• Eligibility will be based on the following inclusion and exclusion criteria.

INCLUSION CRITERIA:

Screening Phase:

• Males or females, 12 years of age or older.
• Diagnosis of sickle cell disease (including, but not limited to SS, SC, SD, or S-beta zero/plus 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 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.
• For 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/plus thalassemia).
• At least mild pulmonary hypertension with TRV greater than or equal to 2.7 m/s by echocardiogram.
• 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 or SF less than 22 percent.

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)

Subjects who are antigoagulated and have proliferative retinopathy (unless they have had ophthalmologist recommended intervention (e.g., phototherapy) or have been otherwise cleared by the ophthalmologist to participate in the study.