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.

Abbott Structural Heart Santa Clara Calif

Adult Congenital Heart Disease Unit Queen Elizabeth Hospital Birmingham Birmingham United Kingdom

Department of Cardiac and Vascular Diseases Institute of Cardiology Jagiellonian University Medical College John Paul 2 Hospital Krakow Poland

Department of Cardiology Rigshospitalet University of Copenhagen Copenhagen Denmark

Department of Cardiology Royal Adelaide Hospital Adelaide South Australia Australia

Department of Cardiovascular Surgery 2nd Faculty of Medicine Charles University Prague Motol University Hospital Motol Prague Czech Republic

Department of Congenital Heart Disease Pediatric Cardiology Deutsches Herzzentrum der Charité Charité Universitaetsmedizin Berlin Berlin Germany

Department of Pediatric and Adult Congenital Cardiology Bordeaux University Hospital Pessac France

Department of Pediatrics National Taiwan University Hospital Taipei Taiwan

Division of Cardiac Surgery Children's National Heart Institute Children's National Hospital Washington DC

IHU Liryc Electrophysiology and Heart Modeling Institute Fondation Bordeaux Université Pessac Bordeaux France

Providence Adult and Teen Congenital Heart Program Providence Sacred Heart Medical Center and Children's Hospital Spokane Wash

Research and Development Actelion Pharmaceuticals Ltd A Johnson and Johnson Company Allschwil Switzerland

Statistics and Decision Sciences Actelion Pharmaceuticals Ltd A Johnson and Johnson Company Allschwil Switzerland

Statistics and Decision Sciences Janssen Cilag SpA Imperia Italy

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