A Phase 1/2 interventional study of Treprostinil iontophoresis and Remodulin® placebo iontophoresis in Diabetic Foot Ulcer, sponsored by University Hospital, Grenoble. Terminated at 1 site in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-12-12.
Sponsored by University Hospital, Grenoble · Phase 1/2, Interventional, and Treatment
Assess the effect of iontophoresis of treprostinil on wound closure over 12 weeks, in patients with DFU.
In the present study the investigators aim at establishing the proof-of-concept of iontophoresis of treprostinil as a potential treatment of diabetic foot ulcers in humans. The main hypothesis is that in patients with DFUs, the pharmacodynamic effect of a PGI2 analogue potentiates the effect of low-intensity current on microvascular function, tissue oxygenation and healing.
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:
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.
1,054 studies on the registry are indexed under Diabetic Foot; 222 are open to participants now.
This study's enrollment of 4 is below the median of 60 across 826 interventional studies indexed under Diabetic Foot.
Browse Diabetic Foot studies →University Hospital, Grenoble is the lead sponsor of 815 studies on the registry; 205 are open to participants now.
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Patients with type 2 diabetes according to the criteria of the American Diabetes Association (ADA), with one or more foot ulcer of microvascular or mixed etiology:
Exclusion Criteria:
Gel of treprostinil 1 mg/mL (target concentration) * Part 1: 1 administration/day, on separate days, with 72h between two doses. Ascending doses are 0.025 mg/mL, 0.05mg/mL, 0.1 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 0.7 mg/mL, and 1 mg/mL. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm². * Part 2: 1 administration/day at the maximum tolerated dose (MTD) for 10 days; dressing will be changed by a trained nurse every 2 days. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm².
Drug: Treprostinil iontophoresis
Placebo will be made from the placebo of Remodulin® incorporated into hydrogel (Suprasorb® G). The route and frequency of administration will be the same as for the investigational drug (topical administration by iontophoresis).
Device: Remodulin® placebo iontophoresis
subjects randomized to the standard of care group (no iontophoresis) will only undergo standard blood test at visit 0 or 1, unless tests \<1 month before inclusion are available This group is not double blind Standard care consists on debridement and dressings
We will administer treprostinil at increasing doses by a iontophoresis.
Placebo iontophoresis will be performed using Remodulin® placebo (United Therapeutics) delivered with Axion GmbH electrodes connected to a PeriIont generator (Perimed). * Part 1: 1 administration/day, on separate days, with 72h between two doses. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm². * Part 2: 1 administration/day for 10 days. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm².
Comparison of wound closure between the 3 groups: iontophoresis of treprostinil, iontophoresis of placebo, and standard of care, over12 weeks.
Wound closure is expressed as the percentage change non-reepithelialized skin area over time (12-week follow-up), assessed with a digital camera and image analysis software.
Time frame: Up to 12 weeks
The percentage of patients with complete healing at the last follow-up visit
Wound area will be assessed with a digital camera and image analysis software.
Time frame: week 12
Comparison of time to complete healing between groups
Time to complete reepithelialization will be sought in the medical record on a monthly basis.
Time frame: From date of randomization until the date of documented healing, assessed up to 12 months.
The effect of iontophoresis of treprostinil on skin perfusion assessed with laser speckle contrast imaging at the site of the ulcer and around the wound
Cutaneous perfusion will be assessed as cutaneous vascular conductance, and compared between groups
Time frame: day 9
Comparison of skin oxygenation around the lesion and on healed skin (when possible)
Comparison using transcutaneous pressure of oxygen
Time frame: Day 0 and Day 9 and week 12
8-hour PK profile. AUC0-8
8-hour PK profile. AUC0-8 will be calculated from seven time points: immediately after the end of iontophoresis ( T0), 15 min, 30 min, 1h, 2h, 4h, and 8h
Time frame: part 1 : V1 (day0) V2 (day3 or more after V1) V3 (day3 or more after V2) V4 (day3 or more after V3), Part 2 : at days 0 and 9
Incidence of treatment-emergent adverse events, among which hypotension, any cutaneous reaction at the site of iontophoresis, local pain, liver enzymes.
All adverse events will be rated according to the NIH Common Terminology Criteria for Adverse Events.
Time frame: During all the study, 3 months of follow-up for every subject
Evaluation of safety via blood pressure
Blood pressure will be continuously recorded with digital photoplethysmography.
Time frame: During all the study, 3 months of following for every subject
Evaluation of safety via the appearance of the wound
Photographs of the wound will be taken and sent to investigators, blinded to the group
Time frame: During all the study, 3 months of following for every subject
Plan to share: Undecided
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University Hospital, Grenoble