A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Phase III Study to Assess the Effects of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 742
- 试验地点
- 153
- 主要终点
- Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event)
研究概览
简要总结
The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two different doses of macitentan (ACT-064992) (3 and 10 mg) vs placebo in patients with symptomatic PAH. The main study objective is to demonstrate that macitentan (ACT-064992) prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk profile of macitentan (ACT-064992) in the treatment of patients with symptomatic PAH.
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
- •Signed informed consent prior to initiation of any study mandated procedure.
- •Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV.
- •Patients with the following types of pulmonary arterial hypertension (PAH) belonging to groups 1.1 to 1.3 of the Venice classification:
- •Idiopathic (IPAH);
- •Familial (FPAH); or
- •Related to:
- •Collagen vascular disease;
- •Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair;
- •Human immunodeficiency virus (HIV) infection; or
- •Drugs and toxins.
- •PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following:
- •Mean pulmonary artery pressure (mPAP) > 25 mmHg at rest;
- •Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg; and
- •Pulmonary vascular resistance (PVR) at rest >= 320 dyn×sec/cm^
- •6-minute walk distance (6MWD) >= 50 m.
- •Men or women > 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception).
排除标准
- •PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy.
- •PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected.
- •PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
- •Persistent pulmonary hypertension of the newborn.
- •Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.
- •Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after bronchodilator administration.
- •Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value.
- •Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
- •Estimated creatinine clearance < 30 mL/min
- •Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal.
- •Hemoglobin < 75% of the lower limit of the normal range.
- •Systolic blood pressure < 100 mmHg.
- •Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.
- •Pregnant or breast-feeding.
- •Known concomitant life-threatening disease with a life expectancy < 12 months.
- •Body weight < 40 kg.
- •Any condition that prevents compliance with the protocol or adherence to therapy.
- •Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise.
- •Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.
- •Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).
- •Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization
- •Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
- •Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.
研究组 & 干预措施
1
Macitentan (ACT-064992) tablet, 3 mg, once daily
干预措施: macitentan (ACT-064992) (Drug)
2
Macitentan (ACT-064992) tablet, 10 mg, once daily
干预措施: macitentan (ACT-064992) (Drug)
3
Matching placebo, once daily
干预措施: placebo (Drug)
结局指标
主要结局
Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event)
时间窗: Up to end of treatment (data presented up to month 36)
Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH). Other worsening of PAH was defined by the combined occurrence of all the following 3 events: At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks. AND worsening of PAH symptoms including at least one of the following: a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics
次要结局
- Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event)(Up to end of treatment (data presented up to month 36))
- Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event)(Up to end of study (data presented up to month 36))
- Change From Baseline to Month 6 in 6-minute Walk Distance(Baseline to month 6)
- Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event)(Up to end of treatment (data presented up to month 36))
- Pulmonary Vascular Resistance at Baseline and Month 6(Baseline to month 6)
- Cardiac Index at Baseline and Month 6(Baseline to month 6)
- Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6(Baseline to month 6)