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

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ClinicalTrials.gov Identifier: NCT03654989
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Grenoble

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.


Condition or disease Intervention/treatment Phase
Diabetic Foot Ulcer Drug: Treprostinil iontophoresis Device: Remodulin® placebo iontophoresis Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Treatment
Official Title: Iontophoresis of Treprostinil to Enhance Wound Healing in Diabetic Foot Skin Ulcers
Estimated Study Start Date : May 2020
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Treprostinil iontophoresis
We will administer treprostinil at increasing doses by a iontophoresis.

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).
Device: Remodulin® placebo 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.

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



Primary Outcome Measures :
  1. 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 ]
    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.


Secondary Outcome Measures :
  1. The percentage of patients with complete healing at the last follow-up visit [ Time Frame: week 12 ]
    Wound area will be assessed with a digital camera and image analysis software.

  2. 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. ]
    Time to complete reepithelialization will be sought in the medical record on a monthly basis.

  3. 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 ]
    Cutaneous perfusion will be assessed as cutaneous vascular conductance, and compared between groups

  4. Comparison of skin oxygenation around the lesion and on healed skin (when possible) [ Time Frame: Day 0 and Day 9 and week 12 ]
    Comparison using transcutaneous pressure of oxygen

  5. 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 ]
    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

  6. 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 ]
    All adverse events will be rated according to the NIH Common Terminology Criteria for Adverse Events.

  7. Evaluation of safety via blood pressure [ Time Frame: During all the study, 3 months of following for every subject ]
    Blood pressure will be continuously recorded with digital photoplethysmography.

  8. Evaluation of safety via the appearance of the wound [ Time Frame: During all the study, 3 months of following for every subject ]
    Photographs of the wound will be taken and sent to investigators, blinded to the group



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03654989


Contacts
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Contact: Matthieu Roustit, PharmD, PhD +33-476-769-260 MRoustit@chu-grenoble.fr
Contact: Adeline Paris, pharmacist +33-476-767-383 Aparis@chu-grenoble.fr

Locations
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France
CHU Grenoble Alpes Recruiting
Grenoble, France
Contact: Jean-Luc CRACOWSKI, Pr         
Sponsors and Collaborators
University Hospital, Grenoble
Investigators
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Principal Investigator: Cracowski Jean-luc, Professor Clinical pharmacology unit, grenoble alpes university hospital
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Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT03654989    
Other Study ID Numbers: 38RC17.163
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by University Hospital, Grenoble:
Iontophoresis
Treprostinil
Diabetic
Foot Ulcer
Wound Healing
Additional relevant MeSH terms:
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Diabetic Foot
Foot Ulcer
Skin Ulcer
Ulcer
Pathologic Processes
Diabetic Angiopathies
Vascular Diseases
Cardiovascular Diseases
Leg Ulcer
Skin Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Diabetic Neuropathies
Foot Diseases
Treprostinil
Antihypertensive Agents