Clinical trial NCT01223352: Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: pulmonary arterial hypertension
children
pediatric
bosentan
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2010-10-19
Enrollment: 64
Sex: ALL
Minimum age (years): 3
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. 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)
2. World Health Organization functional Class (WHO FC) I, II or III
3. Male or female ≥ 3 months and \< 12 years of age (maximum age at randomization is 11.5 years)
4. Body weight ≥ 3.5 kg
5. Peripheral oxygen saturation (SpO2) ≥ 88% (at rest, on room air)
6. 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
7. Signed informed consent by the parents or legal representatives

Exclusion Criteria:

1. PAH etiologies other than listed above
2. Non-stable disease status
3. Need or plan to wean patient from intravenous epoprostenol or intravenous or inhaled iloprost
4. Systolic blood pressure \< 80% of the lower limit of normal range
5. Aspartate aminotransferase and/or alanine aminotransferase values \> 1.5 times the upper limit of normal range.
6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
7. Hemoglobin and/or hematocrit levels \< 75% of the lower limit of normal range.
8. Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible Tracleer tablet
9. 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
10. Treatment with another investigational drug within 1 month prior to randomization or planned treatment

Primary outcomes:
measure: Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan
timeFrame: 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
Secondary outcomes:
Other outcomes:
measure: Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan
timeFrame: 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
measure: Time to Reach Cmax [Tmax] of Bosentan
timeFrame: 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
measure: Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056)
timeFrame: 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
measure: Change From Baseline in WHO Functional Class at End of Study
timeFrame: Baseline, up to Week 24 on average
measure: Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study
timeFrame: Baseline, up to Week 24 on average
measure: Number of Patients With Treatment-emergent Liver Function Abnormalities
timeFrame: Baseline, up to Week 24
measure: Number of Patients With Treatment-emergent Hemoglobin Abnormalities
timeFrame: Baseline, up to Week 24
Locations:
Study officials:
affiliation: Actelion
name: Andjela Kusic-Pajic, MD
role: STUDY_DIRECTOR
References: