Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial

Marco Matucci-Cerinic, Christopher P Denton, Daniel E Furst, Maureen D Mayes, Vivien M Hsu, Patrick Carpentier, Fredrick M Wigley, Carol M Black, Barri J Fessler, Peter A Merkel, Janet E Pope, Nadera J Sweiss, Mittie K Doyle, Bernhard Hellmich, Thomas A Medsger Jr, Adele Morganti, Fabrice Kramer, Joseph H Korn, James R Seibold, Marco Matucci-Cerinic, Christopher P Denton, Daniel E Furst, Maureen D Mayes, Vivien M Hsu, Patrick Carpentier, Fredrick M Wigley, Carol M Black, Barri J Fessler, Peter A Merkel, Janet E Pope, Nadera J Sweiss, Mittie K Doyle, Bernhard Hellmich, Thomas A Medsger Jr, Adele Morganti, Fabrice Kramer, Joseph H Korn, James R Seibold

Abstract

Objectives: Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.

Methods: This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.

Results: Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.

Conclusions: Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.

Conflict of interest statement

Competing interests MMC has received fees for speaking and research grant from Actelion Pharmaceuticals and Pfizer, and has received fees for speaking from Glaxo-Smith-Kline Beecham. CPD has received research grant funding to support clinical research fellows, honoraria for lecturing and been a consultant to Actelion Pharmaceuticals, Encysive Pharmaceuticals, Genzyme, Aspreva Pharmaceuticals, Pfizer, Biovitrum and DiGNA. DEF has received grants for research from Actelion and Gilead, has consulted regarding trial design for the same companies and has received funds for being a Continuing Medical Education speaker from Actelion. MDM has received honoraria from Actelion Pharmaceuticals for speaking to doctor groups, as well as funds to cover travel expenses and research costs to conduct clinical trials of bosentan. MDM has received payments from Novartis to participate in a Data Safety Monitoring Board for a clinical trial of a drug not currently on the market; and to conduct a clinical trial of a new agent for scleroderma. MDM has received funds from MediQuest to conduct a clinical trial of topical nitroglycerin preparation to treat Raynaud's phenomenon. VMH has received honoraria and travel expenses from Actelion Pharmaceuticals for serving on an advisory board. PC has received fees from Actelion Pharmaceuticals as a speaker and moderator at the ‘Journée Française de la Sclérodermie Systémique’ in 2006 and 2007 and for participation in the Scientific Board on Systemic Sclerosis (2003–2008). FMW has been compensated for presenting in lecture format materials and data from studies related to the use of bosentan; FMW was an investigator in the RAPIDS-2 trial supported by Actelion. BJF has received funds for consulting from Actelion, Encysive and Gilead, for research from Actelion, and for speaking from Encysive and Gilead. PAM has received research funding from the following companies, each of which are involved in research related to the topic of this article: Actelion, Encysive, Genentech, Genzyme and Novartis. JEP has been a consultant and speaker for Actelion. Research in this study and other studies was funded by Actelion. MKD has received honoraria and travel expenses from Actelion Pharmaceuticals for serving on an advisory board and was an investigator for the RAPIDS-2 trial supported by Actelion. BH has received speaker honoraria from Actelion Pharmaceuticals, the manufacturer of bosentan. TAM has been paid honoraria by Actelion for giving lectures unrelated to Actelion products. FK is a full-time employee of and holds stock options in Actelion Pharmaceuticals. AM is a full-time employee of Actelion Pharmaceuticals Italia Srl and holds stock options in Actelion Pharmaceuticals. JHK received research funding from the following companies, each of which are involved in research related to the topic of this article: Actelion and Genzyme. JRS has funded research and a consultancy agreement with Actelion Pharmaceuticals, the sponsor of this study. JS, in the past, received honoraria for lectures supported by Actelion. He also has funded research and consultancy relationships with Pfizer, Encysive, United Therapeutics, Centocor, FibroGen, Bristol-Myers Squibb, Lilly, Genzyme and Gilead, all of which have commercial interests in treating scleroderma and its vascular complications. No conflicts of interest are reported by CMB and NJS.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Mean number of new digital ulcers in the study population up to weeks 12 and 24. p Values were determined using the Pitman permutation. Two patients on bosentan had no week 12 assessment.
Figure 3
Figure 3
Kaplan–Meier estimates of time to complete healing of the cardinal ulcer.
Figure 4
Figure 4
Proportions of patients with new digital ulcers (DUs) by number of new DUs up to week 24. Patients in the placebo group had up to 16 new DUs.

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