Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE)

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ClinicalTrials.gov Identifier: NCT02891850

Recruitment Status : Completed

First Posted : September 8, 2016

Results First Posted : January 22, 2021

Last Update Posted : February 26, 2021

Sponsor:

Information provided by (Responsible Party):

Bayer

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Pulmonary Arterial Hypertension
Interventions	Drug: Riociguat (Adempas, BAY63-2521) Drug: Sildenafil Drug: Tadalafil
Enrollment	225

Participant Flow

Recruitment Details	Study was conducted at multiple centers in 21 countries between 11-JAN-2017 (first participant first visit) and 03-MAR-2020 (last participant last visit).
Pre-assignment Details	293 participants were screened in this study. Of these, 67 participants did not enter the treatment period (60 screening failures; 2 withdraw during screening; 2 withdraw following physician decision; 3 withdraw due to other reasons). 226 participants were randomized, of which 1 participant withdraw before treated.


Arm/Group Title	Riociguat	PDE-5i
Arm/Group Description	Participants received BAY63-2521 ta...	Participants remained on their curr...
Arm/Group Description	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Period Title: Overall Study
Started ^[1]	111	114
Completed	104	107
Not Completed	7	7
Reason Not Completed
Adverse Event	3	0
Death	0	4
Physician Decision	1	0
Pregnancy	1	0
Withdrawal by Subject	2	3
[1] Treated

Baseline Characteristics

Arm/Group Title		Riociguat	PDE-5i	Total
Arm/Group Description		Participants received BAY63-2521 ta...	Participants remained on their curr...	Total of all reporting groups
Arm/Group Description		Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.	Total of all reporting groups
Overall Number of Baseline Participants		111	114	225
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	111 participants	114 participants	225 participants
		49.4 (16.16)	49.2 (15.64)	49.3 (15.86)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	111 participants	114 participants	225 participants
	Female	82 73.9%	95 83.3%	177 78.7%
	Male	29 26.1%	19 16.7%	48 21.3%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	111 participants	114 participants	225 participants
	Hispanic or Latino	32 28.8%	31 27.2%	63 28.0%
	Not Hispanic or Latino	75 67.6%	80 70.2%	155 68.9%
	Unknown or Not Reported	4 3.6%	3 2.6%	7 3.1%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	111 participants	114 participants	225 participants
	American Indian or Alaska Native	1 0.9%	0 0.0%	1 0.4%
	Asian	17 15.3%	19 16.7%	36 16.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	4 3.6%	5 4.4%	9 4.0%
	White	86 77.5%	89 78.1%	175 77.8%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	3 2.7%	1 0.9%	4 1.8%

Outcome Measures

1.Primary Outcome


Title	Number of Participants With Satisfactory Clinical Response at Week 24
Description	The treatment is assessed as efficient (participants with satisfactory...
Description	The treatment is assessed as efficient (participants with satisfactory clinical response) in case at least 2 out of the following 3 criteria were fulfilled 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24 World Health Organization Functional Class (WHO FC) I or II at Week 24 N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7) and in absence of the defined criteria of clinical worsening
Time Frame	At Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with evaluable participants


Arm/Group Title	Riociguat	PDE-5i
Arm/Group Description:	Participants received BAY63-2521 ta...	Participants remained on their curr...
Arm/Group Description:	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed	111	113
Measure Type: Count of Participants Unit of Measure: Participants
With satisfactory clinical response	45 40.5%	23 20.4%
Without satisfactory clinical response	66 59.5%	90 79.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat, PDE-5i
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	The hypothesis was that there was no difference in the satisfactory clinical response rates in terms of odds ratio (OR) when treated with riociguat compared with participants who remained on their previous therapy.

Statistical Test of Hypothesis	P-Value	0.0007
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratified by PAH category at baseline

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.78
	Confidence Interval	(2-Sided) 95% 1.526 to 5.060
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks
Description	Six-minute walk distance (6MWD) was conducted to test the physical lim...
Description	Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured.
Time Frame	From baseline and up to 24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with evaluable participants


Arm/Group Title	Riociguat	PDE-5i
Arm/Group Description:	Participants received BAY63-2521 ta...	Participants remained on their curr...
Arm/Group Description:	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed	111	113
Mean (Standard Deviation) Unit of Measure: meters (m)
	36.448 (65.9748)	13.884 (67.1552)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat, PDE-5i
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	The hypothesis was that there was no difference in the change of 6MWD in terms of mean difference when treated with riociguat compared with participants who remained on their previous therapy.

Statistical Test of Hypothesis	P-Value	0.0542
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	Stratified by PAH category at baseline

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.56
	Confidence Interval	(2-Sided) 95% 5.03 to 40.10
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24
Description	N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blo...
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	From baseline and up to 24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with evaluable participants


Arm/Group Title	Riociguat	PDE-5i
Arm/Group Description:	Participants received BAY63-2521 ta...	Participants remained on their curr...
Arm/Group Description:	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed	108	113
Mean (Standard Deviation) Unit of Measure: picograms per milliliter (pg/mL)
	-88.234 (533.9179)	81.414 (1267.6142)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat, PDE-5i
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	The hypothesis was that there was no difference in the change of NT-proBNP in terms of mean difference when treated with riociguat compared with participants who remained on their previous therapy.

Statistical Test of Hypothesis	P-Value	0.1067
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	Stratified by PAH category at baseline

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-169.65
	Confidence Interval	(2-Sided) 95% -426.18 to 86.88
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24
Description	The participant's functional class was determined by using the WHO cla...
Description	The participant's functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms).
Time Frame	From baseline and up to 24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with evaluable participants


Arm/Group Title	Riociguat	PDE-5i
Arm/Group Description:	Participants received BAY63-2521 ta...	Participants remained on their curr...
Arm/Group Description:	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed	111	113
Mean (Standard Deviation) Unit of Measure: class
	-0.5 (0.58)	-0.2 (0.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat, PDE-5i
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	The hypothesis was that there was no difference in the change from baseline in WHO FC in terms of mean difference when treated with riociguat compared with participants who remained on their previous therapy.

Statistical Test of Hypothesis	P-Value	0.0007
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	Stratified by PAH category at baseline

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95% -0.42 to -0.11
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Number of Participants With Adjudicated Clinical Worsening at Week 24
Description	Clinical worsening was defined as death of any cause, hospitalization ...
Description	Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated).
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with evaluable participants


Arm/Group Title	Riociguat	PDE-5i
Arm/Group Description:	Participants received BAY63-2521 ta...	Participants remained on their curr...
Arm/Group Description:	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.	Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
Overall Number of Participants Analyzed	111	113
Measure Type: Count of Participants Unit of Measure: Participants
	1 0.9%	10 8.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Riociguat, PDE-5i
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	The hypothesis was that there was no difference in the clinical worsening rates in terms of odds ratio (OR) when treated with riociguat compared with participants who remained on their previous therapy.

Statistical Test of Hypothesis	P-Value	0.0047
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratified by PAH category at baseline

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95% 0.013 to 0.725
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	The adverse events were considered to be treatment emergent if they had started or worsened after the first treatment administration and up to 2 days after end of treatment. Since maximum study duration was 24 weeks, this could be up to 24 weeks + 2 days.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Riociguat		PDE-5i
Arm/Group Description	Participants received BAY63-2521 ta...		Participants remained on their curr...
Arm/Group Description	Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.		Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
All-Cause Mortality
	Riociguat		PDE-5i
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/111 (0.00%)		4/114 (3.51%)
Serious Adverse Events Serious Adverse Events
	Riociguat		PDE-5i
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/111 (7.21%)		19/114 (16.67%)
Blood and lymphatic system disorders
Iron deficiency anaemia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Cardiac disorders
Arrhythmia supraventricular ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Atrial fibrillation ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	2
Cardiac failure ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Right ventricular failure ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Gastrointestinal disorders
Gastrointestinal haemorrhage ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Small intestinal obstruction ^* 1	1/111 (0.90%)	3	0/114 (0.00%)	0
General disorders
Chest pain ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Infections and infestations
Gastroenteritis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Pneumonia ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Tracheobronchitis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Viral infection ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Respiratory tract infection ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Investigations
Pulmonary arterial pressure increased ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Metabolism and nutrition disorders
Dehydration ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Musculoskeletal and connective tissue disorders
Osteonecrosis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Nervous system disorders
Epilepsy ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Syncope ^* 1	1/111 (0.90%)	1	1/114 (0.88%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Dyspnoea exertional ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Epistaxis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Pulmonary hypertension ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Pulmonary arterial hypertension ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	3
Surgical and medical procedures
Drug therapy enhancement ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Vascular disorders
Hypotension ^* 1	2/111 (1.80%)	3	0/114 (0.00%)	0
1 Term from vocabulary, MedDRA (22.1) * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Riociguat		PDE-5i
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/111 (69.37%)		72/114 (63.16%)
Blood and lymphatic system disorders
Anaemia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Anaemia megaloblastic ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Iron deficiency anaemia ^* 1	2/111 (1.80%)	2	0/114 (0.00%)	0
Leukopenia ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Lymphopenia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Neutropenia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Cardiac disorders
Arrhythmia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Atrial fibrillation ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Cardiac failure chronic ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Palpitations ^* 1	3/111 (2.70%)	4	4/114 (3.51%)	4
Sinus tachycardia ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Tachycardia ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Ventricular extrasystoles ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Ear and labyrinth disorders
Vertigo ^* 1	2/111 (1.80%)	3	0/114 (0.00%)	0
Eye disorders
Astigmatism ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Cataract ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Eye irritation ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Glaucoma ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Retinal disorder ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Ocular discomfort ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Gastrointestinal disorders
Abdominal discomfort ^* 1	3/111 (2.70%)	3	0/114 (0.00%)	0
Abdominal distension ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Abdominal pain ^* 1	3/111 (2.70%)	3	0/114 (0.00%)	0
Abdominal pain lower ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Abdominal pain upper ^* 1	3/111 (2.70%)	3	1/114 (0.88%)	1
Constipation ^* 1	4/111 (3.60%)	5	0/114 (0.00%)	0
Diarrhoea ^* 1	6/111 (5.41%)	6	3/114 (2.63%)	3
Dyspepsia ^* 1	10/111 (9.01%)	10	0/114 (0.00%)	0
Flatulence ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Gastritis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Gastrooesophageal reflux disease ^* 1	8/111 (7.21%)	10	1/114 (0.88%)	1
Gingival hypertrophy ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Irritable bowel syndrome ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Nausea ^* 1	5/111 (4.50%)	6	3/114 (2.63%)	3
Toothache ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Vomiting ^* 1	3/111 (2.70%)	3	0/114 (0.00%)	0
Gastrointestinal hypermotility ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Reflux gastritis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
General disorders
Asthenia ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Chest discomfort ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Chest pain ^* 1	5/111 (4.50%)	8	5/114 (4.39%)	5
Drug ineffective ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Fatigue ^* 1	6/111 (5.41%)	7	2/114 (1.75%)	2
Malaise ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Oedema ^* 1	2/111 (1.80%)	2	2/114 (1.75%)	2
Oedema mucosal ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Oedema peripheral ^* 1	3/111 (2.70%)	4	4/114 (3.51%)	4
Pyrexia ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Peripheral swelling ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Hepatobiliary disorders
Hepatomegaly ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Immune system disorders
Drug hypersensitivity ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Hypersensitivity ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Infections and infestations
Acute sinusitis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Body tinea ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Bronchitis ^* 1	1/111 (0.90%)	1	2/114 (1.75%)	2
Conjunctivitis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Diverticulitis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Enterobiasis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Eye infection ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Fungal infection ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Gastroenteritis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Hepatitis E ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Herpes zoster ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Influenza ^* 1	1/111 (0.90%)	1	2/114 (1.75%)	2
Laryngitis ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Lower respiratory tract infection ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Nasopharyngitis ^* 1	8/111 (7.21%)	8	5/114 (4.39%)	5
Otitis media ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Pneumonia ^* 1	2/111 (1.80%)	2	1/114 (0.88%)	1
Rhinitis ^* 1	0/111 (0.00%)	0	4/114 (3.51%)	4
Sinusitis ^* 1	2/111 (1.80%)	2	6/114 (5.26%)	8
Tonsillitis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Upper respiratory tract infection ^* 1	4/111 (3.60%)	4	7/114 (6.14%)	8
Urinary tract infection ^* 1	2/111 (1.80%)	2	3/114 (2.63%)	3
Viral infection ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Pharyngotonsillitis ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Febrile infection ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Bronchitis viral ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Mycobacterial infection ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Respiratory tract infection ^* 1	1/111 (0.90%)	2	0/114 (0.00%)	0
Injury, poisoning and procedural complications
Ligament sprain ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Muscle strain ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Limb injury ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Bone contusion ^* 1	1/111 (0.90%)	1	1/114 (0.88%)	1
Investigations
Blood pressure decreased ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Blood pressure systolic increased ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Catheterisation cardiac ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Haemoglobin decreased ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Prothrombin time prolonged ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Hepatic enzyme increased ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
N-terminal prohormone brain natriuretic peptide increased ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Metabolism and nutrition disorders
Dehydration ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Fluid retention ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Gout ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Hyperuricaemia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Hypokalaemia ^* 1	0/111 (0.00%)	0	4/114 (3.51%)	4
Iron deficiency ^* 1	2/111 (1.80%)	2	4/114 (3.51%)	4
Decreased appetite ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Type 2 diabetes mellitus ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	1/111 (0.90%)	1	3/114 (2.63%)	3
Arthritis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Back pain ^* 1	1/111 (0.90%)	1	6/114 (5.26%)	6
Muscle spasms ^* 1	2/111 (1.80%)	2	1/114 (0.88%)	1
Musculoskeletal pain ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Myalgia ^* 1	1/111 (0.90%)	1	1/114 (0.88%)	1
Neck pain ^* 1	2/111 (1.80%)	2	1/114 (0.88%)	1
Pain in extremity ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	2
Pain in jaw ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Spinal osteoarthritis ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Systemic lupus erythematosus ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Intervertebral disc protrusion ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Nervous system disorders
Diabetic neuropathy ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Dizziness ^* 1	5/111 (4.50%)	5	2/114 (1.75%)	2
Headache ^* 1	14/111 (12.61%)	16	8/114 (7.02%)	8
Hypoaesthesia ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Migraine ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Presyncope ^* 1	1/111 (0.90%)	1	2/114 (1.75%)	2
Syncope ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Psychiatric disorders
Anxiety ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	3
Depression ^* 1	2/111 (1.80%)	2	0/114 (0.00%)	0
Insomnia ^* 1	0/111 (0.00%)	0	3/114 (2.63%)	3
Sleep disorder ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Stress ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Renal and urinary disorders
Polyuria ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Urinary incontinence ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Reproductive system and breast disorders
Dysmenorrhoea ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Menometrorrhagia ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Adnexa uteri cyst ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Respiratory, thoracic and mediastinal disorders
Asthma ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Cough ^* 1	0/111 (0.00%)	0	7/114 (6.14%)	7
Dry throat ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Dyspnoea ^* 1	3/111 (2.70%)	4	5/114 (4.39%)	6
Dyspnoea exertional ^* 1	2/111 (1.80%)	3	0/114 (0.00%)	0
Epistaxis ^* 1	3/111 (2.70%)	3	3/114 (2.63%)	4
Hypoxia ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Lung disorder ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Nasal congestion ^* 1	1/111 (0.90%)	1	1/114 (0.88%)	1
Nasal polyps ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Productive cough ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Pulmonary embolism ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Pulmonary hypertension ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Pulmonary oedema ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Rhinitis allergic ^* 1	2/111 (1.80%)	2	0/114 (0.00%)	0
Rhinorrhoea ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Sleep apnoea syndrome ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Throat irritation ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Paranasal sinus hypersecretion ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Pulmonary arterial hypertension ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Bronchial hyperreactivity ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Oropharyngeal pain ^* 1	0/111 (0.00%)	0	2/114 (1.75%)	2
Skin and subcutaneous tissue disorders
Acne ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Erythema ^* 1	1/111 (0.90%)	1	0/114 (0.00%)	0
Hyperhidrosis ^* 1	1/111 (0.90%)	1	1/114 (0.88%)	1
Pruritus ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Rash ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Surgical and medical procedures
Tooth extraction ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Vascular disorders
Circulatory collapse ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Flushing ^* 1	1/111 (0.90%)	1	1/114 (0.88%)	1
Hypertension ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Hypotension ^* 1	13/111 (11.71%)	19	6/114 (5.26%)	11
Orthostatic hypotension ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
Jugular vein distension ^* 1	0/111 (0.00%)	0	1/114 (0.88%)	1
1 Term from vocabulary, MedDRA (22.1) * Indicates events were collected by non-systematic assessment

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.

Results Point of Contact

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Name/Title:	Therapeutic Area Head
Organization:	Bayer
Phone:	(+) 1-888-8422937
EMail:	clinical-trials-contact@bayer.com

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

Hoeper MM, Al-Hiti H, Benza RL, Chang SA, Corris PA, Gibbs JSR, Grünig E, Jansa P, Klinger JR, Langleben D, McLaughlin VV, Meyer GMB, Ota-Arakaki J, Peacock AJ, Pulido T, Rosenkranz S, Vizza CD, Vonk-Noordegraaf A, White RJ, Chang M, Kleinjung F, Meier C, Paraschin K, Ghofrani HA, Simonneau G; REPLACE investigators. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jun;9(6):573-584. doi: 10.1016/S2213-2600(20)30532-4. Epub 2021 Mar 24.

Layout table for additonal information

Responsible Party:	Bayer
ClinicalTrials.gov Identifier:	NCT02891850
Other Study ID Numbers:	18588 2016-001067-36 ( EudraCT Number )
First Submitted:	August 26, 2016
First Posted:	September 8, 2016
Results First Submitted:	January 4, 2021
Results First Posted:	January 22, 2021
Last Update Posted:	February 26, 2021

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