| Contributors: |
Khanna, D; Denton, Cp; Merkel, Pa; Krieg, T; Le Brun, Fo; Marr, A; Papadakis, K; Pope, J; Matucci Cerinic, M; Furst, De; Zochling, J; Stevens, W; Proudman, S; Feenstra, J; Youssef, P; Soroka, N; Tyabut, T; Mikhailova, Ei; Rashkov, R; Batalov, A; Yablanski, K; Keystone, E; Jones, N; Dunne, J; Masetto, A; Calabresse, Rj; Cabezas, Pc; Silva, Mo; Sariego, Ia; Escalente, Wj; Anić, B; Kaliterna, Dm; Morović Vergles, J; Novak, S; Prus, V; Artuković, M; Soukup, T; Bečvař, R; Fojtík, Z; Mouthon, L; Kollert, F; Krieg, Tm; Riemekasten, G; Lahner, N; Fierlbeck, G; Ahmadi Simab, K; Diehm, C; Szücs, G; Kumánovics, G; Nagy, G; Pal, S; Veeravalli, Sc; Danda, D; Ferri, Clodoveo; Cerinic, Mm; Cozzi, F; Ferraccioli, G; Wiland, P; Rudnicak, L; Zwolak, R; Roszkiewicz, J; Oleynikov, V; Nikulenkova, N; Lesnyak, O; Kaydashev, I; Kurytar, O; Piura, O; Chopyak, V; Chatterjee, S; Hsu, V; Hummers, L; Martin, R; Domsic, R; Schiopu, E; Shanahan, J; Murphy, Ft; Kaine, J; Davis, W; Grau, R; Eimon, A; Catoggio, Lj; Laborde, Ha; Caeiro, F; Savio, Vg; Amitrano, Cb; Vanthuyne, M; Zeng, X; Zhang, X; Zhu, P; Velásquez Franco, Cj; Choueka, P; Sanchez, Pj; Hermann, W; Sticherling, M; Steinbrink, K; Hein, R; Aschoff, R |
| Description: |
IMPORTANCE: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. OBJECTIVE: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. INTERVENTIONS: Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or >3). MAIN OUTCOMES AND MEASURES: The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. RESULTS: In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more ... |