- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03654989
Iontophoresis of Treprostinil to Enhance Wound Healing in Diabetic Foot Skin Ulcers (InTREPiD)
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Matthieu Roustit, pharmD, PhD
- Phone Number: +33-476-769-260
- Email: MRoustit@chu-grenoble.fr
Study Contact Backup
- Name: Adeline Paris, pharmacist
- Phone Number: +33-476-767-383
- Email: Aparis@chu-grenoble.fr
Study Locations
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Grenoble, France
- CHU Grenoble Alpes
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
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.
Exclusion Criteria:
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treprostinil iontophoresis
Gel of treprostinil 1 mg/mL (target concentration)
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We will administer treprostinil at increasing doses by a iontophoresis.
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Placebo Comparator: 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).
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Placebo iontophoresis will be performed using Remodulin® placebo (United Therapeutics) delivered with Axion GmbH electrodes connected to a PeriIont generator (Perimed).
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No Intervention: Standard care
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
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Comparison of wound closure between the 3 groups: iontophoresis of treprostinil, iontophoresis of placebo, and standard of care, over12 weeks.
Time Frame: Up to 12 weeks
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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.
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Up to 12 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The percentage of patients with complete healing at the last follow-up visit
Time Frame: week 12
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Wound area will be assessed with a digital camera and image analysis software.
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week 12
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Comparison of time to complete healing between groups
Time Frame: From date of randomization until the date of documented healing, assessed up to 12 months.
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Time to complete reepithelialization will be sought in the medical record on a monthly basis.
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From date of randomization until the date of documented healing, assessed up to 12 months.
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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
Time Frame: day 9
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Cutaneous perfusion will be assessed as cutaneous vascular conductance, and compared between groups
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day 9
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Comparison of skin oxygenation around the lesion and on healed skin (when possible)
Time Frame: Day 0 and Day 9 and week 12
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Comparison using transcutaneous pressure of oxygen
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Day 0 and Day 9 and week 12
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8-hour PK profile. AUC0-8
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
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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
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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
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Incidence of treatment-emergent adverse events, among which hypotension, any cutaneous reaction at the site of iontophoresis, local pain, liver enzymes.
Time Frame: During all the study, 3 months of follow-up for every subject
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All adverse events will be rated according to the NIH Common Terminology Criteria for Adverse Events.
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During all the study, 3 months of follow-up for every subject
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Evaluation of safety via blood pressure
Time Frame: During all the study, 3 months of following for every subject
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Blood pressure will be continuously recorded with digital photoplethysmography.
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During all the study, 3 months of following for every subject
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Evaluation of safety via the appearance of the wound
Time Frame: During all the study, 3 months of following for every subject
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Photographs of the wound will be taken and sent to investigators, blinded to the group
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During all the study, 3 months of following for every subject
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Cracowski Jean-luc, Professor, Clinical pharmacology unit, grenoble alpes university hospital
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 38RC17.163
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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