Macitentan in Pediatric Pulmonary Arterial Hypertension (TOMORROW): A Randomized Clinical Trial

Objective: To evaluate pharmacokinetics (PK), efficacy, and safety of macitentan vs standard of care (SoC) in pediatric pulmonary arterial hypertension (PAH). 

Study design: TOMORROW was a multicenter, open-label, phase 3 clinical trial in patients aged ≥2-<18 years World Health Organization Functional Class I-III. Patients were randomized (1:1) to macitentan (bodyweight-based dosing) or SoC (≤2 PAH-specific therapies). The primary endpoint was steady-state C_trough plasma concentration of macitentan and aprocitentan (active metabolite) at week 12. Secondary endpoints included time-to-first clinical event committee-confirmed disease progression, safety/tolerability, change in NT-proBNP, and quality of life. 

Results: We randomized 148 patients (macitentan: n = 73; SoC: n = 75). The PK profile was consistent with adults; mean (SD) steady-state C_trough concentrations were 185 (114.3) and 983 (324.1) ng/mL. Mean treatment duration was 183.36 weeks (macitentan) and 130.59 weeks (SoC). Hazard ratios (95% CI) for time-to-event analyses (macitentan vs SoC) were 0.828 (0.460-1.492) for disease progression, 0.912 (0.393-2.118) for PAH hospitalization, and 1.530 (0.429-5.457) for PAH mortality ( P > .05 for all). Percentage of baseline NT-proBNP was 72% (macitentan) vs 101% (SoC) at week 12 ( P = .086) and 76% vs 78% at week 24 ( P = .884). Macitentan showed clinically meaningful improvements in quality of life assessments vs SoC for children ( P = .043) and parents ( P = .020) at week 24. The safety profile of macitentan was consistent with that seen in adults. 

Conclusions: TOMORROW was a novel study assessing PK and the long-term efficacy and safety of macitentan vs SoC in pediatric PAH. The results confirm the adequacy of the macitentan dosing in this population and provided signals of potential benefit of macitentan over SoC for children with PAH. Trial registration ClinicalTrials.gov (ID number, NCT02932410; https://clinicaltrials.gov/study/NCT02932410 ).