A Multicenter, Open-label, Randomized, Study With Single-arm Extension Period to Assess the Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With Pulmonary Arterial Hypertension
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 165
- 试验地点
- 170
- 主要终点
- Participants >=2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12 Based on Body Weight
研究概览
简要总结
This is a prospective, multicenter, open-label, randomized, controlled, parallel Phase 3 study with an open-label single-arm extension period to evaluate pharmacokinetics (PK), safety and efficacy of macitentan in children with pulmonary arterial hypertension (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
- None
入排标准
- 年龄范围
- 1 Month 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent by the parent(s) or legally designated representative and assent from developmentally capable children prior to initiation of any study-mandated procedure
- •Males or females between greater than or equal to (>=) 1 month and less than (<) 18 years of age
- •Participants with body weight >= 3.5 kilograms (kg) at randomization
- •Pulmonary arterial hypertension (PAH) diagnosis confirmed by historical RHC (mPAP greater than or equal to [>=] 25 millimeters of mercury [mmHg], and Pulmonary artery wedge pressure [PAWP] less than or equal to [<=] 15 mmHg, and Pulmonary vascular resistance index [PVRi] greater than [>] 3 WU × m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by Left atrium pressure [LAP] or Left ventricular end diastolic pressure [LVEDP] (in absence of mitral stenosis) assessed by heart catheterization
- •PAH belonging to the Nice 2013 Updated Classification Group 1 (including participants with Down Syndrome) and of following etiologies: idiopathic PAH; heritable PAH; PAH associated with congenital heart disease (CHD); Drug or toxin induced PAH; PAH associated with HIV; PAH associated with connective tissue diseases (PAH-aCTD); and World health organization (WHO) Functional class I to III
- •Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to the end of study (EOS)
排除标准
- •Participants with PAH due to portal hypertension, schistosomiasis, or with pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn
- •Participants with PAH associated with Eisenmenger syndrome, or with moderate to large left-to-right shunts
- •Participants receiving a combination of > 2 PAH-specific treatments at randomization.
- •Treatment with intravenous (IV) or subcutaneous (SC) prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing
- •Hemoglobin or hematocrit <75 percent (%) of the lower limit of normal range
- •Serum Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) greater than (>) 3 times the upper limit of normal range
- •Pregnancy (including family planning) or breastfeeding.
- •Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol
- •Severe hepatic impairment, for example Child-Pugh Class C
- •Clinical signs of hypotension which in the investigator's judgment would preclude initiation of a PAH-specific therapy
- •Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 micro-moles per liter [micro-mol/L])
- •Participants with known diagnosis of bronchopulmonary dysplasia
研究组 & 干预措施
Macitentan
Macitentan is administered once daily via oral route. Children less than (<) 2 years old (y.o.) will be assigned as a cohort to the macitentan group without randomization. The dose will be adjusted to the participant's age (for those < 2 y.o.) or to the participant's body weight (for those greater than or equal to (>=) 2 y.o.). single-arm extension period (SAEP) will start at end of core period (EOCP) visit and ends at end of study (EOS) visit.
干预措施: Macitentan (Drug)
Standard-of-care
Standard-of-care as per site's clinical practice which may comprise treatment with pulmonary arterial hypertension (PAH) non-specific treatment and/or up to two PAH-specific medications excluding macitentan and intravenous/subcutaneous (IV/SC) prostanoids.
干预措施: Standard-of-care (Other)
结局指标
主要结局
Participants >=2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12 Based on Body Weight
时间窗: Pre-dose at Week 12
Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 based on body weight were reported. This outcome measure was planned to be analyzed for specified arms only.
Participants >=2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12 Based on Age Group
时间窗: Pre-dose at Week 12
Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 based on age group were reported. This outcome measure was planned to be analyzed for specified arms only.
Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4
时间窗: Pre-dose at Week 4
Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 4 were reported. This outcome measure was planned to be analyzed for specified arms only.
Participants From China With >=12 to <18 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12
时间窗: Pre-dose at Week 12
Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 were reported.
次要结局
- Time to the First Clinical Event Committee (CEC)-Confirmed Disease Progression Event(Baseline (Day 1) up to end of core study period (EOCP; up to 7.08 years))
- Time to First CEC-confirmed Hospitalization for PAH(Baseline (Day 1) up to EOCP (up to 7.08 years))
- Time to CEC-confirmed Death Due to PAH(Baseline (Day 1) up to EOCP (up to 7.08 years))
- Time to Death (All Causes)(Baseline (Day 1) up to 7.26 years)
- Percentage of Participants With World Health Organization (WHO) Functional Class (FC) I or II Versus III or IV(At Weeks 12 and 24)
- Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Weeks 12 and 24(Baseline (Day 1), Weeks 12 and 24)
- Change From Baseline in Mean Daily Time Spent in Moderate to Vigorous Physical Activity as Measured by Accelerometry at Week 48(Baseline (Day 1), Week 48)
- Change From Baseline in Body Surface Area (BSA) Normalized Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography at Week 24(Baseline (Day 1), Week 24)
- Change From Baseline in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography at Week 24(Baseline (Day 1), Week 24)
- Change From Baseline in Quality of Life Measured by Pediatric Quality of Life Inventory Version 4.0 (PedsQL 4.0) Generic Core Scales Short Form (SF-15)(Baseline (Day 1), Week 24)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Baseline (Day 1) up to 7.26 years)
- Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)(Baseline (Day 1) up to 7.26 years)
- Number of Participants With AEs Leading to Premature Discontinuation of Macitentan or Standard of Care (SoC)(Baseline (Day 1) up to 7.26 years)
- Number of Participants With AEs of Special Interest(Baseline (Day 1) up to 7.26 years)
- Number of Participants With Marked Laboratory Abnormalities(Baseline (Day 1) up to 7.26 years)
- Change From Baseline in Selected Laboratory Parameters(Baseline (Day 1) up to 7.26 years)
- Change From Baseline in Vital Signs (Blood Pressure, Heart Rate)(Baseline (Day 1) up to 7.26 years)
- Change From Baseline in Growth Variable(Baseline (Day 1) up to 7.26 years)
- Change From Baseline in Sexual Maturation Measured by Tanner Stage(Baseline (Day 1) up to 7.26 years)