title: Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifiers: NCT01474109, NCT01474122.
authors.affiliation: Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: Centre for Rheumatology and Connective Tissue Disease, Royal Free Hospital, London, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.affiliation: Division of Rheumatology, University of Pennsylvania, Philadelphia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Franck-Olivier
authors.initials: FO
authors.lastname: Le Brun
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Angelina
authors.initials: A
authors.lastname: Marr
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Kelly
authors.initials: K
authors.lastname: Papadakis
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Pope
authors.affiliation: Department of Experimental and Clinical Medicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.affiliation: Division of Rheumatology, UCLA, Los Angeles.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
mesh_terms: D000284:Administration, Oral; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D005260:Female; D005385:Fingers; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000150:complications*; D012883:Skin Ulcer / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D019332:Endothelin-1; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan