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

NCT03654989 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 38RC17.163
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetic Foot Ulcer

Keywords

Iontophoresis; Treprostinil; Diabetic; Foot Ulcer; Wound Healing

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 12 weeks

Secondary Outcomes (8)

• 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

Study Arms (3)

Treprostinil iontophoresis

EXPERIMENTAL

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

Remodulin® Placebo iontophoresis

PLACEBO COMPARATOR

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

Standard care

NO INTERVENTION

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

Interventions

Treprostinil iontophoresis DRUG

We will administer treprostinil at increasing doses by a iontophoresis.

Treprostinil iontophoresis

Remodulin® placebo iontophoresis DEVICE

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.

Remodulin® Placebo iontophoresis

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Grenoble: lead

Study Sites (1)

CHU Grenoble Alpes

Grenoble, France

Location

MeSH Terms

Conditions

Diabetic Foot; Foot Ulcer

Condition Hierarchy (Ancestors)

Diabetic Angiopathies; Vascular Diseases; Cardiovascular Diseases; Leg Ulcer; Skin Ulcer; Skin Diseases; Skin and Connective Tissue Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Diabetic Neuropathies; Foot Diseases

Study Officials

• Cracowski Jean-luc, Professor

  Clinical pharmacology unit, grenoble alpes university hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 2 sub-studies: * Preliminary safety study, Phase I: single ascending dose study that aims at establishing the safety, tolerability, and PK of the procedure in patients with active ulcers; we propose an accelerated titration design with 7 doses of gel. The accelerated phase (first four doses) uses single-patient cohorts per dose. After these doses, a standard 3+3 design will be performed. Any occurrence of dose-limiting toxicity (DLT) during the accelerated phase halts the accelerated titration and the cohort is expended to the standard 3+3 design. Two instances of DLT at a dose level halt escalation, and D-1 is the maximum tolerated dose. * Proof-of-concept study, Phase II: Thirty-six patients with DFU associated with microvascular dysfunction will be randomized into three groups: Treprostinil iontophoresis; Placebo iontophoresis; Standard care. Drug administration, but not standard care, will be double-blind. After a 10-day treatment, follow-up includes 6 visits over 10 weeks.

Study Record Dates

• First Submitted: August 20, 2018
• First Posted: August 31, 2018
• Study Start: January 28, 2020
• Primary Completion: December 7, 2021
• Study Completion: December 7, 2021
• Last Updated: December 12, 2023

Record last verified: 2023-12

Locations

FR (1)