Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease

NCT00492531 | Terminated Phase 2 Results DMC

• 2 other identifiers: 07017707-H-0177
• Study Type: interventional
• Target: 74
• Locations: 2 countries
• Sites: 9

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.

Conditions

Sickle Cell Disease; Pulmonary Hypertension

Keywords

Interventional Study; 6-Minute Walk; Sickle Cell Anemia; Sildenafil/Viagra; Tricuspid Regurgitant Velocity; Sickle Cell Disease; Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity

  16 weeks

• Borg Dyspnea Score

  baseline to 16 weeks

• Brain Natriuretic Peptide(BNP)Levels.

  16 weeks

Study Arms (2)

Sildenafil

EXPERIMENTAL

There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo.

Drug: Sildenafil

Placebo

PLACEBO COMPARATOR

There was a balancing of treatment group assignment across Tricuspid Regurgitant Jet velocity(TRV)measured on Echo

Drug: Placebo

Interventions

Sildenafil DRUG

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.

Also known as: phosphodiesterase-5(PDE5) inhibitor

Sildenafil

Placebo DRUG

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.

Also known as: Sugar pill

Placebo

Eligibility Criteria

• Age: 12 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (9)

Children's Hospital, Oakland

Oakland, California, 94609, United States

Location

University of Colorado

Denver, Colorado, 80220-3706, United States

Location

Howard University Hospital

Washington D.C., District of Columbia, 20060, United States

Location

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

Childrens Hospital, Pittsburgh

Pittsburgh, Pennsylvania, 15213-2583, United States

Location

Imperial College London and Hammersmith Hospital

London, United Kingdom

Location

Related Publications (11)

• 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.

  PMID: 8956017 BACKGROUND

• 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.

  PMID: 8074054 BACKGROUND

• 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.

  PMID: 2209119 BACKGROUND

• D'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.

  PMID: 37439373 DERIVED

• 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.

  PMID: 34990411 DERIVED

• 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.

  PMID: 34014839 DERIVED

• 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.

  PMID: 31322833 DERIVED

• 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.

  PMID: 24988120 DERIVED

• 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.

  PMID: 22983573 DERIVED

• 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.

  PMID: 21900080 DERIVED

• 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.

  PMID: 21527519 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell; Hypertension, Pulmonary

Interventions

Sildenafil Citrate; Phosphodiesterase 5 Inhibitors; Sugars

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Carbohydrates

Limitations and Caveats

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

• 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

gladwinmt@upmc.edu

412-692-2117

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chair of Medicine

Study Record Dates

• First Submitted: June 26, 2007
• First Posted: June 27, 2007
• Study Start: June 1, 2007
• Primary Completion: September 1, 2009
• Study Completion: October 1, 2009
• Last Updated: January 6, 2016
• Results First Posted: June 6, 2011

Record last verified: 2015-12

Locations

US (8); GB (1)