Iontophoresis of Treprostinil to Enhance Wound Healing in Diabetic Foot Skin Ulcers
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Comparison of wound closure between the 3 groups: iontophoresis of treprostinil, iontophoresis of placebo, and standard of care, over12 weeks.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
Double blind (for the two groups treated with iontophoresis of treprostinil or placebo); open for the standard of care group.
The preparation of syringes of gel containing treprostinil or placebo will be centralized. Both gels will be physically identical, and investigators will not have access to the randomization list or to preparation records. This ensures proper blinding at treatment initiation. Treatment kits will subsequently be given to research nurses to continue the treatment at home. Nurses will not have access to the randomization list or preparation records either, which guarantees proper blinding throughout the 10-day treatment.
Unblinding will be done in case of any suspicion of an unexpected serious adverse reaction, prior to the declaration of the event to the competent authorities. Unblinding may be done 24/24h by the Pharmacy department.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •The ulcer size must be ≥1 cm² and <20 cm²
- •Grade 1A, 1C, 2A or 2C (University of Texas Classification of Diabetic Foot)
- •Patient affiliated to social security insurance or beneficiary of social security insurance.
排除标准
- •History of hypersensitivity reaction to treprostinil
- •Pulmonary veno-occlusive disease (PVOD)
- •Systemic treatment with any PGI2 analogue in the past two months.
- •Critical ischemia of the lower limb, defined as leg pain at rest associated with ankle pressure <50 mmHg.
- •Infected wound, treated with antibiotics in the past 15 days.
- •Active or uncontrolled cardiovascular disease as follows:
- •Myocardial infarction, or angina within 6 months of study participation
- •Arrhythmia (uncontrolled, highly symptomatic, requires treatment or life-threatening).
- •Congestive heart failure.
- •Stroke or transient ischemic attack within 3 months of study participation
- •Uncontrolled hypertension: systolic blood pressure> 180 mmHg or diastolic blood pressure> 105 mmHg (2 abnormal readings during visit)
- •Valvular heart disease
- •Severe liver disease (Child-Pugh C) at the time of enrollment
- •Active gastroduodenal ulcer
- •Intracerebral hemorrhage
- •Trauma or any clinical event susceptible to be responsible for hemorrhage within 6 months of study participation
- •Renal disease (creatinine > 2 mg/dL and/or estimated glomerular filtration rate<30 mL/min, history of dialysis)
- •Unstable diabetes that has resulted in hyperosmolar coma or ketoacidosis, and/or documented increase or decrease in HbA1c of more than 2.0% within the previous 3 months.
- •Pregnancy or Lactation
- •Females of childbearing potential not using an effective form of birth control as determined by the investigators.
- •Participant involved in another interventional clinical study
- •Person deprived of liberty by judicial order
- •Person under guardianship or curatorship
研究组 & 干预措施
Treprostinil iontophoresis
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.
干预措施: Treprostinil iontophoresis (Drug)
Remodulin® Placebo 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).
干预措施: Remodulin® placebo iontophoresis (Device)
结局指标
主要结局
Comparison of wound closure between the 3 groups: iontophoresis of treprostinil, iontophoresis of placebo, and standard of care, over12 weeks.
时间窗: Up to 12 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.
次要结局
- Incidence of treatment-emergent adverse events, among which hypotension, any cutaneous reaction at the site of iontophoresis, local pain, liver enzymes.(During all the study, 3 months of follow-up for every subject)
- Evaluation of safety via blood pressure(During all the study, 3 months of following for every subject)
- Evaluation of safety via the appearance of the wound(During all the study, 3 months of following for every subject)
- The percentage of patients with complete healing at the last follow-up visit(week 12)
- Comparison of time to complete healing between groups(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(day 9)
- Comparison of skin oxygenation around the lesion and on healed skin (when possible)(Day 0 and Day 9 and week 12)
- 8-hour PK profile. AUC0-8(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)