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.

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 Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

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.

Intervention(s) in this Clinical Trial

• Drug: Sildenafil
  • Administered on an escalating scale of 20, 40, 80 mg, orally, 3 times daily for 16 weeks.
• Drug: Placebo
  • Administered on an escalating scale of 20, 40, 80 mg, orally, 3 times daily for 16 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • TRV greater than or equal to 7.7 but less than 3.0
• Placebo Comparator: 2
  • TRV greater than or equal to 7.7 but less than 3.0
• Experimental: 3
  • TRV greater than or equal to 3.0
• Placebo Comparator: 4
  • TRV greater than or equal to 3.0

Primary Measures

• Determine the efficacy of 16 weeks of sildenafil therapy on exercise capacity.
  • Time Frame: 16 weeks
    Safety Issue?: No

Secondary Measures

• Hemodynamic parameters
  • Time Frame: 16 weeks
    Safety Issue?: No

INCLUSION CRITERIA:

Screening Phase:

• Males or females, 12 years of age or older.
• Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, SD, or SB degree/plus thalassemia phenotype is required).
• 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.

Main Interventional Trial:

• Males or females, 12 years of age or older.
• For female subjects, on a reliable method of birth control or not physically able to bear children.
• Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, SD, or SB degree/plus thalassemia phenotype is required).
• At least mild pulmonary hypertension with TRV greater than or equal to 2.7 m/s by echocardiogram.
• For subjects undergoing right heart catheterization, pulmonary capillary wedge pressure less than or equal to 24 mmHg.
• Six-minute walk distance of 150-500 m.
• In the opinion of the investigator, ability to complete the protocol scheduled assessments during the 16-week, double-blind phase.
• Provision of informed consent and, where applicable, assent.

EXCLUSION CRITERIA:

• Current pregnancy or lactation.

Any one of the following medical conditions:

• Stroke within the last six weeks.
• New 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 provided they are on a stable dose for greater than or equal to 3 months.
• Left ventricular ejection fraction less than 40 percent or clinically significant ischemic, valvular or constrictive heart disease: LVEF less than 40 percent by MUGA or SF less than 22 percent by echo.
• Subjects who are 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 antagonists, or PDE-5 inhibitor.
• Protease inhibitor therapy for the treatment of HIV.
• Subjects taking potent CYP3A4 inhibitor therapy (e.g., itraconazole, ritonavir, ketoconazole)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 12 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Overall Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00492531

Study ID Number: 070177

ClinicalTrials.gov Identifier: NCT00492531

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page