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JAMA. 2016 May 10;315(18):1975-88. doi: 10.1001/jama.2016.5258.

Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials.

Collaborators (146)

Zochling J, Stevens W, Proudman S, Feenstra J, Youssef P, Soroka N, Tyabut T, Mikhailova EI, Rashkov R, Batalov A, Yablanski K, Keystone E, Pope J, 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 C, 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, Furst DE, Hsu V, Hummers L, Martin R, Domsic R, Schiopu E, Khanna D, 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 PS, Sanchez PJ, Hermann W, Sticherling M, Steinbrink K, Hein R, Aschoff R, Sfikakis P, Settas L, Fraser A, Veale D, Balbir-Gurman A, Lidar M, Litinsky I, Levy Y, Carrillo-Vazquez SM, Rodriguez-Reyna T, Medrano-Ramirez G, Morales-Torres J, Pacheco-Tena CF, Sanchez-Ortiz A, Vonk MC, Stebbings S, Solanki K, Steele R, Ng KP, Zubrzycka-Sienkiewicz A, Brzosko M, Szepietowski JC, Hrycaj P, da Silva IF, dos Santos Lda C, Coelho PJ, Rios G, Chernykh T, Grunina E, Stanislav M, Ally M, Kalla A, Birlik AM, Kovalenko V, Petrov A, Shevchuk S, Stanislavchuk M, Anderson M, Denton CP, Herrick A, Belch J, Chung L, Csuka ME, Frech T, Goldberg A, Kahaleh B, Mayes MD, Rothfield N, Simms RW, Spiera R, Steen V, Varga J, Sikes D, Derk CT, Merkel PA, Kohen MD.

Author information

1
Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor.
2
Centre for Rheumatology and Connective Tissue Disease, Royal Free Hospital, London, United Kingdom.
3
Division of Rheumatology, University of Pennsylvania, Philadelphia.
4
Department of Dermatology, University of Cologne, Cologne, Germany.
5
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
6
Department of Medicine, Division of Rheumatology, University of Western Ontario, London, Ontario, Canada.
7
Department of Experimental and Clinical Medicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy.
8
Division of Rheumatology, UCLA, Los Angeles.

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 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 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.

TRIAL REGISTRATION:

clinicaltrials.gov Identifiers: NCT01474109, NCT01474122.

PMID:
27163986
DOI:
10.1001/jama.2016.5258
[Indexed for MEDLINE]

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