A multicenter, open-label, randomized study with single-arm extension period to assess the pharmacokinetics, safety and efficacy of macitentan versus standard of care in children with pulmonary arterial hypertension

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• "Etiology 1. Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn. 2. Subjects with PAH associated with open shunts, as specified below: a. Eisenmenger syndrome b. Moderate to large left-to-right shunts. 3. Subjects with the following congenital cardiac abnormalities: a. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, pulmonary atresia with ventricular septal defect, unless operatively repaired and with no residual shunt b. Univentricular heart and/or subjects with Fontan-palliation. 4. Subjects with pulmonary hypertension due to lung disease (e.g., bronchopulmonary dysplasia). 5. Criterion added per Amendment 8 Version 9: Subjects with known diagnosis of bronchopulmonary dysplasia. Treatment and intervention 6. Subjects receiving a combination of > 2 PAH-specific treatments at randomization. 7. Treatment with IV or SC prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing. 8. Criterion added per Amendment 8 Version 9: In children ≥ 2 y.o.: Previous treatment with macitentan at any time. 9. Treatment with another investigational drug within 4 weeks prior to randomization. 10. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH. 11. Treatment with strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s wort (hypericum perforatum), within 4 weeks prior to randomization. 12. Systemic treatment with strong inhibitors of CYP3A4 such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole within 4 weeks prior to randomization. 13. Criterion modified per Amendment 3.1 Version 4.1: Systemic treatment with moderate dual CYP3A4/ CYP2C9 inhibitor (e.g., fluconazole and amiodarone), or administration of a combination of a moderate CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (e.g., miconazole, piperine) within 4 weeks prior to randomization Baseline abnormalities 14. Subjects with pulmonary vein stenosis. 15. Known concomitant life-threatening disease with a life expectancy < 12 months. 16. Hemoglobin or hematocrit < 75% of the lower limit of normal range (LLN). 17. Serum AST and/or ALT > 3 ×ULN. 18. Criterion modified per Amendment 6 Version 7: Severe hepatic impairment, e.g., Child-Pugh Class C [see Appendix 1]. 19. Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy. 20. Criterion added per Amendment 6 Version 7: Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 µmol/L) Pregnancy and breastfeeding 21. Pregnancy (including family planning) or breastfeeding. Other categories 22. Known hypersensitivity to ERAs, or any of the excipients. 23. Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study treatment. "