Iontophoresis of Treprostinil to Enhance Wound Healing in Diabetic Foot Skin Ulcers (InTREPiD)

Description

Diabetic foot ulcers (DFUs) represent a serious public health problem associated with significant morbidity and health costs. Despite optimal etiologic treatment and local care, amputation is frequent, stressing the need for new treatments. Tissue ischemia is the primary cause for nonhealing DFUs. The cutaneous microcirculation, by providing tissue perfusion, fluid hemostasis, and delivery of oxygen and nutrients, plays a critical role in the pathophysiology and impaired healing of DFUs.

The investigators therefore hypothesize that the skin microcirculation, and more specifically the prostacyclin (PGI2) pathway, is an interesting target for the local treatment of DFUs. Indeed, besides its potent vasodilator effect, PGI2 plays a role in the promotion of fibroblast migration and angiogenesis in wound models.

However, the benefit of systemic (i.e. IV or SC) treatments is counterbalanced by potentially serious vasodilatation-induced side effects (e.g. severe headaches, flushing, tachycardia and hypotension). These properties are dose-limiting and are associated with safety issues and increased costs. The paradox is that impaired microvasculature prevents the drug, when administered intravenously, from diffusing properly to the wound. Elevated doses are therefore needed, leading to adverse drug reactions.

The originality of this approach is to locally deliver negatively charged PGI2 analogues into and around the wound under the influence of a low-intensity current, through a method called iontophoresis. Iontophoresis enables a controlled delivery of ionized drugs into/through the skin under the influence of low-intensity current. In addition, endogenous electrical signals in the wound are known to play a role in healing, by increasing the directed migration of keratinocytes, fibroblasts and neutrophils. Exogenous electric stimulation would mimic this phenomenon with a positive impact on wound healing. In summary, both the drug and its vehicle could therefore work synergistically, while delivering the drug locally therefore limiting side effects due to systemic diffusion.

This is a prospective, monocentric, controlled, randomized, double-blinded phase I/II study The main objective is to assess the effect of iontophoresis of treprostinil on wound closure over 12 weeks, in patients with DFU. The investigators will compare wound closure, expressed as the percentage change of the wound area over time (12-week follow-up), between 3 groups: iontophoresis of treprostinil, iontophoresis of placebo, and standard of care. Wound area will be assessed with a digital camera and image analysis software.

Secondary objectives are:

• To assess the effect of iontophoresis of treprostinil on complete healing over 3 months
• To assess the effect of iontophoresis of treprostinil on the time to complete healing
• To assess the effect of iontophoresis of treprostinil on skin perfusion at the site of the ulcer and around the wound
• To evaluate the effect of iontophoresis of treprostinil on skin oxygenation around the lesion and on healed skin
• To assess the pharmacokinetics (PK) of topical administration of treprostinil over damaged (wounded)
• To evaluate the safety of the procedure

The study will be divided into two consecutive parts:

Part 1: 8 to 24 patients with DFU (depending on the total number of doses tested, and the number of doses per patient) will be included in a single ascending dose (SAD) safety study of treprostinil iontophoresis.

Part 2: 36 patients with DFU associated with microvascular dysfunction (+/- neuropathy) will be randomized into three groups to receive either: 1. Treprostinil iontophoresis; 2. Placebo iontophoresis; 3. Standard care. Drug administration (placebo or treprostinil), but not standard care, will be double-blind. After a 10-day treatment, follow-up includes 6 visits over 10 weeks.

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