Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: bosentan
Intervention description: 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.
Intervention MeSH terms: Bosentan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 64.0
Sex: All
Minimum age: 3 Months
Maximum age: 12 Years
Healthy volunteers: No
Keywords: pulmonary arterial hypertension; children; pediatric; bosentan

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