Sickle Cell DiseasePhase 2NCT00492531
Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease
A Phase 2 study testing Sildenafil in people with Sickle Cell Disease and Pulmonary Hypertension, run by National Heart, Lung, and Blood Institute (NHLBI) at 9 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 12 to 70 years
- Conditions the study is for
- Sickle Cell Disease, Pulmonary Hypertension
- What is being tested?
- Sildenafil
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 74 participants
- Where
- 9 sitesin 2 countries
- Study dates
- Jun 2007to Oct 2009
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 70 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
9 sites in 2 countries.
9 sites in 2 countries
United States8 sites
Johns Hopkins University
Baltimore, Maryland, 21205
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
University of Illinois at Chicago
Chicago, Illinois, 60612
University of Colorado
Denver, Colorado, 80220-3706
Children's Hospital, Oakland
Oakland, California, 94609
Childrens Hospital, Pittsburgh
Pittsburgh, Pennsylvania, 15213-2583
Albert Einstein College of Medicine
The Bronx, New York, 10461
Howard University Hospital
Washington D.C., District of Columbia, 20060
United Kingdom1 site
Imperial College London and Hammersmith Hospital
London
About this study
Official title: Treatment of Pulmonary Hypertension and Sickle Cell Disease With Sildenafil Therapy
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.
Read more
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.
Read the 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.
- Conditions
- Sickle Cell Disease, Pulmonary Hypertension
- Being tested
- Sildenafil, Placebo
- Keywords
- Interventional Study, 6-Minute Walk, Sickle Cell Anemia, Sildenafil/Viagra, Tricuspid Regurgitant Velocity, Sickle Cell Disease, Pulmonary Hypertension
- Medical subject headings
- Anemia, Sickle Cell, Hypertension, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SildenafilDrug
Also called phosphodiesterase-5(PDE5) inhibitor
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.
PlaceboDrug
Also called Sugar pill
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.
| Study group | Role | What they receive |
|---|---|---|
| Sildenafil | Experimental | There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo. Receives: Drug: Sildenafil |
| Placebo | Placebo comparator | There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to week 16/Imputed last visit.
Secondary outcomes (3)
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.
Measured: 16 weeks
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.
Measured: baseline to 16 weeks
Brain Natriuretic Peptide(BNP)Levels.
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2007 (estimated)
- Study startJun 2007
- Primary completionSep 2009
- Study completionOct 2009
Why it stopped: Subjects on drug were more likely to have severe pain crises requiring hospitalization.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 74 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Mark Gladwin, National Heart, Lung, and Blood Institute (NHLBI)
- Investigators
- Mark T Gladwin, M.D, Principal investigator, Professor of Medicine: Chief, Pulmonary, Allergy and Critical CRE Medicine: Director, Hemostasis and Vascular Biology Research Institute; University of Pittsburgh School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00492531
- Sponsor's protocol ID
- 070177
- Other IDs
- 07-H-0177
- Status last verified
- Dec 2015
- First submitted
- 26 Jun 2007
- Last updated
- 6 Jan 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am. 1996 Dec;10(6):1289-303. doi: 10.1016/s0889-8588(05)70401-9.
PubMed 8956017Sutton 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. doi: 10.1016/0002-9149(94)90760-9. No abstract available.
PubMed 8074054Verresen 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.
PubMed 2209119Eskandari N, Pappano E, Ruiz MA, Mahmud N, Ren G, Ivy Z, Gaitonde S, Gordeuk VR, Gladwin MT, Malik P, Quinn CT, Saraf SL. Renin-angiotensin-aldosterone system inhibition exacerbates anemia in sickle cell disease. Blood. 2026 Aug 6;148(6):783-788. doi: 10.1182/blood.2026033813.
PubMed 42224366D'Alessandro A, Nouraie SM, Zhang Y, Cendali F, Gamboni F, Reisz JA, Zhang X, Bartsch KW, Galbraith MD, Espinosa JM, Gordeuk VR, Gladwin MT. Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment. Haematologica. 2023 Dec 1;108(12):3418-3432. doi: 10.3324/haematol.2023.283288.
PubMed 37439373Liggett 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.
PubMed 34990411Page 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.
PubMed 34014839Sinha 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.
PubMed 31322833Gladwin 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.
PubMed 24988120Nouraie 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.
PubMed 22983573Sachdev 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.
PubMed 21900080Machado 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.
PubMed 21527519