An Open-label, Prospective Multicenter Study to Assess the Pharmacokinetics, Tolerability, Safety and Efficacy of the Pediatric Formulation of Bosentan Two Versus Three Times a Day 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
- 64
- 主要终点
- Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan
研究概览
简要总结
The primary objective of AC-052-373 was to assess the pharmacokinetic (PK) profile of two dosing regimens of the pediatric formulation of bosentan in children with pulmonary arterial hypertension (PAH) <12 years of age.
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
- 3 Months 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •PAH diagnosis confirmed with right heart catheterization (RHC):
- •Idiopathic or heritable PAH, or
- •Associated PAH persisting after complete repair of a congenital heart defect (PAH has to be persistent for at least 6 months after surgery) or
- •PAH-Congenital Heart Disease (PAH-CHD) associated with systemic-to-pulmonary shunts (after global amendment dated 09 May 2012)
- •World Health Organization functional Class (WHO FC) I, II or III
- •Male or female ≥ 3 months and < 12 years of age (maximum age at randomization is 11.5 years)
- •Body weight ≥ 3.5 kg
- •Peripheral oxygen saturation (SpO2) ≥ 88% (at rest, on room air)
- •Baseline PAH-therapy (Calcium channel blocker, bosentan, prostanoid, phosphodiesterase type-5 inhibitor) if present, has to be stable for at least 3 months prior to screening. During the study, all background treatments should remain stable
- •Signed informed consent by the parents or legal representatives
排除标准
- •PAH etiologies other than listed above
- •Non-stable disease status
- •Need or plan to wean patient from intravenous epoprostenol or intravenous or inhaled iloprost
- •Systolic blood pressure < 80% of the lower limit of normal range
- •Aspartate aminotransferase and/or alanine aminotransferase values > 1.5 times the upper limit of normal range.
- •Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
- •Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal range.
- •Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible Tracleer tablet
- •Treatment with forbidden medication within 2 weeks or at least 5 times the half-life prior to randomization, whichever is the longest:
- •Glibenclamide (glyburide)
- •Cyclosporin A
- •Sirolimus
- •Tacrolimus
- •Fluconazole
- •Rifampicin (rifampin)
- •Ritonavir
- •Co-administration of CYP2C9 inhibitors (e.g., amiodarone, voriconazole) and moderate/strong CYP3A4 inhibitors (e.g., amprenavir, erythromycin, ketoconazole, diltiazem, itraconazole)
- •Endothelin receptor antagonists (ERAs) other than bosentan
- •Treatment with another investigational drug within 1 month prior to randomization or planned treatment
研究组 & 干预措施
Bosentan 2 mg/Kg t.i.d.
2 mg/kg bosentan administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks
干预措施: bosentan (Drug)
Bosentan 2 mg/Kg b.i.d.
2 mg/kg bosentan administered twice daily (morning and evening) for a planned duration of 24 weeks
干预措施: bosentan (Drug)
结局指标
主要结局
Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan
时间窗: 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment
Daily exposure was measured by the area under the plasma concentration-time curve over a period of 24 hours \[AUC(0-24)\]. Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) \[AUC(0-24c)\].
次要结局
未报告次要终点