Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers

NCT05099367 | Unknown DMC

• 1 other identifier: 38RC18.314
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Prospective, monocentric, pathophysiological study, comparing 3 parallel groups: healthy controls; patients with diabetes and without DFU; patients with diabetes and with DFU. To address secondary objectives, samples from a fourth group will be collected.

Conditions

Diabetes Mellitus, Type 2; Diabetic Foot

Outcome Measures

Primary Outcomes (1)

• Exploring PGI2 pathway in skin microvascular reactivity

  Comparison of skin perfusion measured with laser speckle contrast imaging (LSCI) on the calf, and expressed as arbitrary perfusion units, in response to local cathodal current application, between the three groups

  Day 1

Secondary Outcomes (9)

• Involvement of COX-1 and 2 in cutaneous current-induced vasodilation

  Day 1

• Involvement of sensory nerves in cutaneous current-induced vasodilation

  Day 1

• IP receptor function

  Day 1

• Involvement of NO et EETs pathways in cutaneous current-induced vasodilation

  Day 1

• Expression of different components of PGI2 pathway in the skin : PTGS1/2

  Day 1

Study Arms (4)

Group 1 : healthy subject

OTHER

15 healthy subject without diabetes

Diagnostic Test: Microdialysis, current induced vasodilation; Diagnostic Test: Skin biopsy

Group 2 : diabetes without ulcer

OTHER

15 patients with diabetes type II and without foot ulcer

Diagnostic Test: Microdialysis, current induced vasodilation; Diagnostic Test: Skin biopsy

Group 3 : diabetes with ulcer active or <2 years

OTHER

15 patients with diabetes type II and with foot ulcer (active or \<2years)

Diagnostic Test: Microdialysis, current induced vasodilation; Diagnostic Test: Skin biopsy

Group 4 : Patients with type 2 diabetes, neuropathy and DFU undergoing lower limb

OTHER

Patients with type 2 diabetes and neuropathy and DFU undergoing lower lunb surgery for skin ulcer

Diagnostic Test: peri-ulcerated skin biopsy

Interventions

Microdialysis, current induced vasodilation DIAGNOSTIC_TEST

CIV will be applied over all microdialysis fibers: one perfused with saline, one perfused with a preferential COX-1 blocker; and one perfused with a preferential COX-2 blocker. CIV will be applied over all fibers in the following conditions: one perfused with saline, one perfused with fluconazole and L-NMMA, and the last one perfused with lidocaine.Dialysate collection will be performed after each CIV: dermal PGI2 metabolite (6-ketoPGF1α) and other COX-dependent prostanoids or metabolite (e.g. 11-dehydroTXB2) will be collected in the dialysate fluid and quantified. One hour after the last condition, treprostinil will be perfused over all fibers.

Group 1 : healthy subject; Group 2 : diabetes without ulcer; Group 3 : diabetes with ulcer active or <2 years

Skin biopsy DIAGNOSTIC_TEST

Skin biopsy will be proposed. It will be performed on the internal superior calf (medial gastrocnemius), at a reasonable distance from the foot

Group 1 : healthy subject; Group 2 : diabetes without ulcer; Group 3 : diabetes with ulcer active or <2 years

peri-ulcerated skin biopsy DIAGNOSTIC_TEST

Non-ulcerated skin from the peri-wound area will be collected. These patient will not undergo all the procedures included in this protocol.

Group 4 : Patients with type 2 diabetes, neuropathy and DFU undergoing lower limb

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Groups 1,2,3,4:
• Informed consent signed
• Affiliated to social security insurance or beneficiary of social security insurance
• Aged of 18 or older
• Group 1: healthy volunteers:
• Free from all acute and chronic pathology
• Group 2: diabetic patients without DFU:
• Patients with type 2 diabetes according to the criteria of the American Diabetes Association (ADA), without DFU or history of DFU
• Group 3: diabetic patients with DFU or recent history of DFU (occurred within the last two years):
• Patients with type 2 diabetes according to the criteria of the American Diabetes Association (ADA) with: One or more active grade 1A, 1C, 2A or 2C (University of Texas Classification of Diabetic Foot) foot ulcer of microvascular or mixed etiology; Or a recent history (\<2 years) of foot ulcer of microvascular or mixed etiology.
• Group 4 (to collect samples of foot skin biopsies to address secondary objectives ):
• Patients with type 2 diabetes according to the criteria of the American Diabetes Association (ADA),with neuropathy and DFU undergoing lower-limb surgery for skin ulcer (e.g. toe amputation).

You may not qualify if:

• Groups 1, 2 and 3:
• 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.
• Presence of diabetic peripheral neuropathy above the ankle, defined as a scoring \>3 of at least two of the four stimuli of the Neuropathy Disability Score (i.e. pinprick sensation, light touch, vibration, and temperature perception) (37).
• Infected wound, treated with antibiotics in the past 15 days.
• Critical ischemia of the lower limb, defined as leg pain at rest associated with ankle pressure \<70 mmHg.
• History of hypersensitivity reaction to treprostinil, fluconazole, other azole compounds, L-NMMA, ketorolac, meloxicam, or any NSAIDs or acetylsalicylic acid, lidocaine (or any local anesthetic with an amide bond), or their excipients
• History of asthma, rhinitis, nasal polyps, angioedema, hives rash, or any other allergic reaction due to acetylsalicylic acid or any NSAID taking
• Pulmonary veno-occlusive disease (PVOD)
• Porphyria
• Hyperkalemia
• Active or uncontrolled cardiovascular disease as follows: Myocardial infarction, or angina within the previous 6 months; Severe ischemic heart disease; Arrhythmia (uncontrolled, symptomatic, requiring treatment or life-threatening); Congestive heart failure, or decompensated heart failure not medically controlled; Stroke or transient ischemic attack within the previous 3 months; Uncontrolled hypertension: systolic blood pressure (SBP)\> 180 mmHg or diastolic blood pressure (DBP)\> 105 mmHg (2 abnormal readings during visit) Valvular heart disease
• Severe liver disease (Child-Pugh C) at the time of enrollment
• Renal disease (creatinine \>2 mg/dL and/or estimated glomerular filtration rate (GFR) \<30 mL/min, history of dialysis)
• Active peptic ulcer disease, recent gastrointestinal bleeding or perforation, or history of peptic ulcer disease or gastrointestinal bleeding or perforation with NSAIDs
• Intracerebral or gastrointestinal hemorrhage, hemostasis disorder or every clinical status that may lead to bleeding

Sponsors & Collaborators

• University Hospital, Grenoble: lead
• National Research Agency, France: collaborator

Study Sites (1)

CHU Grenoble Alpes Centre d'investigation clinique

Grenoble, 38000, France

RECRUITING

Related Publications (4)

• Knebel SM, Sprague RS, Stephenson AH. Prostacyclin receptor expression on platelets of humans with type 2 diabetes is inversely correlated with hemoglobin A1c levels. Prostaglandins Other Lipid Mediat. 2015 Jan-Mar;116-117:131-5. doi: 10.1016/j.prostaglandins.2014.12.002. Epub 2015 Jan 21.

  PMID: 25617843 BACKGROUND

• Gohin S, Sigaudo-Roussel D, Conjard-Duplany A, Dubourg L, Saumet JL, Fromy B. What can current stimulation tell us about the vascular function of endogenous prostacyclin in healthy rat skin in vivo? J Invest Dermatol. 2011 Jan;131(1):237-44. doi: 10.1038/jid.2010.267. Epub 2010 Sep 9.

  PMID: 20827283 BACKGROUND

• Gibbons CH, Freeman R, Veves A. Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology. Diabetes Care. 2010 Dec;33(12):2629-34. doi: 10.2337/dc10-0763. Epub 2010 Aug 30.

  PMID: 20805259 BACKGROUND

• Hellmann M, Roustit M, Gaillard-Bigot F, Cracowski JL. Cutaneous iontophoresis of treprostinil, a prostacyclin analog, increases microvascular blood flux in diabetic malleolus area. Eur J Pharmacol. 2015 Jul 5;758:123-8. doi: 10.1016/j.ejphar.2015.03.066. Epub 2015 Apr 3.

  PMID: 25843412 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetic Foot

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Diabetic Angiopathies; Vascular Diseases; Cardiovascular Diseases; Foot Ulcer; Leg Ulcer; Skin Ulcer; Skin Diseases; Skin and Connective Tissue Diseases; Diabetes Complications; Diabetic Neuropathies

Central Study Contacts

Alicia Guigui, pharmD,

CONTACT

+33-476-765-820; aguigui@chu-grenoble.fr

Matthieu Roustit, pharmD, PhD

CONTACT

+33-476-769-260; MRoustit@chu-grenoble.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, monocentric, pathophysiological study, comparing 3 parallel groups: healthy controls; patients with diabetes and without DFU; patients with diabetes and with DFU. To address secondary objectives , samples from a fourth group (patients with diabetes, neuropathy and DFU undergoing lower-limb amputation) will be collected.

Study Record Dates

• First Submitted: October 4, 2021
• First Posted: October 29, 2021
• Study Start: October 1, 2021
• Primary Completion: February 28, 2025
• Study Completion: August 31, 2025
• Last Updated: December 6, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

FR (1)