Digital Ulcers in Ssc Treated with Oral Treprostinil: A Randomized, Double-Blind, Placebo-Controlled Study with Open-Label Follow-up

Abstract

Prostacyclins are routinely used to treat vascular features of systemic sclerosis (SSc, scleroderma) but require parenteral infusion or inhalation. This study evaluated the safety and efficacy of oral treprostinil in digital ulcers secondary to SSc. Methods: This was a randomized (1:1) placebo-controlled, multicenter study in adults with SSc and at least one active digital ulcer at entry. Oral treprostinil was administered twice daily and titrated to maximum tolerated dose with clinical assessments at Weeks 5, 10, 15 and 20. The primary endpoint was change in net digital ulcer burden. Secondary outcomes included ulcer healing and prevention, measures of hand function, quality of life, Raynaud phenomenon and global assessments. Simplified data were gathered during open-label follow up. Results: Enrolled were 147 patients (109F/38M), mean age 48.8 years with SSc of mean duration 10.5 years. At week 20, mean net ulcer burden was reduced-0.43 ulcers on treprostinil (1.80 vs. 1.37) and-0.10 ulcers on placebo (1.61 vs. 1.51; p = 0.20). There were no effects on ulcer healing or prevention, and small, inconsistent effects on Raynaud phenomenon, global assessment, hand function and quality-of-life measures. In open-label follow-up, there was a continued, small reduction in net ulcer burden (-0.52 month 3, n = 104;-0.64 month 12, n = 36). Common adverse effects were headache, nausea, diarrhea, jaw pain, flushing and other gastrointestinal symptoms. Conclusions: Administration of oral treprostinil twice daily over 20 weeks was associated with small and statistically insignificant reduction in net ulcer burden in comparison to placebo.

Update of EULAR recommendations for the treatment of systemic sclerosis

“…One meta-analysis published in 2013 included, in addition to the two above-mentioned RCTs with intravenous iloprost, two additional RCTs, one with oral iloprost (100 or 200 µg/day vs placebo for 6 weeks) and one with oral treprostinil (slow release up to 16 mg two times a day for 20 weeks) 32 37 38. This analysis revealed a trend towards a beneficial effect of prostanoids over placebo for healing of DUs (the pooled risk ratio (RR); 95% CI) for number of patients with DUs improvement or healing: RR 1.33; 95% CI 0.97 to 1.84; p=0.08 38.…”

ESVM guidelines – the diagnosis and management of Raynaud’s phenomenon

“…Digital sympathectomy is a highly specialised procedure, performed only in specialist centres. Although a systematic review indicated that there is no good evidence base for surgical procedures (including sympathectomy) for RP [35], this is unsurprising given the small numbers of patients coming to surgery and the diffi culties inherent in running clinical trials of surgical procedures.…”

“…Oral PGs have been shown to be ineff ective in their current form [34]. A recent multicentre study of oral treprostinil in patients with systemic sclerosis-related digital ulcers [35] showed a small but statistically insignifi cant reduction in net ulcer burden…”

Editorial: Clinical Trials in Raynaud's Phenomenon: A Spoonful of Sugar (Pill) Makes the Medicine Go Down (in Flames)

“…Subjects receiving active drug achieved dose levels of approximately one‐half those achieved in trials in pulmonary arterial hypertension, in which titration was extended over 3 months. Similar limitations of dosing characterized the large trial of oral treprostinil for the RP‐related clinical complication of digital ischemic ulcerations, which also had negative results. Investigators in a past trial of oral iloprost for RP chose a fixed low dose based on estimates of tolerability .…”