Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

Authors

  • J. R. Seibold,

    Corresponding author
    1. University of Connecticut, Farmington
    • Division of Rheumatology, University of Connecticut Health Center, MARB MC 5353, Room N3020, 263 Farmington Avenue, Farmington, CT 06034
    Search for more papers by this author
    • Dr. Seibold has received consulting fees and/or honoraria from Actelion, FibroGen, Pfizer (more than $10,000 each), Encysive, United Therapeutics, and FibroGen (less than $10,000 each); he has received research funding from Actelion, Pfizer, Encysive, FibroGen, Centocor, Bristol-Myers Squibb, Genzyme, Eli Lilly, Gilead Sciences, and United Therapeutics. Dr. Seibold's spouse is a full-time employee of Actelion.

    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

  • C. P. Denton,

    1. Royal Free and University College Medical School, London, UK
    Search for more papers by this author
    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

    • Dr. Denton has received consulting fees and/or honoraria from Actelion, Pfizer, Encysive, BioVitrum, GlaxoSmithKline, and Genzyme (less than $10,000 each); he has received research funding from Actelion, Encysive, Genzyme, and Aspreva.

  • D. E. Furst,

    1. David Geffen School of Medicine at the University of California, Los Angeles
    Search for more papers by this author
    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

    • Dr. Furst has received consulting fees, speaking fees, advisory board service honoraria, and/or other honoraria from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen Idec, Centocor, Genentech, Gilead Sciences, GlaxoSmithKline, Merck, Nitec, Novartis, UCB, Wyeth and Xoma (less than $10,000 each); he has received research grants from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.

  • L. Guillevin,

    1. Hôpital Cochin, Paris, France
    Search for more papers by this author
    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

    • Dr. Guillevin has received consulting fees from Actelion (less than $10,000) and is a member of the Actelion France scientific council.

  • L. J. Rubin,

    1. University of California, San Diego
    Search for more papers by this author
    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

    • Dr. Rubin has received consulting fees from Actelion (more than $10,000) and has served as the principal investigator for Actelion-funded research.

  • A. Wells,

    1. National Heart and Lung Institute, London, UK
    Search for more papers by this author
    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

    • Dr. Wells has received consulting fees and honoraria from Actelion (less than $10,000), has served on an Actelion speakers bureau, and has received research funding from Actelion.

  • M. Matucci Cerinic,

    1. University of Florence, Florence, Italy
    Search for more papers by this author
    • Dr. Matucci Cerinic has received a research grant from Actelion.

  • G. Riemekasten,

    1. Charité Universitätsmedizin Berlin, Berlin, Germany
    Search for more papers by this author
    • Dr. Riemekasten has received consulting fees and honoraria from Actelion (less than $10,000), has served on an Actelion advisory board, and has received a research grant from Actelion.

  • P. Emery,

    1. Chapel Allerton Hospital and University of Leeds, Leeds, UK
    Search for more papers by this author
    • Dr. Emery has received consulting fees from Actelion (less than $10,000) and has received research funding from Actelion.

  • H. Chadha-Boreham,

    1. Actelion Pharmaceuticals, Allschwil, Switzerland
    Search for more papers by this author
    • Dr. Chadha-Boreham owns stock options in Actelion.

    • Drs. Chadha-Boreham, Charef, and Roux are full-time employees of Actelion.

  • P. Charef,

    1. Actelion Pharmaceuticals, Allschwil, Switzerland
    Search for more papers by this author
    • Drs. Chadha-Boreham, Charef, and Roux are full-time employees of Actelion.

  • S. Roux,

    1. Actelion Pharmaceuticals, Allschwil, Switzerland
    Search for more papers by this author
    • Drs. Chadha-Boreham, Charef, and Roux are full-time employees of Actelion.

  • C. M. Black

    1. Royal Free and University College Medical School, London, UK
    Search for more papers by this author
    • Drs. Seibold, Denton, Furst, Guillevin, Rubin, Wells, and Black were members of the steering committee for this study.

    • Dr. Black has received consulting fees and honoraria from Actelion, Pfizer, Encysive, and Genzyme (less than $10,000 each).


  • ClinicalTrials.gov identifier: NCT00070590.

Abstract

Objective

Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD).

Method

Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150–500 meters or a 6-minute walk distance of ≥500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed.

Results

Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant).

Conclusion

No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Ancillary