Bosentan in Children With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The aim of the study is to demonstrate that the exposure to bosentan in children with idiopathic pulmonary arterial hypertension (PAH) or familial pulmonary arterial hypertension, using a pediatric formulation, is similar to that in adults with PAH and to evaluate the tolerability and safety of a pediatric formulation of bosentan in this patient population.

Official Title
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An Open Label, Multicenter Study to Assess the Pharmacokinetics, Tolerability, and Safety of a Pediatric Formulation of Bosentan in Children With Idiopathic or Familial 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: Signed informed consent by the parents or the legal representatives. Males or females >= 2 and < 12 years of age. Idiopathic PAH or familial PAH diagnosed by right heart catheterization (Clinical classification of pulmonary hypertension, Venice 2003). World Health Organization (WHO) functional class II or III. Oxygen saturation (SpO2) >= 88% (at rest, on room air). PAH treatment-naïve patients or patients already treated with either: Bosentan monotherapy Intravenous epoprostenol monotherapy Intravenous or inhaled iloprost monotherapy Combination of bosentan and intravenous epoprostenol Combination of bosentan and intravenous or inhaled iloprost. All patients should start the study drug (bosentan pediatric formulation) at 2 mg/kg twice daily (b.i.d.), whether or not they were previously treated with bosentan. PAH therapy stable for at least 3 months prior to Screening. Stable treatment with calcium channel blockers, if any, for at least 3 months prior to Screening. Patient's PAH condition stable for at least 3 months prior to Screening. Exclusion Criteria: PAH associated with conditions other than idiopathic or familial PAH. Non-stable patients, e.g., history (in the last 3 months prior to Screening) of recurrent syncope, or signs and symptoms of non-compensated right heart failure. Need or plan to wean patients from intravenous epoprostenol, or intravenous, or inhaled iloprost. Body weight < 4 kg. Systolic blood pressure < 80%, the lower limit of normal range, according to age and gender. AST and/or ALT values > 3 times the upper limit of normal ranges. 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 ranges. Pregnancy. Known intolerance or hypersensitivity to bosentan or any of the excipients.

Ages Eligible for Study
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Minimum Age: 2 Years
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosentan<br>The initial dose of bosentan was 2 mg/kg b.i.d. for 4 weeks. After 4 weeks, the initial dose was up-titrated to the maintenance dose of 4 mg/kg b.i.d. up to the end of the study treatment at Week 12. If the maintenance dose was not well tolerated, the dose could be down-titrated to the initial dose. | Drug: Bosentan<br>* Pediatric oral formulation of bosentan, i.e., 32 mg dispersible and breakable tablets<br>* Other names: Ro 47-0203;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve during a dose interval (AUCt) for bosentan | AUCt was assessed at steady state (i.e., after at least 2 weeks of treatment with a same dose of the study drug) over 12 hours . | At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of bosentan and its metabolites | Maximum observed plasma concentration for bosentan and its metabolites was directly derived from their respective plasma concentration-time curves. | At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose | 
| Time to reach the maximum plasma concentration (tmax) of bosentan and its metabolites |  | At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose | 
| Area under the plasma concentration-time curve during a dose interval (AUCt) for the metabolites of bosentan | AUCt was assessed at steady state (i.e., after at least 2 weeks of treatment with a same dose of the study drug) over 12 hours. | At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose | 

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