Treprostinil iontophoresis in systemic sclerosis-related digital skin ulcers: A single ascending dose safety study

Abstract

Digital skin ulcers are a severe complication of systemic sclerosis(SSc). The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a two-stage, randomized, placebo-controlled single ascending dose study in healthy volunteers and patients with SSc-related digital ulcer (SSc-DU). We further explored the effect of the procedure on skin blood flux. The objectives were to assess the safety of an iontophoresis of treprostinil hydrogel administered on healthy volunteers finger pad, leg and foot and asses the safety of ascending doses in patients with SSc-DU. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 different locations (i.e. 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1 mg/mL hydrogel of treprostinil. We then randomly treated SSc-DUs in a 3/1 ratio treprostinil or placebo respectively. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated (according to the CTCAE), while skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88460 ± 6436 versus 12730 ± 3397%BL.min respectively, P < 0.001) and on the sole of the foot (AUC0-3 h at 20124 ± 6119 versus 3142 ± 3036% BL.min respectively, P = 0.018) with a trend on the finger (AUC0-3 h was 10773 ± 4888). Among five patients with SSc-UD, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil was safe in SSc patients with digital ulcers. Treprostinil at 1 mg/mL will be used in the next study, i.e. repeated iontophoresis in SSc-related ulcer.