Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Conditions:	Sickle Cell Disease Pulmonary Hypertension
Interventions:	Drug: Sildenafil Drug: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects with Sickle cell hemoglobinopathy were recruited from 10 centers(9 in United States and 1 in United Kingdom)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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).

Participant Flow: Overall Study

	Sildenafil	Placebo
STARTED	37	37
COMPLETED	15 ^[1]	14 ^[2]
NOT COMPLETED	22	23
Withdrawn(More than one reason selected)	22	23

[1]	Of 15 subjects who completed study, 13 were enrolled in Open label.
[2]	Of 14 subjects who completed study, 13 were enrolled in Open label.

Baseline Characteristics

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Reporting Groups

	Description
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).
Total	Total of all reporting groups

Baseline Measures

	Sildenafil	Placebo	Total
Number of Participants [units: participants]	37	37	74
Age [units: years] Mean ± Standard Deviation	47 ± 13	44 ± 14	45 ± 13
Gender [units: participants]
Female	23	23	46
Male	14	14	28
Ethnicity (NIH/OMB) [units: Participants]
Not Hispanic or Latino	32	37	69
Unknown or Not Reported	5	0	5
Race (NIH/OMB) [units: participants]
Black or African American	36	37	73
Unknown or Not Reported	1	0	1
6 minute walk ^[1] [units: Meters] Mean ± Standard Deviation	381 ± 75	386 ± 75	383 ± 75
Tricuspid regurgitant jet velocity (TRV) ^[2] [units: m/s] Mean ± Standard Deviation	3.0 ± 0.5	3.0 ± 0.3	3.0 ± 0.3

[1]	The distance walked in six minute was used to assess the exercise capacity of the patient at baseline.
[2]	Tricuspid regurgitant jet velocity was measured by transthoracic Doppler Echocardiography.

Outcome Measures

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1. Primary:

Change in Exercise Capacity as Assessed by 6 Minute Walk. [ Time Frame: Baseline to week 16/Imputed last visit. ]

Measure Type	Primary
Measure Title	Change in Exercise Capacity as Assessed by 6 Minute Walk.
Measure Description	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.
Time Frame	Baseline to week 16/Imputed last visit.
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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).

Reporting Groups

	Description
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).

Measured Values

	Sildenafil	Placebo
Number of Participants Analyzed [units: participants]	37	37
Change in Exercise Capacity as Assessed by 6 Minute Walk. [units: meters] Mean ± Standard Deviation	-16 ± 20	-7 ± 20

Statistical Analysis 1 for Change in Exercise Capacity as Assessed by 6 Minute Walk.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.70
Mean Difference (Net) ^[4]	-9
95% Confidence Interval	( -56 to 38 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	6 minute walk was based on ANCOVA model with treatment as a fixed effect and 6 minute walk distance, TRV stratum and study site as covariate.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	No text entered.

2. Secondary:

Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity
Measure Description	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.
Time Frame	16 weeks
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
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).

Measured Values

	Sildenafil	Placebo
Number of Participants Analyzed [units: participants]	37	37
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity [units: meters/second] Mean ± Standard Deviation
Baseline	3.1 ± 0.5	3.0 ± 0.3
Week 6	3.2 ± 0.7	2.9 ± 0.3
Week 16	2.9 ± 0.5	2.9 ± 0.3

No statistical analysis provided for Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity

3. Secondary:

Borg Dyspnea Score [ Time Frame: baseline to 16 weeks ]

Measure Type	Secondary
Measure Title	Borg Dyspnea Score
Measure Description	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.
Time Frame	baseline to 16 weeks
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
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).

Measured Values

	Sildenafil	Placebo
Number of Participants Analyzed [units: participants]	37	37
Borg Dyspnea Score [units: Score on a scale] Mean ± Standard Deviation
Baseline	2.5 ± 2.1	2.1 ± 2.0
Week 6	3.4 ± 2.3	1.8 ± 1.3
Week 10	2.7 ± 2.0	2.7 ± 1.7
Week 16	2.0 ± 1.6	2.8 ± 2.4

No statistical analysis provided for Borg Dyspnea Score

4. Secondary:

Brain Natriuretic Peptide(BNP)Levels. [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Brain Natriuretic Peptide(BNP)Levels.
Measure Description	No text entered.
Time Frame	16 weeks
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
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).

Measured Values

	Sildenafil	Placebo
Number of Participants Analyzed [units: participants]	35	35
Brain Natriuretic Peptide(BNP)Levels. [units: pg/dl] Mean ± Standard Deviation
Baseline	2.3 ± 0.6	2.0 ± 0.6
Week 6	2.4 ± 0.4	2.0 ± 0.7
Week 10	2.3 ± 0.5	2.2 ± 0.6
Week 16	2.5 ± 0.7	2.3 ± 0.6

No statistical analysis provided for Brain Natriuretic Peptide(BNP)Levels.

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There is NOT 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
As a result of early termination due to safety findings, the study was underpowered to assess the effects of sildenafil therapy on the predetermined efficacy endpoints.

Results Point of Contact:

Name/Title: Mark Gladwin
Organization: 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
e-mail: gladwinmt@upmc.edu

Publications:

Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am. 1996 Dec;10(6):1289-303. Review.

Sutton LL, Castro O, Cross DJ, Spencer JE, Lewis JF. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994 Sep 15;74(6):626-8. No abstract available.

Verresen D, De Backer W, Vermeire P. Pulmonary hypertension and sickle hemoglobinopathy. Chest. 1990 Oct;98(4):1042. No abstract available.

Publications automatically indexed to this study:

Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, Oriss TB, Zeng Q, Kato GJ, Gibbs JS, Hildesheim ME, Sachdev V, Barst RJ, Machado RF, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli E, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Castro OL, Goldsmith JC, Gordeuk VR, Gladwin MT; Walk-PHASST Investigators and Patients. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica. 2013 Mar;98(3):464-72. doi: 10.3324/haematol.2012.068965. Epub 2012 Sep 14.

Sachdev V, Kato GJ, Gibbs JS, Barst RJ, Machado RF, Nouraie M, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli EM, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Castro OL, Taylor JG 6th, Hannoush H, Goldsmith JC, Gladwin MT, Gordeuk VR; Walk-PHASST Investigators. Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom. Circulation. 2011 Sep 27;124(13):1452-60. Epub 2011 Sep 6.

Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, Gibbs JS, Little JA, Schraufnagel DE, Krishnamurti L, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Onyekwere O, Castro OL, Sachdev V, Waclawiw MA, Woolson R, Goldsmith JC, Gladwin MT; walk-PHaSST Investigators and Patients. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood. 2011 Jul 28;118(4):855-64. Epub 2011 Apr 28.

Responsible Party:	Mark T. Gladwin, M.D.Professor of Medicine: Chief, Pulmonary, Allergy and Critical CRE Medicine: Director, Hemostasis and Vascular Biology Research Institute; University of Pittsburgh School of Medicine, Hemostasis and Vascular Biology Research Institute; University of Pittsburgh School of Medicine
ClinicalTrials.gov Identifier:	NCT00492531 History of Changes
Other Study ID Numbers:	070177, 07-H-0177
Study First Received:	June 26, 2007
Results First Received:	April 28, 2011
Last Updated:	June 3, 2011
Health Authority:	United States: Federal Government United States: Food and Drug Administration