126 (1.59%)
Vascular disorders
Flushing * 1	5/254 (1.97%)	2/63 (3.17%)	7/126 (5.56%)
Hypotension * 1	24/254 (9.45%)	2/63 (3.17%)	3/126 (2.38%)
Hot flush * 1	1/254 (0.39%)	1/63 (1.59%)	6/126 (4.76%)
* 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:

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.

Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655.

Rosenkranz S, Ghofrani HA, Beghetti M, Ivy D, Frey R, Fritsch A, Weimann G, Saleh S, Apitz C. Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Heart. 2015 Nov;101(22):1792-9. doi: 10.1136/heartjnl-2015-307832. Epub 2015 Jul 1.

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.

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

Humbert M, Coghlan JG, Ghofrani HA, Grimminger F, He JG, Riemekasten G, Vizza CD, Boeckenhoff A, Meier C, de Oliveira Pena J, Denton CP. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017 Feb;76(2):422-426. doi: 10.1136/annrheumdis-2015-209087. Epub 2016 Jul 25.

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:	NCT00810693 History of Changes
Other Study ID Numbers:	12934; 2008-003482-68 ( EudraCT Number )
First Submitted:	December 17, 2008
First Posted:	December 18, 2008
Results First Submitted:	November 5, 2013
Results First Posted:	February 26, 2014
Last Update Posted:	November 28, 2016