Universität zu Köln

Khanna, Dinesh, Denton, Christopher P., Merkel, Peter A., Krieg, Thomas, Le Brun, Franck-Olivier, Marr, Angelina, Papadakis, Kelly, Pope, Janet ORCID: 0000-0003-1479-5302, Matucci-Cerinic, Marco and Furst, Daniel E. (2016). Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis DUAL-1 and DUAL-2 Randomized Clinical Trials. JAMA-J. Am. Med. Assoc., 315 (18). S. 1975 - 1989. CHICAGO: AMER MEDICAL ASSOC. ISSN 1538-3598

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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, 10mg 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 3mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10mg 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 3mg 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Khanna, Dinesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Denton, Christopher P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkel, Peter A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krieg, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Le Brun, Franck-Olivier UNSPECIFIED UNSPECIFIED UNSPECIFIED Marr, Angelina UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadakis, Kelly UNSPECIFIED UNSPECIFIED UNSPECIFIED Pope, Janet UNSPECIFIED orcid.org/0000-0003-1479-5302 UNSPECIFIED Matucci-Cerinic, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Furst, Daniel E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-275775
DOI:	10.1001/jama.2016.5258
Journal or Publication Title:	JAMA-J. Am. Med. Assoc.
Volume:	315
Number:	18
Page Range:	S. 1975 - 1989
Date:	2016
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	1538-3598
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLASMA ENDOTHELIN-1 LEVELS; EULAR SCLERODERMA TRIALS; HEALTH-ASSESSMENT QUESTIONNAIRE; FIBROSIS; BOSENTAN; RECOMMENDATIONS; PREVENTION; SUBSETS; HISTORY Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27577