Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease

This study has been terminated.
(Subjects on drug were more likely to have severe pain crises requiring hospitalization.)
Sponsor:
Information provided by:
National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:
NCT00492531
First received: June 26, 2007
Last updated: June 3, 2011
Last verified: June 2011
  Purpose

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.


Condition Intervention Phase
Sickle Cell Disease
Pulmonary Hypertension
Drug: Sildenafil
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Treatment of Pulmonary Hypertension and Sickle Cell Disease With Sildenafil Therapy

Resource links provided by NLM:


Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:
  • Change in Exercise Capacity as Assessed by 6 Minute Walk. [ Time Frame: Baseline to week 16/Imputed last visit. ] [ Designated as safety issue: No ]
    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 [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: baseline to 16 weeks ] [ Designated as safety issue: No ]
    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. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Enrollment: 74
Study Start Date: June 2007
Study Completion Date: October 2009
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Sugar pill

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.
  Eligibility

Ages Eligible for Study:   12 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00492531

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

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Interventional Study
6-Minute Walk
Sickle Cell Anemia
Sildenafil/Viagra
Tricuspid Regurgitant Velocity
Sickle Cell Disease
Pulmonary Hypertension

Additional relevant MeSH terms:
Anemia, Sickle Cell
Hypertension
Hypertension, Pulmonary
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Sildenafil
Phosphodiesterase 5 Inhibitors
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014