Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: Dual-1 and Dual-2 randomized clinical trials

Gianfranco Ferraccioli, Dinesh Khanna, Christopher P. Denton, Peter A. Merkel, Thomas M. Krieg, Franck-Olivier Le Brun, Angelina Marr, Kelly Papadakis, Janet Pope, Marco Matucci-Cerinic, Daniel E. Furst, Jane Zochling, Wendy Stevens, Susanna Proudman, John Feenstra, Peter Youssef, Nikolay Soroka, Tamara Tyabut, Elena Ivanovna Mikhailova, Rasho RashkovAnastas Batalov, Kiril Yablanski, Edward Keystone, Niall Jones, James Dunne, Ariel Masetto, Renato Jiménez Calabresse, Pedro Claudio Miranda Cabezas, Marta Ofelia Aliste Silva, Imgadt Annelise Goecke Sariego, William José Otero Escalente, Branimir Anić, Dušanka Martinović Kaliterna, Jadranka Morović-Vergles, Srdan Novak, Višnja Prus, Marinko Artuković, Tomaáš Soukup, Radim Bečvař, Zdeněk Fojtík, Luc Mouthon, Florian Kollert, Gabriela Riemekasten, Nina Lahner, Gerhard Fierlbeck, Keihan Ahmadi-Simab, Curt Diehm, Gabriella Szücs, Gábor Kumánovics, György Nagy, Sarvajeet Pal, Sarath Chandra Mouli Veeravalli, Debashish Danda, Clodeveo Ferri, Franco Cozzi, Piotr Wiland, Lidia Rudnicak, Robert Zwolak, Jadwiga Roszkiewicz, Valentin Oleynikov, Natalya Nikulenkova, Olga Lesnyak, Igor Kaidashev, Oleksandr Kurytar, Olena Piura, Valentyna Chopyak, Soumya Chatterjee, Vivien Hsu, Laura Hummers, Richard Martin, Robyn Domsic, Elena Schiopu, Joseph Shanahan, Frederik T. Murphy, Jeffrey Kaine, William Davis, Rafael Grau, Alicia Eimon, Luis Jose Catoggio, Hugo Armando Laborde, Francisco Caeiro, Veronica Gabriela Savio, Cristina Beatriz Amitrano, Marie Vanthuyne, Xioafeng Zeng, Xiao Zhang, Ping Zhu, Carlos Jaime Velásquez-Franco, Philippe Selim Chalem Choueka, Patricia Julieta Vélez Sanchez, Walter Hermann, Michael Sticherling, Kerstin Steinbrink, Rüdiger Hein, Roland Aschoff, Petros Sfikakis, Lukas Settas, Alexander Fraser, Douglas Veale, Alexandra Balbir-Gurman, Merav Lidar, Irena Litinsky, Yair Levy, Sandra Miriam Carrillo-Vazquez, Tatiana Rodriguez-Reyna, Gabriel Medrano-Ramirez, Jorge Morales-Torres, Cesar Francisco Pacheco-Tena, Adriana Sanchez-Ortiz, Madelon C. Vonk, Simon Stebbings, Kamal Solanki, Richard Steele, Kristine Ng, Anna Zubrzycka-Sienkiewicz, Marek Brzosko, Jacek C. Szepietowski, Pawel Hrycaj, Ivone Fernandes Santos Da Silva, Lelita Da Conceiçao Dos Santos, Paulo Jorge Clemente Coelho, Grissel Rios, Tatiana Chernykh, Elena Grunina, Marina Stanislav, Mahmood Ally, Asgar Kalla, Ahmet Merih Birlik, Volodymyr Kovalenko, Andriy Petrov, Sergiy Shevchuk, Mykola Stanislavchuk, Marina Anderson, Ariane Herrick, Jill Belch, Lorinda Chung, Mary Ellen Csuka, Tracy Frech, Avram Goldberg, Bashar Kahaleh, Maureen D. Mayes, Naomi Rothfield, Robert William Simms, Robert Spiera, Virgina Steen, John Varga, David Sikes, Chris T. Derk, Michael D. Kohen

Risultato della ricerca: Contributo in rivistaArticolo in rivista

66 Citazioni (Scopus)

Abstract

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 trialwas 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 3mg 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 10mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. Conclusions and Relevance: Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.
Lingua originaleEnglish
pagine (da-a)1975-1988
Numero di pagine14
RivistaJAMA
Volume315
DOI
Stato di pubblicazionePubblicato - 2016
Pubblicato esternamente

Keywords

  • Administration, Oral
  • Double-Blind Method
  • Endothelin-1
  • Female
  • Fingers
  • Humans
  • Male
  • Medicine (all)
  • Middle Aged
  • Outcome Assessment (Health Care)
  • Pyrimidines
  • Scleroderma, Systemic
  • Skin Ulcer
  • Sulfonamides

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