Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: bosentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosentan 2 mg/Kg t.i.d.<br>2 mg/kg bosentan administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks | Drug: bosentan<br>* 32 mg quadrisected dispersible tablet. The dosage of bosentan (2 mg/Kg) was adjusted according to the patient's body weight at initiation of the study treatment. Dosage readjustment was permitted after 12 weeks of treatment.<br>* Other names: ACT-050088;|
| Experimental: Bosentan 2 mg/Kg b.i.d.<br>2 mg/kg bosentan administered twice daily (morning and evening) for a planned duration of 24 weeks | Drug: bosentan<br>* 32 mg quadrisected dispersible tablet. The dosage of bosentan (2 mg/Kg) was adjusted according to the patient's body weight at initiation of the study treatment. Dosage readjustment was permitted after 12 weeks of treatment.<br>* Other names: ACT-050088;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan | 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)]. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary arterial hypertension, children, pediatric, bosentan