Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Bosentan in Patients With Symptomatic Pulmonary Hypertension Associated With Sickle Cell Disease
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 12
- 主要终点
- Change from Baseline to End of Study in 6MWT distance. A mean difference from placebo of at least 35 m is considered clinically relevant.
研究概览
简要总结
The study will assess the effect of bosentan on pulmonary vascular resistance and exercise capacity in Sickle Cell Disease (SCD) patients diagnosed with Pulmonary Hypertension. It consists of 3 phases: screening, treatment and follow-up. During the screening visit, the study doctor will decide if patients meet the study requirements. All potential patients will have a diagnosis of increased pulmonary artery pressures that is shown by right heart catheterization conducted shortly prior to start of study treatment. Patients will be asked to perform exercise capacity test (walking as far as possible for 6 minutes). Following the baseline visit the treatment phase consists of 4 additional clinic visits during which the good and bad effects of the drug are reviewed and exercise capacity test will be repeated. Patients will be treated for 16 weeks. Blood samples will be collected every month, or more often, if needed. At the end of the study some of the patients will be asked to repeat the right heart catheterization. All patients will repeat an exercise capacity test. After completion of the study, patients will have the option of enrolling in a long-term follow-up study where all patients will receive active drug. Patients electing not to participate in the extension study will be followed up for safety assessments for about 28 days after the end of the study treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Screening Criteria:
- •Males or females > or = 12 years of age with a documented history of SCD
- •Patients with symptomatic PH 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 < or = 10%
- •Six-minute walk test (6MWT) distance > or = 150 m and < or = 450 m
- •Pulmonary hypertension 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) > or - 25 mmHg
- •Pulmonary capillary wedge pressure (PCWP) measured by right heart catheterization or left ventricular end diastolic pressure (LVEDP) measured by left heart catheterization, if PCWP measurement is not reliable. Two subsets of patients will be considered for this study:
- •PCWP < or = 15 mm Hg, if PVR at rest < 160 dyn.sec/cm5
- •PCWP of 16-25 mm Hg with any PVR value
- •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
排除标准
- •Left ventricular ejection fraction < 40% (echo/Doppler)
- •Systolic blood pressure (SBP) < 85 mmHg
- •Uncontrolled hypertension with SBP > 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
- •cirrhosis or portal hypertension
- •ALT > or = 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
研究组 & 干预措施
2
干预措施: bosentan (Drug)
结局指标
主要结局
Change from Baseline to End of Study in 6MWT distance. A mean difference from placebo of at least 35 m is considered clinically relevant.
时间窗: 16 weeks
次要结局
- Time to clinical worsening from Baseline to End of Study.(16 weeks)