Trial Outcomes & Findings for Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease (NCT NCT00492531)

Last Updated: 2016-01-06

Results Overview

The primary outcome measure was change in exercise capacity assessed by 6 minute walk distance in meters from baseline to 16 weeks. Subjects without a week 16 assessment had their last observation carried forward.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

74 participants

Primary outcome timeframe

Baseline to week 16/Imputed last visit.

Results posted on

2016-01-06

Participant Flow

Subjects with Sickle cell hemoglobinopathy were recruited from 10 centers(9 in United States and 1 in United Kingdom)

Participant milestones

Participant milestones
Measure	Sildenafil Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Overall Study STARTED	37	37
Overall Study COMPLETED	15	14
Overall Study NOT COMPLETED	22	23

Reasons for withdrawal

Reasons for withdrawal
Measure	Sildenafil Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Overall Study Withdrawn(More than one reason selected)	22	23

Baseline Characteristics

Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sildenafil n=37 Participants Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=37 Participants Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Total n=74 Participants Total of all reporting groups
Age, Continuous	47 years STANDARD_DEVIATION 13 • n=99 Participants	44 years STANDARD_DEVIATION 14 • n=107 Participants	45 years STANDARD_DEVIATION 13 • n=206 Participants
Sex: Female, Male Female	23 Participants n=99 Participants	23 Participants n=107 Participants	46 Participants n=206 Participants
Sex: Female, Male Male	14 Participants n=99 Participants	14 Participants n=107 Participants	28 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants n=99 Participants	37 Participants n=107 Participants	69 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=99 Participants	0 Participants n=107 Participants	5 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	36 Participants n=99 Participants	37 Participants n=107 Participants	73 Participants n=206 Participants
Race (NIH/OMB) White	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
6 minute walk	381 Meters STANDARD_DEVIATION 75 • n=99 Participants	386 Meters STANDARD_DEVIATION 75 • n=107 Participants	383 Meters STANDARD_DEVIATION 75 • n=206 Participants
Tricuspid regurgitant jet velocity (TRV)	3.0 m/s STANDARD_DEVIATION 0.5 • n=99 Participants	3.0 m/s STANDARD_DEVIATION 0.3 • n=107 Participants	3.0 m/s STANDARD_DEVIATION 0.3 • n=206 Participants

PRIMARY outcome

Timeframe: Baseline to week 16/Imputed last visit.

Population: All efficacy and safety analyses were conducted on the intent-to-treat (ITT) population, defined as all randomized subjects, regardless of therapy received. Pre-defined imputation rules:A value of 0 meters was imputed for subjects who died during the MIT.Subjects without a week 16 assessment had their last observation carried forward (LOCF).

Outcome measures

Outcome measures
Measure	Sildenafil n=37 Participants Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=37 Participants Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Change in Exercise Capacity as Assessed by 6 Minute Walk.	-16 meters Standard Deviation 20	-7 meters Standard Deviation 20

SECONDARY outcome

Timeframe: 16 weeks

Secondary outcome measure was change from baseline in Pulmonary hypertension at week 16 as assessed by Tricuspid regurgitant jet velocity(TRV). Tricuspid regurgitant jet velocity was measured by transthoracic Doppler Echocardiography.

Outcome measures

Outcome measures
Measure	Sildenafil n=37 Participants Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=37 Participants Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity Week 16	2.9 meters/second Standard Deviation 0.5	2.9 meters/second Standard Deviation 0.3
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity Baseline	3.1 meters/second Standard Deviation 0.5	3.0 meters/second Standard Deviation 0.3
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity Week 6	3.2 meters/second Standard Deviation 0.7	2.9 meters/second Standard Deviation 0.3

SECONDARY outcome

Timeframe: baseline to 16 weeks

Borg dyspnea score was used to measure the level of severity of breathlessness perceived by the patient before and after 6 minute walk. The severity is measured on a 10 point scale with 0= nothing at all and 10=maximum severity of breathlessness.

Outcome measures

Outcome measures
Measure	Sildenafil n=37 Participants Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=37 Participants Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Borg Dyspnea Score Baseline	2.5 Score on a scale Standard Deviation 2.1	2.1 Score on a scale Standard Deviation 2.0
Borg Dyspnea Score Week 6	3.4 Score on a scale Standard Deviation 2.3	1.8 Score on a scale Standard Deviation 1.3
Borg Dyspnea Score Week 10	2.7 Score on a scale Standard Deviation 2.0	2.7 Score on a scale Standard Deviation 1.7
Borg Dyspnea Score Week 16	2.0 Score on a scale Standard Deviation 1.6	2.8 Score on a scale Standard Deviation 2.4

SECONDARY outcome

Timeframe: 16 weeks

Outcome measures

Outcome measures
Measure	Sildenafil n=35 Participants Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=35 Participants Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Brain Natriuretic Peptide(BNP)Levels. Baseline	2.3 pg/dl Standard Deviation 0.6	2.0 pg/dl Standard Deviation 0.6
Brain Natriuretic Peptide(BNP)Levels. Week 6	2.4 pg/dl Standard Deviation 0.4	2.0 pg/dl Standard Deviation 0.7
Brain Natriuretic Peptide(BNP)Levels. Week 10	2.3 pg/dl Standard Deviation 0.5	2.2 pg/dl Standard Deviation 0.6
Brain Natriuretic Peptide(BNP)Levels. Week 16	2.5 pg/dl Standard Deviation 0.7	2.3 pg/dl Standard Deviation 0.6

Adverse Events

Sildenafil

Serious events: 17 serious events

Other events: 30 other events

Deaths: 0 deaths

Placebo

Serious events: 8 serious events

Other events: 28 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Sildenafil n=37 participants at risk Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=37 participants at risk Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Congenital, familial and genetic disorders SCA with Crisis	48.6% 18/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	35.1% 13/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Nervous system disorders Headache	35.1% 13/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	10.8% 4/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	13.5% 5/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	16.2% 6/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Blood and lymphatic system disorders Blood and Lymphatic system disorders	10.8% 4/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	16.2% 6/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Eye disorders Eye disorders	13.5% 5/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	10.8% 4/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Eye disorders Blurred vision	13.5% 5/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
General disorders General Disorders and administration site conditions	16.2% 6/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	8.1% 3/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Infections and infestations Infections and infestations	13.5% 5/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	37.8% 14/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.

Additional Information

Mark Gladwin

Professor of Medicine: Chief, Pulmonary, Allergy and Critical Care Medicine: Director, Hemostasis and Vascular Biology Research Institute; University of Pittsburgh School of Medicine

Phone: 412-692-2117

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Sildenafil n=37 participants at risk Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).	Placebo n=37 participants at risk Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Blood and lymphatic system disorders Acute chest syndrome	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	8.1% 3/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Blood and lymphatic system disorders Anemia	5.4% 2/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Congenital, familial and genetic disorders Sickle cell anemia with crisis	35.1% 13/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	13.5% 5/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Infections and infestations Bronchitis	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Infections and infestations Lower respiratory tract infection	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Metabolism and nutrition disorders Hyperkalemia	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	5.4% 2/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Vascular disorders Hypertension	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Vascular disorders Hypotension	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Cardiac disorders Atrial fibrillation	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Cardiac disorders Congestive Cardiac failure	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Eye disorders Vitreous hemorrhage	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
General disorders Pyrexia	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Injury, poisoning and procedural complications Traumatic brain injury	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Psychiatric disorders Suicide attempt	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.
Respiratory, thoracic and mediastinal disorders Acute pulmonary edema	2.7% 1/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.	0.00% 0/37 • Safety assessments were conducted at baseline, weeks 6, 10 (excluding echocardiography), and 16. Treatment group differences in AEs and SAEs were evaluated via Cochran-Mantel-Haenszel chi-square tests, controlling for TRV stratum. The study was stopped early due to the higher percentage of subjects experiencing an SAE in the sildenafil arm as compared to the placebo arm.