Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO Phase 3 trial and open-label extension.
Journal
The Journal of thoracic and cardiovascular surgery
Journal Volume
169
Journal Issue
2
ISSN
1097-685X
Date Issued
2025-02
Author(s)
Clift, Paul
Berger, Felix
Sondergaard, Lars
Antonova, Petra
Disney, Patrick
Nicolarsen, Jeremy
Thambo, Jean-Benoît
Tomkiewicz Pajak, Lidia
Schophuus Jensen, Annette
Efficace, Michela
Friberg, Michael
Haberle, Diana
Walter, Verena
d'Udekem, Yves
Abstract
Objectives: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). Methods: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer 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 oxygen consumption was −0.16 ± 2.86 versus −0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, −0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. 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 because RUBATO-DB did not meet its primary or secondary end point. Conclusions: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment. © 2024 The Authors
Subjects
Fontan procedure
congenital
endothelin receptor antagonist
exercise test
heart defects
open label
SDGs
Type
journal article