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Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers (PGI2HEAL)

Primary Purpose

Diabetes Mellitus, Type 2, Diabetic Foot

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Microdialysis, current induced vasodilation
Skin biopsy
peri-ulcerated skin biopsy
Sponsored by
University Hospital, Grenoble
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type 2

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria:

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).

Exclusion criteria

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
  • Chronic venous disease defined as stage 4a and 4b of the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification
  • Cutaneous condition deemed incompatible with skin biopsy and dermal microdialysis by the investigator
  • History of necrotic angiodermatitis
  • Trauma or any clinical event susceptible to be responsible for hemorrhage within the previous 6 months
  • Concomitant treatment with pentoxifylline, anticoagulants, probenecid, medicinal products known to prolong the QT interval or anti-inflammatory or analgesic dose of acetylsalicylic acid
  • If concomitant treatment with NSAIDs, participants have to be stopped 1 week before the inclusion
  • Pregnancy or Lactation
  • Females with childbearing potential, defined as a premenopausal female capable of becoming pregnant, and not using an highly effective form of birth control. Effective birth control methods include: oral, implant or patch hormone contraception; intrauterine device; abstinence and outercourse; tubal ligation; vasectomy.

Groups 1,2,3 and 4:

  • Participant involved in another interventional clinical study
  • Person deprived of liberty by judicial order
  • Person under guardianship or curatorship

Sites / Locations

  • CHU Grenoble Alpes Centre d'investigation cliniqueRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Other

Other

Other

Other

Arm Label

Group 1 : healthy subject

Group 2 : diabetes without ulcer

Group 3 : diabetes with ulcer active or <2 years

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

Arm Description

15 healthy subject without diabetes

15 patients with diabetes type II and without foot ulcer

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Involvement of COX-1 and 2 in cutaneous current-induced vasodilation
1. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, during local infusion of ketorolac (COX-1 blocker), and meloxicam (COX-2 blocker), using skin microdialysis, between the three groups.
Involvement of sensory nerves in cutaneous current-induced vasodilation
2. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, after local infusion of lidocaine, between the three groups.
IP receptor function
3. Comparison of skin perfusion measured with LSCI on the calf, in response to intradermal infusion of treprostinil using skin microdialysis, between the three groups.
Involvement of NO et EETs pathways in cutaneous current-induced vasodilation
4. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, during local infusion of NG-Monomethyl-L-arginine (L-NMMA) and fluconazole using skin microdialysis, between the three groups.
Expression of different components of PGI2 pathway in the skin : PTGS1/2
5. Comparison of the expression of Prostaglandin-Endoperoxide Synthase (PTGS1/2 (COX1/2)), in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Expression of different components of PGI2 pathway in the skin : PTGIS
5. Comparison of the expression of PTGIS (CYP8A1) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Expression of different components of PGI2 pathway in the skin : PTGIR
5. Comparison of the expression of PTGIR (IP-receptor) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Expression of different components of PGI2 pathway in the skin : TBXA2R
5. Comparison of the expression of TXA2R (TP-receptor) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
role of PGI2 pathway on cell migration in vitro
6. Cell migration observed on wounded 3D skin equivalents made from cells collected from the three groups and from a fourth group of patients undergoing lower-limb surgery. Fibroblasts and kératinocytes migration on 3D reconstructed skin models.

Full Information

First Posted
October 4, 2021
Last Updated
November 2, 2022
Sponsor
University Hospital, Grenoble
Collaborators
National Research Agency, France
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1. Study Identification

Unique Protocol Identification Number
NCT05099367
Brief Title
Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers
Acronym
PGI2HEAL
Official Title
Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2021 (Actual)
Primary Completion Date
February 28, 2023 (Anticipated)
Study Completion Date
August 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Grenoble
Collaborators
National Research Agency, France

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes mellitus, and associated with major morbidity. Indeed, diabetes is the primary cause of non-traumatic lower-limb amputation, and the rise in the prevalence of type 2 diabetes worldwide increases the global burden of DFUs. The treatment of DFUs is particularly challenging. Besides etiologic measures, local therapy of foot ulcers mainly relies on debridement of the wound and dressings. Essential complementary measures include pressure off-loading and infection control. However, despite these treatments, complications are frequent, stressing the need for new treatments. The microcirculation has a key role in tissue survival, and several classical pathways explain how hyperglycemia damages the microvessels. There is growing evidence that the PGI2 pathway is dysregulated in diabetes, which contributes to microvascular dysfunction. Besides its vasodilator effect, recent data has revealed the major role of PGI2 in angiogenesis. In the skin, such effect on healing might be enhanced by the role of PGI2 in the regulation of fibroblast and keratinocytes migration and proliferation. In the past few decades, studies in diabetic patients with ulcers have shown numerous structural and functional abnormalities of the cutaneous microcirculation, supporting its critical role in the pathophysiology of DFUs. However, the detailed mechanisms underlying endothelial dysfunction in the skin of diabetic patients remain largely unexplored in vivo. A better understanding of the specificities of microvascular changes in the diabetic foot is essential to developing new treatments for this pressing clinical need. Objectives are to explore the role of the PGI2 pathway in skin microvascular reactivity, in healthy subjects and in diabetic patients with and without DFU To determine the involvement of COX-1 and COX-2 in cutaneous current-induced vasodilation (CIV), in healthy subjects and in diabetic patients with and without DFU. To determine the involvement of sensory nerves in cutaneous CIV, in healthy subjects and in diabetic patients with and without DFU. To compare the function of the IP receptor between healthy subjects and diabetic patients with and without DFU. To determine the involvement of the nitric oxide (NO) and epoxyeicosatrienoic acids (EETs) pathway in cutaneous CIV, in healthy subjects and in diabetic patients with and without DFU. To assess cutaneous expression of the different components of the PGI2 pathway in the skin of healthy subjects and of diabetic patients with and without DFU. To assess the role of the PGI2 pathway on cell migration in vitro

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2, Diabetic Foot

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
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.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1 : healthy subject
Arm Type
Other
Arm Description
15 healthy subject without diabetes
Arm Title
Group 2 : diabetes without ulcer
Arm Type
Other
Arm Description
15 patients with diabetes type II and without foot ulcer
Arm Title
Group 3 : diabetes with ulcer active or <2 years
Arm Type
Other
Arm Description
15 patients with diabetes type II and with foot ulcer (active or <2years)
Arm Title
Group 4 : Patients with type 2 diabetes, neuropathy and DFU undergoing lower limb
Arm Type
Other
Arm Description
Patients with type 2 diabetes and neuropathy and DFU undergoing lower lunb surgery for skin ulcer
Intervention Type
Diagnostic Test
Intervention Name(s)
Microdialysis, current induced vasodilation
Intervention Description
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.
Intervention Type
Diagnostic Test
Intervention Name(s)
Skin biopsy
Intervention Description
Skin biopsy will be proposed. It will be performed on the internal superior calf (medial gastrocnemius), at a reasonable distance from the foot
Intervention Type
Diagnostic Test
Intervention Name(s)
peri-ulcerated skin biopsy
Intervention Description
Non-ulcerated skin from the peri-wound area will be collected. These patient will not undergo all the procedures included in this protocol.
Primary Outcome Measure Information:
Title
Exploring PGI2 pathway in skin microvascular reactivity
Description
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
Time Frame
Day 1
Secondary Outcome Measure Information:
Title
Involvement of COX-1 and 2 in cutaneous current-induced vasodilation
Description
1. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, during local infusion of ketorolac (COX-1 blocker), and meloxicam (COX-2 blocker), using skin microdialysis, between the three groups.
Time Frame
Day 1
Title
Involvement of sensory nerves in cutaneous current-induced vasodilation
Description
2. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, after local infusion of lidocaine, between the three groups.
Time Frame
Day 1
Title
IP receptor function
Description
3. Comparison of skin perfusion measured with LSCI on the calf, in response to intradermal infusion of treprostinil using skin microdialysis, between the three groups.
Time Frame
Day 1
Title
Involvement of NO et EETs pathways in cutaneous current-induced vasodilation
Description
4. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, during local infusion of NG-Monomethyl-L-arginine (L-NMMA) and fluconazole using skin microdialysis, between the three groups.
Time Frame
Day 1
Title
Expression of different components of PGI2 pathway in the skin : PTGS1/2
Description
5. Comparison of the expression of Prostaglandin-Endoperoxide Synthase (PTGS1/2 (COX1/2)), in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Time Frame
Day 1
Title
Expression of different components of PGI2 pathway in the skin : PTGIS
Description
5. Comparison of the expression of PTGIS (CYP8A1) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Time Frame
Day 1
Title
Expression of different components of PGI2 pathway in the skin : PTGIR
Description
5. Comparison of the expression of PTGIR (IP-receptor) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Time Frame
Day 1
Title
Expression of different components of PGI2 pathway in the skin : TBXA2R
Description
5. Comparison of the expression of TXA2R (TP-receptor) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Time Frame
Day 1
Title
role of PGI2 pathway on cell migration in vitro
Description
6. Cell migration observed on wounded 3D skin equivalents made from cells collected from the three groups and from a fourth group of patients undergoing lower-limb surgery. Fibroblasts and kératinocytes migration on 3D reconstructed skin models.
Time Frame
Day 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria: 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). Exclusion criteria 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 Chronic venous disease defined as stage 4a and 4b of the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification Cutaneous condition deemed incompatible with skin biopsy and dermal microdialysis by the investigator History of necrotic angiodermatitis Trauma or any clinical event susceptible to be responsible for hemorrhage within the previous 6 months Concomitant treatment with pentoxifylline, anticoagulants, probenecid, medicinal products known to prolong the QT interval or anti-inflammatory or analgesic dose of acetylsalicylic acid If concomitant treatment with NSAIDs, participants have to be stopped 1 week before the inclusion Pregnancy or Lactation Females with childbearing potential, defined as a premenopausal female capable of becoming pregnant, and not using an highly effective form of birth control. Effective birth control methods include: oral, implant or patch hormone contraception; intrauterine device; abstinence and outercourse; tubal ligation; vasectomy. Groups 1,2,3 and 4: Participant involved in another interventional clinical study Person deprived of liberty by judicial order Person under guardianship or curatorship
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alicia Guigui, pharmD,
Phone
+33-476-765-820
Email
aguigui@chu-grenoble.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Matthieu Roustit, pharmD, PhD
Phone
+33-476-769-260
Email
MRoustit@chu-grenoble.fr
Facility Information:
Facility Name
CHU Grenoble Alpes Centre d'investigation clinique
City
Grenoble
ZIP/Postal Code
38000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roustit
Email
mroustit@chu-grenoble.fr
First Name & Middle Initial & Last Name & Degree
paris
Email
aparis@chu-grenoble.fr

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers can request access to anonymized individual patient-level data sending an e-mail to : jlcracowski@chu-grenoble.fr or mroustit@chu-grenoble.fr
Citations:
PubMed Identifier
25617843
Citation
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.
Results Reference
background
PubMed Identifier
20827283
Citation
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.
Results Reference
background
PubMed Identifier
20805259
Citation
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.
Results Reference
background
PubMed Identifier
25843412
Citation
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.
Results Reference
background

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

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