Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: Dual-1 and Dual-2 randomized clinical trials

DUAL-1 and DUAL-2 Investigators

Research output: Contribution to journalArticle

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 trialwas 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 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 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.

Original languageEnglish (US)
Pages (from-to)1975-1988
Number of pages14
JournalJAMA - Journal of the American Medical Association
Volume315
Issue number18
DOIs
StatePublished - May 10 2016

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Systemic Scleroderma
Ulcer
Randomized Controlled Trials
Placebos
macitentan
Endothelin-1
Nasopharyngitis
Skin Ulcer
Therapeutics
Respiratory Tract Infections
Headache
Anemia

ASJC Scopus subject areas

  • Medicine(all)

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Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis : Dual-1 and Dual-2 randomized clinical trials. / DUAL-1 and DUAL-2 Investigators.

In: JAMA - Journal of the American Medical Association, Vol. 315, No. 18, 10.05.2016, p. 1975-1988.

Research output: Contribution to journalArticle

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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 = "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 trialwas 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 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 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.",
author = "{DUAL-1 and DUAL-2 Investigators} and Dinesh Khanna and Denton, {Christopher P.} and Merkel, {Peter A.} and Krieg, {Thomas M.} and {Le Brun}, {Franck Olivier} and Angelina Marr and Kelly Papadakis and Janet Pope and Marco Matucci-Cerinic and Furst, {Daniel E.} and Jane Zochling and Wendy Stevens and Susanna Proudman and John Feenstra and Peter Youssef and Nikolay Soroka and Tamara Tyabut and Mikhailova, {Elena Ivanovna} and Rasho Rashkov and Anastas Batalov and Kiril Yablanski and Edward Keystone and Niall Jones and James Dunne and Ariel Masetto and Calabresse, {Renato Jim{\'e}nez} and Cabezas, {Pedro Claudio Miranda} and Silva, {Marta Ofelia Aliste} and Sariego, {Imgadt Annelise Goecke} and Escalente, {William Jos{\'e} Otero} and Branimir Anić and Kaliterna, {Dušanka Martinović} and Jadranka Morović-Vergles and Srdan Novak and Višnja Prus and Marinko Artuković and Toma{\'a}š Soukup and Radim Bečvař and Zdeněk Fojt{\'i}k and Luc Mouthon and Florian Kollert and Gabriela Riemekasten and Nina Lahner and Gerhard Fierlbeck and Keihan Ahmadi-Simab and Curt Diehm and Gabriella Sz{\"u}cs and G{\'a}bor Kum{\'a}novics and Gy{\"o}rgy Nagy and Laura Hummers",
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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 - DUAL-1 and DUAL-2 Investigators

AU - Khanna, Dinesh

AU - Denton, Christopher P.

AU - Merkel, Peter A.

AU - Krieg, Thomas M.

AU - Le Brun, Franck Olivier

AU - Marr, Angelina

AU - Papadakis, Kelly

AU - Pope, Janet

AU - Matucci-Cerinic, Marco

AU - Furst, Daniel E.

AU - Zochling, Jane

AU - Stevens, Wendy

AU - Proudman, Susanna

AU - Feenstra, John

AU - Youssef, Peter

AU - Soroka, Nikolay

AU - Tyabut, Tamara

AU - Mikhailova, Elena Ivanovna

AU - Rashkov, Rasho

AU - Batalov, Anastas

AU - Yablanski, Kiril

AU - Keystone, Edward

AU - Jones, Niall

AU - Dunne, James

AU - Masetto, Ariel

AU - Calabresse, Renato Jiménez

AU - Cabezas, Pedro Claudio Miranda

AU - Silva, Marta Ofelia Aliste

AU - Sariego, Imgadt Annelise Goecke

AU - Escalente, William José Otero

AU - Anić, Branimir

AU - Kaliterna, Dušanka Martinović

AU - Morović-Vergles, Jadranka

AU - Novak, Srdan

AU - Prus, Višnja

AU - Artuković, Marinko

AU - Soukup, Tomaáš

AU - Bečvař, Radim

AU - Fojtík, Zdeněk

AU - Mouthon, Luc

AU - Kollert, Florian

AU - Riemekasten, Gabriela

AU - Lahner, Nina

AU - Fierlbeck, Gerhard

AU - Ahmadi-Simab, Keihan

AU - Diehm, Curt

AU - Szücs, Gabriella

AU - Kumánovics, Gábor

AU - Nagy, György

AU - Hummers, Laura

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 trialwas 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 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 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.

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 trialwas 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 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 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.

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U2 - 10.1001/jama.2016.5258

DO - 10.1001/jama.2016.5258

M3 - Article

C2 - 27163986

AN - SCOPUS:84968808222

VL - 315

SP - 1975

EP - 1988

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0098-7484

IS - 18

ER -