Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO phase 3 trial and open-label extension.

OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in Fontan-palliated patients over a 52-week, multicenter, randomized, placebo-controlled, double-blind trial (RUBATO-DB) and an open-label extension trial (RUBATO-OL).

METHODS: Patients aged ≥12 years, New York Heart Association functional class II/III, underwent total cavopulmonary connection >1 year pre-screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, primary efficacy endpoint was change in peak oxygen consumption (VO2 ) from baseline to week 16; secondary endpoints were change from baseline over 52 weeks in peak VO2 and change in mean count/minute of daily physical activity via accelerometer (PA-Ac) from baseline to week 16. Safety was assessed throughout both studies.

RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n=68) or placebo (n=69); 92.7% completed 52-week double-blind treatment. At week 16, mean (SD) change in peak VO2 was -0.16 (2.86) versus -0.67 (2.66) mL/kg/min with macitentan versus placebo (median unbiased treatment difference estimate: 0.62 mL/kg/min [99% repeated confidence interval -0.62; 1.85], p=0.19). No treatment effect was observed in either of the secondary endpoints. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache and fatigue. RUBATO-OL was prematurely discontinued as RUBATO-DB did not meet its primary or secondary endpoint.

CONCLUSIONS: The primary endpoint of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in Fontan-palliated patients. Macitentan was generally well tolerated over long-term treatment.