Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease

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.

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.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease; Pulmonary Hypertension
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

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:

1. 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.
2. 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.
3. 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.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Imperial College London and Hammersmith Hospital
• United States
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital, Oakland
  • Colorado
    • Denver, Colorado, United States, 80220-3706
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213-2583
      • Childrens Hospital, Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sildenafil; There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo.	Drug: Sildenafil; 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.; Other Names: phosphodiesterase-5(PDE5) inhibitor
Placebo Comparator: Placebo; There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo	Drug: Placebo; 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.; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to week 16/Imputed last visit.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	baseline to 16 weeks
Brain Natriuretic Peptide(BNP)Levels.		16 weeks

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: 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

Publications and helpful links

General 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.
• 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. doi: 10.1016/0002-9149(94)90760-9. No abstract available.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. doi: 10.1161/CIRCULATIONAHA.111.032920. 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. doi: 10.1182/blood-2010-09-306167. Epub 2011 Apr 28.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: June 26, 2007
• First Submitted That Met QC Criteria: June 26, 2007
• First Posted (Estimate): June 27, 2007

Study Record Updates

• Last Update Posted (Estimate): January 6, 2016
• Last Update Submitted That Met QC Criteria: December 7, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Sickle Cell Disease; Sickle Cell Anemia; 6-Minute Walk; Interventional Study; Sildenafil/Viagra; Tricuspid Regurgitant Velocity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Hypertension; Anemia, Sickle Cell; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Sildenafil Citrate; Phosphodiesterase 5 Inhibitors
• Other Study ID Numbers: 070177; 07-H-0177 (Other Identifier: IRB Approval number , NHLBI)