TY - JOUR
T1 - Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis
T2 - DUAL-1 and DUAL-2 Randomized Clinical Trials
AU - Khanna, Dinesh
AU - Denton, Christopher P
AU - Merkel, Peter A
AU - Krieg, Thomas
AU - Le Brun, Franck-Olivier
AU - Marr, Angelina
AU - Papadakis, Kelly
AU - Pope, Janet
AU - Matucci-Cerinic, Marco
AU - Furst, Daniel E
AU - DUAL-1 Investigators
AU - Belch, Jill
PY - 2016/5/10
Y1 - 2016/5/10
N2 - 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.
AB - 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.
KW - Administration, Oral
KW - Double-Blind Method
KW - Endothelin-1
KW - Female
KW - Fingers
KW - Humans
KW - Male
KW - Middle Aged
KW - Outcome Assessment (Health Care)
KW - Pyrimidines
KW - Scleroderma, Systemic
KW - Skin Ulcer
KW - Sulfonamides
U2 - 10.1001/jama.2016.5258
DO - 10.1001/jama.2016.5258
M3 - Article
C2 - 27163986
SN - 0098-7484
VL - 315
SP - 1975
EP - 1988
JO - JAMA: the Journal of the American Medical Association
JF - JAMA: the Journal of the American Medical Association
IS - 18
ER -
