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 (Lead / Corresponding author), Christopher P Denton, Peter A Merkel, Thomas Krieg, Franck-Olivier Le Brun, Angelina Marr, Kelly Papadakis, Janet Pope, Marco Matucci-Cerinic, Daniel E Furst, DUAL-1 Investigators

    Research output: Contribution to journalArticle

    40 Citations (Scopus)

    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 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.

    Original languageEnglish
    Pages (from-to)1975-88
    Number of pages14
    JournalJAMA: the Journal of the American Medical Association
    Volume315
    Issue number18
    DOIs
    Publication statusPublished - 10 May 2016

    Fingerprint

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

    Keywords

    • Administration, Oral
    • Double-Blind Method
    • Endothelin-1
    • Female
    • Fingers
    • Humans
    • Male
    • Middle Aged
    • Outcome Assessment (Health Care)
    • Pyrimidines
    • Scleroderma, Systemic
    • Skin Ulcer
    • Sulfonamides

    Cite this

    Khanna, Dinesh ; Denton, Christopher P ; Merkel, Peter A ; Krieg, Thomas ; Le Brun, Franck-Olivier ; Marr, Angelina ; Papadakis, Kelly ; Pope, Janet ; Matucci-Cerinic, Marco ; Furst, Daniel E ; DUAL-1 Investigators. / Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis : DUAL-1 and DUAL-2 Randomized Clinical Trials. In: JAMA: the Journal of the American Medical Association. 2016 ; Vol. 315, No. 18. pp. 1975-88.
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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 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.",
    keywords = "Administration, Oral, Double-Blind Method, Endothelin-1, Female, Fingers, Humans, Male, Middle Aged, Outcome Assessment (Health Care), Pyrimidines, Scleroderma, Systemic, Skin Ulcer, Sulfonamides",
    author = "Dinesh Khanna and Denton, {Christopher P} and Merkel, {Peter A} and Thomas Krieg and {Le Brun}, Franck-Olivier and Angelina Marr and Kelly Papadakis and Janet Pope and Marco Matucci-Cerinic and Furst, {Daniel E} and {DUAL-1 Investigators} and Jill Belch",
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    language = "English",
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    Khanna, D, Denton, CP, Merkel, PA, Krieg, T, Le Brun, F-O, Marr, A, Papadakis, K, Pope, J, Matucci-Cerinic, M, Furst, DE & DUAL-1 Investigators 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: the Journal of the American Medical Association, vol. 315, no. 18, pp. 1975-88. https://doi.org/10.1001/jama.2016.5258

    Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis : DUAL-1 and DUAL-2 Randomized Clinical Trials. / Khanna, Dinesh (Lead / Corresponding author); Denton, Christopher P; Merkel, Peter A; Krieg, Thomas; Le Brun, Franck-Olivier; Marr, Angelina; Papadakis, Kelly; Pope, Janet; Matucci-Cerinic, Marco; Furst, Daniel E; DUAL-1 Investigators.

    In: JAMA: the Journal of the American Medical Association, Vol. 315, No. 18, 10.05.2016, p. 1975-88.

    Research output: Contribution to journalArticle

    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

    VL - 315

    SP - 1975

    EP - 1988

    JO - JAMA: the Journal of the American Medical Association

    JF - JAMA: the Journal of the American Medical Association

    SN - 0098-7484

    IS - 18

    ER -