Efficacy and Safety of Bosentan in Sickle Cell Disease (SCD) Patients With Pulmonary Arterial Hypertension (PAH)

Inclusion Criteria: Screening Criteria: Males or females ≥ 12 years of age with a documented history of SCD Patients with symptomatic PAH associated with shortness of breath Patients with tricuspid regurgitation jet (TRJ) velocity of > 2.9 m/sec based on echo/Doppler conducted within 6 months prior to randomization and not during SCD crisis Signed written informed consent is obtained from the patient or patient's parent/legal representative prior to initiation of any study related procedure Inclusion Criteria: Patients with hemoglobin (Hb) SS or Hb S/β0 genotype and with Hb A ≤ 10% Six-minute walk test (6MWT) distance ≥ 150 m and ≤ 450 m PAH confirmed by right heart catheterization (RHC) performed at the study site within 3 months of the randomization visit and defined as: Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg measured by RHC or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg measured by left heart catheterization, if PCWP measurement is not reliable Pulmonary vascular resistance (PVR) at rest ≥ 160 dyn.sec/cm5 Women of childbearing potential must have a negative result on their serum pregnancy test and use reliable methods of contraception during study treatment and for 3 months after study treatment termination Exclusion Criteria: Left ventricular ejection fraction < 40% (echo/Doppler) Systolic blood pressure < 85 mmHg Uncontrolled hypertension with systolic blood pressure >160 mmHg and/or diastolic blood pressure > 100 mmHg Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) < 0.5 Total lung capacity (TLC) < 50% of normal predicted value Significant cardiac disease: ischemic, valvular, constrictive Hemoglobin concentration < 6.0 g/dL at the time of randomization Acute liver disease Evidence of cirrhosis or portal hypertension on a liver ultrasound or biopsy ALT ≥ 2 times upper limit of normal (ULN) and/or albumin < 2.8 g/dL 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 Vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) within 2 weeks of randomization or more than 12 VOC and/or ACS within the last 12 months Blood transfusion within 4 weeks prior to randomization Illness with a life expectancy shorter than 6 months HIV with opportunistic infection Psychotic, addictive, or other disorder limiting the ability to provide informed consent or to comply with study requirements Pregnant or lactating women Recently started (< 8 weeks prior to randomization) or planned, exercise-based cardio-pulmonary rehabilitation program Bone marrow transplantation Treatment or planned treatment with another investigational drug within 3 months prior to randomization Treatment for pulmonary hypertension with an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization or with L-arginine within 1 week prior to randomization Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, amiodarone, miconazole and glibenclamide (glyburide) within 1 week prior to randomization Known hypersensitivity to bosentan or any of its excipients