2023-509845-10-00已完成3 期
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
- 入组人数
- 19
- 试验地点
- 9
- 主要终点
- "In subjects ≥ 2 years of age in the macitentan arm: • Trough (pre-dose) plasma concentrations of macitentan and its active metabolite(ACT-132 577) at Week 12 (steady-state) "
研究概览
简要总结
To assess the pharmacokinetics, safety and efficacy of macitentan versus standard of care in children with pulmonary arterial hypertension
研究设计
- 分配方式
- Randomized
- 主要目的
- Prospective, multicenter, open-label, randomized, controlled, parallel group, Phase 3 study"
- 盲法
- None
入排标准
- 年龄范围
- 0 years 至 17 years（0-17 Years）
- 接受健康志愿者
- 是
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.
- •Criterion modified per Amendment 8 Version 9: Males or females between ≥ 1 month and < 18years of age.
- •Criterion modified per Amendment 8 Version 9: Subjects with body weight ≥ 3.5 kg at randomization.
- •Criterion modified per Amendment 6: PAH diagnosis confirmed by historical RHC (mPAP ≥ 25 mm Hg, and PAWP ≤ 15 mm Hg, and PVRi > 3 WU x m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by LAP or LVEDP (in absence of mitral stenosis) assessed by heart catheterization.
- •PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down Syndrome) and of following etiologies: iPAH hPAH PAH associated with CHD: − PAH with co-incidental CHD (confirmed by BCAC) − Post-operative PAH (persisting/recurring/developing ≥ 6 months after repair of CHD) Drug or toxin-induced PAH PAH associated with HIV PAH-aCTD
- •WHO FC I to III.
- •PAH-specific treatment-naïve subjects or subjects on PAH-specific treatment (mono-therapy or combination of two therapies)*.
- •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 EOS . "
排除标准
- •Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.
- •Subjects with PAH associated with open shunts, as specified below: a. Eisenmenger syndrome b. Moderate to large left-to-right shunts.
- •Subjects with the following congenital cardiac abnormalities: a. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, pulmonary atresia with ventricular septal defect, unless operatively repaired and with no residual shunt b. Univentricular heart and/or subjects with Fontan-palliation.
- •Subjects with pulmonary hypertension due to lung disease (e.g., bronchopulmonary dysplasia).
- •Criterion added per Amendment 8 Version 9: Subjects with known diagnosis of bronchopulmonary dysplasia. Treatment and intervention
- •Subjects receiving a combination of > 2 PAH-specific treatments at randomization.
- •Treatment with IV or SC prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing.
- •Criterion added per Amendment 8 Version 9: In children ≥ 2 y.o.: Previous treatment with macitentan at any time.
- •Treatment with another investigational drug within 4 weeks prior to randomization.
- •Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH.
- •Treatment with strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s wort (hypericum perforatum), within 4 weeks prior to randomization.
- •Systemic treatment with strong inhibitors of CYP3A4 such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole within 4 weeks prior to randomization.
- •Criterion modified per Amendment 3.1 Version 4.1: Systemic treatment with moderate dual CYP3A4/ CYP2C9 inhibitor (e.g., fluconazole and amiodarone), or administration of a combination of a moderate CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (e.g., miconazole, piperine) within 4 weeks prior to randomization Baseline abnormalities
- •Subjects with pulmonary vein stenosis.
- •Known concomitant life-threatening disease with a life expectancy < 12 months.
- •Hemoglobin or hematocrit < 75% of the lower limit of normal range (LLN).
- •Serum AST and/or ALT > 3 ×ULN.
- •Criterion modified per Amendment 6 Version 7: Severe hepatic impairment, e.g., Child-Pugh Class C [see Appendix 1].
- •Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy.
- •Criterion added per Amendment 6 Version 7: Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 µmol/L) Pregnancy and breastfeeding
- •Pregnancy (including family planning) or breastfeeding. Other categories
- •Known hypersensitivity to ERAs, or any of the excipients.
- •Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study treatment. "
结局指标
主要结局
"In subjects ≥ 2 years of age in the macitentan arm: • Trough (pre-dose) plasma concentrations of macitentan and its active metabolite(ACT-132 577) at Week 12 (steady-state) "
"In subjects ≥ 2 years of age in the macitentan arm: • Trough (pre-dose) plasma concentrations of macitentan and its active metabolite(ACT-132 577) at Week 12 (steady-state) "
"In subjects less than 2 years of age on macitentan: • Trough concentrations of macitentan and its active metabolite (ACT132577) at Week 4 (steady-state)"
"In subjects less than 2 years of age on macitentan: • Trough concentrations of macitentan and its active metabolite (ACT132577) at Week 4 (steady-state)"
次要结局
- "The secondary endpoints are listed below: • Time to first CEC-confirmed hospitalization for PAH occurring between randomization/Visit 2 and end of core period (EOCP). • Time to CEC-confirmed death due to PAH occurring between randomization/Visit 2 and end of core period (EOCP)."
- • Time to death (all causes) occurring between randomization/Visit 2 and Study Closure.
- "Following secondary endpoints are analyzed up to end of randomized macitentan or SoC + 7 days. Baseline is the last non-missing value observed before or on the day of randomization/ Visit 2 • WHO FC status (I or II vs III or IV) at Week 24. • Percent of Baseline plasma NT-proBNP at Week 24. • Change from Baseline to Week 48 in in mean daily time spent in moderate to vigorous physical activity as measured by accelerometry."
- "• Change from Baseline to Week 24 in tricuspid annular plane systolic excursion (TAPSE), and left ventricular eccentricity index measured by echocardiography (centrally assessed). • Change from Baseline to Week 24 in Quality of Life as measured by the PedsQLTM 4.0 Generic Core Scales Short Form (SF15)1. "
研究者
CTIS Point of Contact
Scientific
Actelion Pharmaceuticals Ltd.
研究点 (9)
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