Back to resultsSildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease
Primary Purpose
Sickle Cell Disease, Pulmonary Hypertension
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sildenafil
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Disease focused on measuring Interventional Study, 6-Minute Walk, Sickle Cell Anemia, Sildenafil/Viagra, Tricuspid Regurgitant Velocity, Sickle Cell Disease, Pulmonary Hypertension
Eligibility Criteria
• Eligibility based on the following inclusion and exclusion criteria.
INCLUSION CRITERIA:
Screening Phase:
- Males or females, greater than or equal to 12 years of age and less than or equal to 70 years of age.
- Diagnosis of sickle cell disease (including, but not limited to SS, SC, SD, or S-beta zero thalassemia).
- Provision of informed consent and, where applicable, assent.
Observational Follow-up Study:
- Satisfaction of screening criteria.
- In the opinion of the investigator, ability to maintain follow-up contact.
- Failure to satisfy the eligibility requirements of the Main Interventional Trial (MIT) OR discontinuation/completion of the MIT/Open-label Follow-up Phase.
- Provision of informed consent and, where applicable, assent.
Main Interventional Trial:
- Males or females, 12 years of age or older and less than or equal to 70 years of age.
- Female subjects, on a reliable method of birth control or not physically able to bear children.
- Electrophoretic documentation of sickle cell disease (including, but not limited to SS, SC, SD, or S-beta zero thalassemia).
- At least mild pulmonary hypertension with TRV greater than or equal to 2.7 m/sec by echocardiogram.
- Six-minute walk distance of 150-500 m.
- In the opinion of the investigator, able to complete the protocol scheduled assessments during the 16-week, double-blind phase.
- Provision of informed consent and, where applicable, assent.
- Subjects with systemic hypertension must be on a stable antihypertensive regimen for greater than or equal to 90 days and a stable dose for greater than or equal to 30 days.
EXCLUSION CRITERIA:
Current pregnancy or lactation.
Any one of the following medical conditions:
- Stroke within the last six weeks.
- Diagnosis of pulmonary embolism within the last three months.
- History of retinal detachment or retinal hemorrhage in the last 6 months.
- Non-arteritic anterior ischemic optic neuropathy (NAION) in one or both eyes.
- History of sustained priapism requiring medical or surgical treatment, unless currently impotent or on transfusion program within the last two years.
- Any unstable (chronic or acute) condition that in the opinion of the investigator will prevent completion of the study.
Subjects taking nitrate-based vasodilators (including, but not limited to nicorandil [available in the UK only]), prostacyclin (inhaled, subcutaneous or intravenous) or endothelin antagonists. Subjects taking calcium channel blockers will be allowed to participate if they are on a stable dose for greater than or equal to 3 months.
Left ventricular ejection fraction (LVEF) less than 40 percent or clinically significant ischemic, valvular or constrictive heart disease: LVEF less than 40 percent or SF less than 22 percent.
Subjects in other research studies with investigational drugs (with the exception of hydroxyurea) unless the other trial has been approved by the walk-PHaSST Executive Committee for co-participation.
Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication, symptomatic hip osteonecrosis.
Tonsillectomies for sleep apnea within 3 months prior to randomization. Active therapy for pulmonary hypertension, including prostacyclin analog, endothelin-1 antagonist, or PDE-5 inhibitor.
Protease inhibitor therapy for HIV treatment Subjects taking potent CYP3A4 inhibitor therapy (e.g., itraconazole, ritonavir, ketoconazole) Subjects who are anticoagulated and have proliferative retinopathy (unless they have had ophthalmologist recommended intervention (e.g., phototherapy) or have been cleared by the ophthalmologist to participate in the study.
Subjects with systolic blood pressure greater than or equal to 140 mmHg OR diastolic blood pressure greater than or equal to 90 mmHg.
Sites / Locations
- Children's Hospital, Oakland
- University of Colorado
- Howard University Hospital
- University of Illinois at Chicago
- Johns Hopkins University
- National Institutes of Health Clinical Center, 9000 Rockville Pike
- Albert Einstein College of Medicine
- Childrens Hospital, Pittsburgh
- Imperial College London and Hammersmith Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Sildenafil
Placebo
Arm Description
There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo.
There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo
Outcomes
Primary Outcome Measures
Change in Exercise Capacity as Assessed by 6 Minute Walk.
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.
Secondary Outcome Measures
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity
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.
Borg Dyspnea Score
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.
Brain Natriuretic Peptide(BNP)Levels.
Full Information
NCT ID
NCT00492531
First Posted
June 26, 2007
Last Updated
December 7, 2015
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT00492531
Brief Title
Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease
Official Title
Treatment of Pulmonary Hypertension and Sickle Cell Disease With Sildenafil Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
December 2015
Overall Recruitment Status
Terminated
Why Stopped
Subjects on drug were more likely to have severe pain crises requiring hospitalization.
Study Start Date
June 2007 (undefined)
Primary Completion Date
September 2009 (Actual)
Study Completion Date
October 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study will examine whether the drug sildenafil can lower blood pressure in the pulmonary artery (the blood vessel that leads from the heart to the lungs) in patients with sickle cell disease and pulmonary hypertension (high blood pressure in the lungs). It will see if this treatment can reduce disease complications, such as shortness of breath, pain crisis, pneumonia, and increase survival.
Patients 12 years of age and older with sickle cell disease and pulmonary hypertension may be eligible for this study. Participants are randomly assigned to receive sildenafil or placebo (sugar pill) for 16 weeks. Before starting treatment, patients have baseline studies, including a pregnancy test for females of childbearing age; a chest x-ray; pulmonary function tests to measure how much air the patient can breathe in and out; an echocardiogram (heart ultrasound); a 6-minute walk test to measure exercise capacity; a quality-of-life assessment and a pain inventory. Patients with moderate to severe pulmonary hypertension undergo heart catheterization to evaluate the severity of hypertension before beginning sildenafil therapy.
During treatment, patients are monitored with the following:
Blood tests: weeks 6, 10 and 16.
Echocardiogram: weeks 6 and 16.
6-minute walk test: weeks 6, 10 and 16.
Measurements of weight, blood pressure and heart rate: weeks 6, 10 and 16.
Pregnancy test for women of childbearing age: weeks 6, 10 and 16.
Pain questionnaire once a day for a week: weeks 6 and 1.0
Quality-of-life questionnaire: week 16.
Heart catheterization: week 16 for patients with moderate to severe hypertension.
At the end of the 16-week period, patients may opt to continue to receive sildenafil and monitoring in an open-label phase of the study for up to 1 year.
Detailed Description
Sickle cell disease (SCD) is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15 percent of African-Americans are homozygous for sickle cell disease, and 8 percent have sickle cell trait. Acute pain crisis, acute chest syndrome (ACS), and pulmonary hypertension are common complications of sickle cell anemia. Pulmonary hypertension (PH) has now been identified as a marker of mortality in adults with sickle cell disease. Sildenafil has been proven beneficial in pulmonary hypertension (PH) and recent phase I/II studies from the intramural National Institutes of Health (NIH) suggest it is well tolerated and efficacious in the SCD population. Furthermore, a number of recent studies have suggested that nitric oxide (NO) based therapies may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia.
The project has 3 distinct components:
Screening Phase. Approximately 1000 subjects with sickle cell disease will be screened. Assessments will include historical and laboratory data, Doppler echocardiogram, 6-minute walk test, plasma/serum, and DNA for banking.
Main Interventional Trial. The randomized, double-blind, placebo controlled phase is designed to determine the effects of 16 weeks of Sildenafil therapy on exercise endurance, cardiopulmonary hemodynamic parameters and symptoms in this patient population. The open-label follow-up phase is designed to provide up to an additional year of Sildenafil therapy to subjects who completed the randomized, double-blind phase.
Observational Follow-up Study. Screened patients who do not qualify for participation in the main interventional trial may be contacted every 6-12 months for up to 3 years to assess major disease-related complications, including mortality.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease, Pulmonary Hypertension
Keywords
Interventional Study, 6-Minute Walk, Sickle Cell Anemia, Sildenafil/Viagra, Tricuspid Regurgitant Velocity, Sickle Cell Disease, Pulmonary Hypertension
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
74 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sildenafil
Arm Type
Experimental
Arm Description
There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Other Intervention Name(s)
phosphodiesterase-5(PDE5) inhibitor
Intervention Description
Oral Sildenafil 20mg three times daily for 6 weeks,followed by 40mg three times daily for 4 weeks followed by 80mg three times daily for 6 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sugar pill
Intervention Description
Placebo 20mg three times daily for 6 weeks,followed by 40mg three times daily for 4 weeks followed by 80mg three times daily for 6 weeks.
Primary Outcome Measure Information:
Title
Change in Exercise Capacity as Assessed by 6 Minute Walk.
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.
Secondary Outcome Measure Information:
Title
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity
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
Title
Borg Dyspnea Score
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
Title
Brain Natriuretic Peptide(BNP)Levels.
Time Frame
16 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
• Eligibility based on the following inclusion and exclusion criteria.
INCLUSION CRITERIA:
Screening Phase:
Males or females, greater than or equal to 12 years of age and less than or equal to 70 years of age.
Diagnosis of sickle cell disease (including, but not limited to SS, SC, SD, or S-beta zero thalassemia).
Provision of informed consent and, where applicable, assent.
Observational Follow-up Study:
Satisfaction of screening criteria.
In the opinion of the investigator, ability to maintain follow-up contact.
Failure to satisfy the eligibility requirements of the Main Interventional Trial (MIT) OR discontinuation/completion of the MIT/Open-label Follow-up Phase.
Provision of informed consent and, where applicable, assent.
Main Interventional Trial:
Males or females, 12 years of age or older and less than or equal to 70 years of age.
Female subjects, on a reliable method of birth control or not physically able to bear children.
Electrophoretic documentation of sickle cell disease (including, but not limited to SS, SC, SD, or S-beta zero thalassemia).
At least mild pulmonary hypertension with TRV greater than or equal to 2.7 m/sec by echocardiogram.
Six-minute walk distance of 150-500 m.
In the opinion of the investigator, able to complete the protocol scheduled assessments during the 16-week, double-blind phase.
Provision of informed consent and, where applicable, assent.
Subjects with systemic hypertension must be on a stable antihypertensive regimen for greater than or equal to 90 days and a stable dose for greater than or equal to 30 days.
EXCLUSION CRITERIA:
Current pregnancy or lactation.
Any one of the following medical conditions:
Stroke within the last six weeks.
Diagnosis of pulmonary embolism within the last three months.
History of retinal detachment or retinal hemorrhage in the last 6 months.
Non-arteritic anterior ischemic optic neuropathy (NAION) in one or both eyes.
History of sustained priapism requiring medical or surgical treatment, unless currently impotent or on transfusion program within the last two years.
Any unstable (chronic or acute) condition that in the opinion of the investigator will prevent completion of the study.
Subjects taking nitrate-based vasodilators (including, but not limited to nicorandil [available in the UK only]), prostacyclin (inhaled, subcutaneous or intravenous) or endothelin antagonists. Subjects taking calcium channel blockers will be allowed to participate if they are on a stable dose for greater than or equal to 3 months.
Left ventricular ejection fraction (LVEF) less than 40 percent or clinically significant ischemic, valvular or constrictive heart disease: LVEF less than 40 percent or SF less than 22 percent.
Subjects in other research studies with investigational drugs (with the exception of hydroxyurea) unless the other trial has been approved by the walk-PHaSST Executive Committee for co-participation.
Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication, symptomatic hip osteonecrosis.
Tonsillectomies for sleep apnea within 3 months prior to randomization. Active therapy for pulmonary hypertension, including prostacyclin analog, endothelin-1 antagonist, or PDE-5 inhibitor.
Protease inhibitor therapy for HIV treatment Subjects taking potent CYP3A4 inhibitor therapy (e.g., itraconazole, ritonavir, ketoconazole) Subjects who are anticoagulated and have proliferative retinopathy (unless they have had ophthalmologist recommended intervention (e.g., phototherapy) or have been cleared by the ophthalmologist to participate in the study.
Subjects with systolic blood pressure greater than or equal to 140 mmHg OR diastolic blood pressure greater than or equal to 90 mmHg.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark T Gladwin, M.D
Organizational Affiliation
Professor of Medicine: Chief, Pulmonary, Allergy and Critical CRE Medicine: Director, Hemostasis and Vascular Biology Research Institute; University of Pittsburgh School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital, Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80220-3706
Country
United States
Facility Name
Howard University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20060
Country
United States
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Albert Einstein College of Medicine
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
Childrens Hospital, Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213-2583
Country
United States
Facility Name
Imperial College London and Hammersmith Hospital
City
London
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
8956017
Citation
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Results Reference
background
PubMed Identifier
8074054
Citation
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Results Reference
background
PubMed Identifier
2209119
Citation
Verresen D, De Backer W, Vermeire P. Pulmonary hypertension and sickle hemoglobinopathy. Chest. 1990 Oct;98(4):1042. doi: 10.1378/chest.98.4.1042a. No abstract available.
Results Reference
background
PubMed Identifier
34990411
Citation
Liggett LA, Cato LD, Weinstock JS, Zhang Y, Nouraie SM, Gladwin MT, Garrett ME, Ashley-Koch A, Telen MJ, Custer B, Kelly S, Dinardo CL, Sabino EC, Loureiro P, Carneiro-Proietti AB, Maximo C; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Reiner AP, Abecasis GR, Williams DA, Natarajan P, Bick AG, Sankaran VG. Clonal hematopoiesis in sickle cell disease. J Clin Invest. 2022 Feb 15;132(4):e156060. doi: 10.1172/JCI156060.
Results Reference
derived
PubMed Identifier
34014839
Citation
Page GP, Kanias T, Guo YJ, Lanteri MC, Zhang X, Mast AE, Cable RG, Spencer BR, Kiss JE, Fang F, Endres-Dighe SM, Brambilla D, Nouraie M, Gordeuk VR, Kleinman S, Busch MP, Gladwin MT; National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology Donor Evaluation Study-III (REDS-III) program. Multiple-ancestry genome-wide association study identifies 27 loci associated with measures of hemolysis following blood storage. J Clin Invest. 2021 Jul 1;131(13):e146077. doi: 10.1172/JCI146077.
Results Reference
derived
PubMed Identifier
31322833
Citation
Sinha AA, Adusumilli T, Cohen HW, Nouraie M, Little J, Manwani D. Splenectomy is not associated with a higher tricuspid regurgitant jet velocity in people with sickle cell anemia. Pediatr Blood Cancer. 2019 Oct;66(10):e27928. doi: 10.1002/pbc.27928. Epub 2019 Jul 19.
Results Reference
derived
PubMed Identifier
24988120
Citation
Gladwin MT, Barst RJ, Gibbs JS, Hildesheim M, Sachdev V, Nouraie M, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli E, Girgis RE, Morris CR, Berman Rosenzweig E, Badesch DB, Lanzkron S, Castro OL, Taylor JG 6th, Goldsmith JC, Kato GJ, Gordeuk VR, Machado RF; walk-PHaSST Investigators and Patients. Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS One. 2014 Jul 2;9(7):e99489. doi: 10.1371/journal.pone.0099489. eCollection 2014.
Results Reference
derived
PubMed Identifier
22983573
Citation
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.
Results Reference
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PubMed Identifier
21900080
Citation
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. doi: 10.1161/CIRCULATIONAHA.111.032920. Epub 2011 Sep 6.
Results Reference
derived
PubMed Identifier
21527519
Citation
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. doi: 10.1182/blood-2010-09-306167. Epub 2011 Apr 28.
Results Reference
derived
Links:
URL
http://clinicalstudies.info.nih.gov/detail/B_2007-H-0177.html
Description
NIH Clinical Center Detailed Web Page
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Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease
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