Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease
Condition: Sickle Cell Disease; Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension; Anemia, Sickle Cell
Intervention: Sildenafil; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Sildenafil Citrate; Phosphodiesterase 5 Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 74.0
Sex: All
Minimum age: 12 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Interventional Study; 6-Minute Walk; Sickle Cell Anemia; Sildenafil/Viagra; Tricuspid Regurgitant Velocity; Sickle Cell Disease; Pulmonary Hypertension

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.
    

Eligibility 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.