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Original Investigation |

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

Dinesh Khanna, MD1; Christopher P. Denton, MD2; Peter A. Merkel, MD3; Thomas Krieg, MD4; Franck-Olivier Le Brun, MSc5; Angelina Marr, BSc5; Kelly Papadakis, MD5; Janet Pope, MD6; Marco Matucci-Cerinic, MD7; Daniel E. Furst, MD8 ; for the DUAL-1 and DUAL-2 Investigators
[+] Author Affiliations
1Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor
2Centre for Rheumatology and Connective Tissue Disease, Royal Free Hospital, London, United Kingdom
3Division of Rheumatology, University of Pennsylvania, Philadelphia
4Department of Dermatology, University of Cologne, Cologne, Germany
5Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
6Department of Medicine, Division of Rheumatology, University of Western Ontario, London, Ontario, Canada
7Department of Experimental and Clinical Medicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
8Division of Rheumatology, UCLA, Los Angeles
JAMA. 2016;315(18):1975-1988. doi:10.1001/jama.2016.5258.
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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

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Figure 1.
Flow of Study Participants for DUAL-1

aBecause multiple exclusions may apply to individual patients, subcategories will not sum to the total.

bCalculated as weight in kilograms divided by height in meters squared.

cBecause treatment could extend beyond week 16, and because premature discontinuation of treatment could occur after week 16, values will not sum to the number randomized for each group.

End of study, for all patients, was defined as the time when the last patient completed the week-16 visit. Within 7 days afterwards, patients completed the end of treatment visit, and within 30 days, they underwent the end-of-study visit. Patients who prematurely discontinued study drug in period 1 (randomization to week 16) or period 2 (after week 16 to end of study) completed the end-of-treatment visit within 7 days of the last administered dose; these patients (upon consent) continued to undergo follow-up every 3 months until the end of study. Adverse events were monitored throughout the study. The term completed study refers to continued participation until the end of study. AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; BMI, body mass index; ITT, intention-to-treat.

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Place holder to copy figure label and caption
Figure 2.
Flow of Study Participants for DUAL-2

aBecause multiple exclusions may apply to individual patients, subcategories will not sum to the total.

bCalculated as weight in kilograms divided by height in meters squared.

cBecause treatment could extend beyond week 16, and because premature discontinuation of treatment could occur after week 16, values will not sum to the number randomized for each group.

dIndicates the independent data monitoring committee’s early termination of the trial.

End of study, for all patients, was defined as the time when the last patient completed the week-16 visit. Within 7 days afterwards, patients completed the end of treatment visit, and within 30 days, they underwent the end-of-study visit. Patients who prematurely discontinued study drug in period 1 (randomization to week 16) or period 2 (after week 16 to end of study) completed the end-of-treatment visit within 7 days of the last administered dose; these patients (upon consent) continued to undergo follow-up every 3 months until the end of study. Adverse events were monitored throughout the study. The term completed study refers to continued participation until the end of study. BMI indicates body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; ITT, intention-to-treat.

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Figure 3.
Time to First Digital Ulcer Complication Up to End of Treatment in DUAL-1 and DUAL-2

Digital ulcer complications were defined as any of the following (resulting from digital ulcer worsening): (1) critical ischemic crisis necessitating hospitalization; (2) gangrene, (auto) amputation; (3) failure of conservative management: surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand systemic sclerosis manifestations; (4) use of parenteral prostanoids; (5) use of endothelin receptor antagonists; (6) required class 2, 3, or 4 narcotics or a >50%-increase in the existing dose compared with baseline; (7) initiation of systemic antibiotics for the treatment of infection attributed to digital ulcers.

A, Treatment effect for macitentan, 3 mg vs placebo: hazard ratio (HR), 0.77 (95% CI, 0.38-1.57); log-rank P = .47; for macitentan, 10 mg vs placebo: HR, 1.12 (95% CI, 0.58-2.15); log-rank P = .74. The median duration (Q1, Q3) of treatment exposure was 41.4 weeks (22.1, 59.9) in the macitentan, 3-mg group, 37.4 weeks (18.3, 63.5) in the macitentan, 10-mg group, and 43.1 weeks (22.9, 65.1) in the placebo group.

B, Treatment effect of macitentan, 3 mg vs placebo: HR, 1.19 (95% CI, 0.61-2.33); log-rank P = .62; for macitentan, 10 mg vs placebo: HR, 1.08 (95% CI, 0.4-2.15); log-rank P = .84. The median duration (Q1, Q3) of treatment exposure was 40.5 weeks (17.7, 61.7) in the macitentan, 3-mg group, 38.6 weeks (15.0, 62.1) in the macitentan, 10-mg group, and 37.4 weeks (17.0, 58.1) in the placebo group.

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