Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00323297
• Collaborator: (none)
• Enrollment: 105
• Locations: 30
• Arms: 2
• Duration (Months): 83
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To assess the efficacy and safety of sildenafil when added to patients with PAH who are taking bosentan as all or part of their background therapy.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Bosentan; Other: Placebo; Drug: Bosentan; Drug: Sildenafil Citrate	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multinational, Multicentre, Randomized, Double-blind Study To Assess The Efficacy And Safety Of Oral Sildenafil 20mg Tid Or Placebo When Added To Bosentan In The Treatment Of Subjects, Aged 18 Years And Above, With Pulmonary Arterial Hypertension (Pah)
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: placebo	Drug: Bosentan; Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil); Other: Placebo; Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil)
Experimental: Active	Drug: Bosentan; Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase; Drug: Sildenafil Citrate; Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 [Week 12]

   6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.

Secondary Outcome Measures

1. Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF [Week 12]

   WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class.

2. Clinical Worsening Events [Week 12]

   No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy.

3. Change From Baseline in Borg Dyspnea Score at Week 12 [Week 12]

   Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]); (very slight); (slight breathlessness); (moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum]); and 10 (maximum).

4. One Year Survival Probability From the Start of Sildenafil Treatment. [One year from the time of starting sildenafil]

   The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil.

5. One Year Survival From the Start of Sildenafil Treatment. [One year from the time of starting sildenafil]

   The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects aged 18 and over above with PAH and for which bosentan therapy is indicated according to national license

• Subjects with a mean pulmonary artery pressure of >25mmHg and a pulmonary artery wedge pressure of <15mmHg at rest via right heart catheterization within 3 years prior to randomization.

• Subjects whose baseline 6 Minute Walk Test distance is >100m and < 450m.

Exclusion Criteria:

• PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria

• Subjects whose 6 Minute Walk Test may be limited by conditions other than PAH related dyspnoea or fatigue eg. claudication from vascular insufficiency or arthritis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	West Los Angeles VA Healthcare, Pulmonary Hypertension Program	Los Angeles	California	United States	90073
2	Henry Ford Hospital	Detroit	Michigan	United States	48202
3	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
4	Baylor College of Medicine	Houston	Texas	United States	77030
5	The Methodist Hospital	Houston	Texas	United States	77030
6	Diagnostics Research Group	San Antonio	Texas	United States	78229
7	St. Vincents Hospital	Darlinghurst	New South Wales	Australia	2010
8	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
9	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 08
10	Institut klinicke a experimentalni mediciny, Klinika kardiologie	Praha 4		Czechia	140 21
11	Clinique des Maladies Respiratoires	Lille		France	59037
12	Hopital Claude Huriez	Lille		France	59037
13	Hopital Adules Brabois	Vandoeuvre Les Nancy		France	54511
14	Unfallkrankenhaus Berlin, Klinik fuer Innere Medizin	Berlin		Germany	12683
15	II. Medizinische Klinik, Kardiologie, Angiologie und Pneumologie	Coburg		Germany	96450
16	Universitaetsklinikum Essen, Zentrum fuer Innere Medizin, Klinik fuer Kardiologie	Essen		Germany	45122
17	Universitaetsklinikum Giessen und Marburg GmbH, Standort Giessen	Giessen		Germany	35392
18	Medizinische Hochschule Hannover	Hannover		Germany	30625
19	Universitaetsklinikum des Saarlandes, Innere Medizin V	Homburg		Germany	66421
20	Medizinische Klinik und Poliklinik I, Universitaetsklinikum Leipzig	Leipzig		Germany	04103
21	Med. Klinik u. Poliklinik I der LMU Muenchen, Klinikum Grosshadern	Muenchen		Germany	81377
22	Praxis fuer Innere Medizin, Kardiologie und Angiologie	Nuernberg		Germany	90402
23	Missionsaerztliche Klinik Wuerzburg, Gemeinnuetzige Gesellschaft mbH	Wuerzburg		Germany	97067
24	Attikon Hospital	Haidari	Athens	Greece	12462
25	Rambam Medical Center	Haifa		Israel	31096
26	Rabin Medical Centre	Petach Tikva		Israel	49100
27	Cardiologia, Azienda Ospedaliera Monaldi, Seconda Università di Napoli	Napoli		Italy	80131
28	Unita' di Ipertensione Polmonare, Dipartimento di Scienze Respiratorie e Cardiovascolari	Roma		Italy	00161
29	Department of Surgery, National Taiwan University Hospital	Taipei		Taiwan	100
30	PVDU	Papworth Everard	Cambridgeshire	United Kingdom	CB23 3RE

Sponsors and Collaborators

• Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT00323297
• Other Study ID Numbers: A1481243; 2006-001464-23; PATHWAYS
• First Posted: May 9, 2006
• Last Update Posted: Feb 1, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Bosentan; Sildenafil Citrate

Study Results

Participant Flow

Recruitment Details	This study was conducted at 29 active centers in 10 countries (10 centers in Germany, 5 centers in the United States of America [USA], 3 centers in France, 2 centers in Australia, Czech Republic, Italy, and Israel, and 1 center in Greece, Taiwan and United Kingdom [UK])
Pre-assignment Detail	Participants were on bosentan therapy for 3 months prior. Participants were randomized to sildenafil or placebo. Part A study was double-blind phase (12 weeks) and Part B was 12 months open-label phase. 53 and 51 participants were randomized to placebo and sildenafil arm respectively. One participant in sildenafil arm did not receive any treatment

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Period Title: Part A (Double Blind Randomized)
STARTED	53	50
COMPLETED	48	43
NOT COMPLETED	5	7
Period Title: Part A (Double Blind Randomized)
STARTED	48	43
COMPLETED	39	31
NOT COMPLETED	9	12

Baseline Characteristics

Arm/Group Title	Placebo	Sildenafil	Total
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	Total of all reporting groups
Overall Participants	53	50	103
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.9 (14.14)	55.2 (15.10)	56.0 (14.57)
Sex: Female, Male (Count of Participants)
Female	41 77.4%	37 74%	78 75.7%
Male	12 22.6%	13 26%	25 24.3%
Six Minute Walk Test (6MWT) (Meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Meters]	350.38 (87.587)	354.44 (73.121)	352.35 (80.520)
Mean Pulmonary Artery Pressure (mPAP) (Millimeter(mm) of mercury(Hg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Millimeter(mm) of mercury(Hg)]	44.9 (13.33)	46.9 (12.47)	45.8 (12.89)
World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension (Number) [Number]
Class I	0 0%	0 0%	0 0%
Class II	15 28.3%	20 40%	35 34%
Class III	38 71.7%	29 58%	67 65%
Class IV	0 0%	1 2%	1 1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12
Description	6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward (LOCF) approach. Statistical analysis was carried out on LOCF values.

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Measure Participants	53	50
Change from baseline at Week 12 (n=46,44)	17.42 (57.270)	14.08 (63.679)
Change from baseline at Week 12 LOCF (n=53,49)	14.08 (57.557)	13.62 (60.950)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sildenafil
	Comments	The estimated sample size was based upon the primary endpoint. A sample size of 51 subjects per treatment group was required to detect a difference of 30 meters between treatments with 80% power at a one-sided significance level of 0.05, assuming a standard deviation of 60 meters. This primary statistical analysis was carried for Week 12 data.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5802
	Comments	A sequential closed-testing procedure was implemented for all secondary endpoints. If no statistically significant treatment effect was found for the primary endpoint then statistical tests were not to be performed on the secondary endpoints.
	Method	ANCOVA
	Comments	The mean difference in method of estimation is the difference between Sildenafil - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.38
	Confidence Interval	(2-Sided) 90%; -21.843 to 17.087
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.722
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF
Description	WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the LOCF approach.

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Measure Participants	53	50
Worsened 2 Classes	0 0%	0 0%
Worsened 1 Class	1 1.9%	0 0%
No Change	45 84.9%	39 78%
Improved 1 Class	7 13.2%	10 20%
Improved 2 Classes	0 0%	0 0%
Discontinued	0 0%	0 0%
Died	0 0%	1 2%
Missing	0 0%	0 0%

3. Secondary Outcome

Title	Clinical Worsening Events
Description	No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication.

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Measure Participants	53	50
None	51 96.2%	47 94%
(A)	0 0%	1 2%
(B)	0 0%	0 0%
(C)	2 3.8%	2 4%
(D)	0 0%	0 0%

4. Secondary Outcome

Title	Change From Baseline in Borg Dyspnea Score at Week 12
Description	Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]); (very slight); (slight breathlessness); (moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum]); and 10 (maximum).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach.

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Measure Participants	53	50
Change from Baseline at Week 12 (n=46,43)	0.16 (1.637)	-0.73 (1.656)
Change from Baseline at Week 12 LOCF (n=53,49)	0.24 (1.709)	-0.62 (1.583)

5. Secondary Outcome

Title	One Year Survival Probability From the Start of Sildenafil Treatment.
Description	The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil.
Time Frame	One year from the time of starting sildenafil

Outcome Measure Data

Analysis Population Description

ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The participants in placebo arm have received Sildenafil on or after Week 12.

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Measure Participants	48	50
Number (90% Confidence Interval) [Probability of death]	0.042	0.040

6. Secondary Outcome

Title	One Year Survival From the Start of Sildenafil Treatment.
Description	The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit.
Time Frame	One year from the time of starting sildenafil

Outcome Measure Data

Analysis Population Description

ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The participants in placebo arm have received Sildenafil on or after Week 12.

Arm/Group Title	Placebo	Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Measure Participants	48	50
Number [Participants who died]	2 3.8%	2 4%

Adverse Events

Time Frame	From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Placebo		Sildenafil
Arm/Group Description	In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.		In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
All Cause Mortality
	Placebo		Sildenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Sildenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/53 (43.4%)		22/50 (44%)
Blood and lymphatic system disorders
Anaemia	2/53 (3.8%)	2	1/50 (2%)	1
Cardiac disorders
Acute coronary syndrome	0/53 (0%)	0	1/50 (2%)	1
Right ventricular failure	1/53 (1.9%)	1	3/50 (6%)	3
Cardiac failure	1/53 (1.9%)	1	1/50 (2%)	1
Cardiovascular disorder	0/53 (0%)	0	1/50 (2%)	1
Coronary artery disease	0/53 (0%)	0	1/50 (2%)	1
Mitral valve incompetence	0/53 (0%)	0	1/50 (2%)	1
Pericardial effusion	1/53 (1.9%)	1	0/50 (0%)	0
Gastrointestinal disorders
Abdominal pain	2/53 (3.8%)	2	0/50 (0%)	0
Inguinal hernia	0/53 (0%)	0	1/50 (2%)	1
General disorders
Asthenia	0/53 (0%)	0	1/50 (2%)	1
Death	0/53 (0%)	0	1/50 (2%)	1
Chest discomfort	0/53 (0%)	0	1/50 (2%)	1
General physical health deterioration	0/53 (0%)	0	1/50 (2%)	1
Oedema peripheral	0/53 (0%)	0	1/50 (2%)	1
Immune system disorders
Contrast media allergy	1/53 (1.9%)	1	0/50 (0%)	0
Infections and infestations
Bronchopneumonia	1/53 (1.9%)	1	2/50 (4%)	2
Erysipelas	2/53 (3.8%)	2	0/50 (0%)	0
Gastritis viral	1/53 (1.9%)	1	0/50 (0%)	0
Abscess	1/53 (1.9%)	1	0/50 (0%)	0
Gangrene	0/53 (0%)	0	1/50 (2%)	1
Osteomyelitis	1/53 (1.9%)	1	0/50 (0%)	0
Pneumonia	2/53 (3.8%)	2	0/50 (0%)	0
Respiratory syncytial virus infection	0/53 (0%)	0	1/50 (2%)	1
Respiratory tract infection	1/53 (1.9%)	1	1/50 (2%)	1
Sepsis	1/53 (1.9%)	1	0/50 (0%)	0
Urinary tract infection	0/53 (0%)	0	1/50 (2%)	1
Injury, poisoning and procedural complications
Post procedural haematoma	1/53 (1.9%)	1	0/50 (0%)	0
Investigations
Haemoglobin decreased	0/53 (0%)	0	1/50 (2%)	1
Walking distance test abnormal	0/53 (0%)	0	1/50 (2%)	1
Metabolism and nutrition disorders
Fluid overload	1/53 (1.9%)	1	0/50 (0%)	0
Fluid retention	1/53 (1.9%)	1	0/50 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoporosis	1/53 (1.9%)	1	0/50 (0%)	0
Back pain	1/53 (1.9%)	1	0/50 (0%)	0
Pain in extremity	1/53 (1.9%)	1	0/50 (0%)	0
Rotator cuff syndrome	1/53 (1.9%)	1	0/50 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/53 (1.9%)	1	0/50 (0%)	0
Breast cancer	0/53 (0%)	0	1/50 (2%)	1
Gastric cancer	1/53 (1.9%)	1	0/50 (0%)	0
Pancreatic neoplasm	0/53 (0%)	0	1/50 (2%)	1
Nervous system disorders
Paresis	1/53 (1.9%)	1	0/50 (0%)	0
Sciatica	1/53 (1.9%)	1	0/50 (0%)	0
Syncope	1/53 (1.9%)	1	0/50 (0%)	0
Psychiatric disorders
Mania	1/53 (1.9%)	1	0/50 (0%)	0
Reproductive system and breast disorders
Uterine haemorrhage	0/53 (0%)	0	1/50 (2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/53 (3.8%)	2	2/50 (4%)	2
Pleural effusion	2/53 (3.8%)	2	0/50 (0%)	0
Pulmonary arterial hypertension	6/53 (11.3%)	6	2/50 (4%)	2
Haemoptysis	0/53 (0%)	0	1/50 (2%)	1
Hypoxia	0/53 (0%)	0	1/50 (2%)	1
Pulmonary hypertension	0/53 (0%)	0	1/50 (2%)	1
Skin and subcutaneous tissue disorders
Skin ulcer	0/53 (0%)	0	1/50 (2%)	1
Surgical and medical procedures
Skin graft	1/53 (1.9%)	1	0/50 (0%)	0
Vascular disorders
Circulatory collapse	0/53 (0%)	0	1/50 (2%)	1
Hypertension	1/53 (1.9%)	1	0/50 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Sildenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/53 (71.7%)		33/50 (66%)
Blood and lymphatic system disorders
Anaemia	4/53 (7.5%)	4	2/50 (4%)	2
Cardiac disorders
Palpitations	3/53 (5.7%)	3	5/50 (10%)	5
Right ventricular failure	4/53 (7.5%)	4	0/50 (0%)	0
Ear and labyrinth disorders
Vertigo	2/53 (3.8%)	2	5/50 (10%)	5
Eye disorders
Vision blurred	0/53 (0%)	0	3/50 (6%)	3
Gastrointestinal disorders
Diarrhoea	5/53 (9.4%)	5	7/50 (14%)	7
Nausea	5/53 (9.4%)	5	1/50 (2%)	1
General disorders
Oedema peripheral	8/53 (15.1%)	8	7/50 (14%)	7
Chest pain	4/53 (7.5%)	4	0/50 (0%)	0
Infections and infestations
Bronchitis	5/53 (9.4%)	5	5/50 (10%)	5
Nasopharyngitis	8/53 (15.1%)	8	5/50 (10%)	5
Upper respiratory tract infection	5/53 (9.4%)	5	2/50 (4%)	2
Respiratory tract infection	1/53 (1.9%)	1	4/50 (8%)	4
Sinusitis	5/53 (9.4%)	5	1/50 (2%)	1
Investigations
Weight increased	3/53 (5.7%)	3	0/50 (0%)	0
Metabolism and nutrition disorders
Gout	3/53 (5.7%)	3	0/50 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	5/53 (9.4%)	5	1/50 (2%)	1
Arthralgia	4/53 (7.5%)	4	0/50 (0%)	0
Musculoskeletal chest pain	3/53 (5.7%)	3	0/50 (0%)	0
Nervous system disorders
Headache	7/53 (13.2%)	7	7/50 (14%)	7
Presyncope	3/53 (5.7%)	3	3/50 (6%)	3
Syncope	3/53 (5.7%)	3	0/50 (0%)	0
Psychiatric disorders
Depression	0/53 (0%)	0	3/50 (6%)	3
Respiratory, thoracic and mediastinal disorders
Pulmonary arterial hypertension	4/53 (7.5%)	4	2/50 (4%)	2
Cough	3/53 (5.7%)	3	1/50 (2%)	1
Dyspnoea	8/53 (15.1%)	8	3/50 (6%)	3
Pulmonary hypertension	0/53 (0%)	0	3/50 (6%)	3
Vascular disorders
Flushing	4/53 (7.5%)	4	5/50 (10%)	5
Hypertension	3/53 (5.7%)	3	1/50 (2%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.