DFU Biofilm: Diabetic Foot Ulcer (DFU) Biofilm Infection and Recurrence

Sponsor

Indiana University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05172089

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Stanford University (Other), Aiyan Diabetes Center (Other), Health and Hospital Corporation of Marion County (Other), University of Arizona (Other)

420

Enrollment

Locations

40.9

Anticipated Duration (Months)

Patients Per Site

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Diabetic foot ulcers (DFU) are one of the most common reasons for hospitalization of diabetic patients and frequently results in amputation of lower limbs. Of the one million people who undergo non-traumatic leg amputations annually worldwide, 75% are performed on people who have type 2 diabetes (T2DM). The risk of death at 10 years for a diabetic with DFU is twice as high as the risk for a patient without a DFU. The rate of amputation in patients with DFU is 38.4%4. Infection is a common (>50%) complication of DFU. Emerging evidence underscores the significant risk that biofilm infection poses to the non-healing DFU. Biofilms are estimated to account for 60% of chronic wound infections. In the biofilm form, bacteria are in a dormant metabolic state. Thus, standard clinical techniques like the colony forming unit (CFU) assay to detect infection may not detect biofilm infection. Thus, biofilm infection may be viewed as a silent maleficent threat in wound care.

Condition or Disease	Intervention/Treatment	Phase
Wound Infection Wound Heal Foot Ulcer Ulcer Foot Diabetic Foot Diabetic Foot Infection	Procedure: Observation of wound infection and time to wound closure Device: Pericam PSI-NR Laser Speckle imaging

Detailed Description

In the current standard of care (SoC), wound closure is defined (FDA) by wound area re-epithelialization without drainage. The investigators' pre-clinical large animal work demonstrates that wounds with a history of biofilm infection may meet above criteria but the repaired wound-site skin is deficient in barrier function. This has led to the concept of functional wound closure wherein the current clinical definition of wound closure is supplemented with a functional parameter - restoration of skin barrier function as measured by low trans-epidermal water loss (TEWL).

This study rests on DFU-patient based findings from a NIDDK-DIACOMP funded pilot study (Sen/Gurtner) showing that closed DFU with deficient barrier function are more likely to recur. Biofilm infection as assessed through Scanning electron microscopy and wheat germ aggluttin assay performed on debrided tissue causes faulty re-epithelialization, compromising skin barrier function at the closed wound site. Such defects are caused by biofilm-inducible miRs which silence junctional proteins necessary for skin barrier function. The IRB protocol associated with this study, rests on our novel patient-based observation that in wound-edge tissue catenin delta1/p120 catenin (CTNND1) is suppressed as measured through immunohistochemistry. CTNND1 is an essential regulator of E-cadherin stability which is regarded as a master organizer in epithelial phenotype and plays a critical role in maintaining the barrier integrity of skin. The investigators' prior study identified miR-9 is a biofilm induced microRNA that targets adherens junction protein E-cadherin. The investigators propose that miR-9 can target CTNND1. The validation of miR targeting will be performed quantitative real time PCR, Western blot analyses, Argonaute 2 pull down assay and on bead assay. Thus this proposal, fully based on the study of DFU patients, seeks to conduct a fully powered clinical study testing whether DFU with a history of biofilm infection closes with deficient barrier function (Aim 2). Aim 3 tests whether such functionally deficient wound closure, manifested as high TEWL, is associated with greater wound recurrence. Per FDA, the significance of association studies is heightened by support of a well-founded biological rationale provided by mechanistic studies. This proposal rests on such mechanisms that have been reported by us in pre-clinical large animal studies.

A chronic hyperglycemic diabetes increases the risk of developing Alzheimer's disease (AD) and vascular dementia (VaD), both in general and elderly population. With the age-related changes of the skin, there is an increased risk of adverse skin barrier function that is key to wound healing. Other age-related skin conditions, such as reduced water and altered lipid content, and lower production of sebum and natural moisturizing factors of the stratum corneum (SC) may also cause dry skin and itching. These conditions together with reduced immune responses, cause aging skin to be more susceptible to infections4. In light of these facts, there is paucity in studies that investigate the mechanism of how compromised skin barrier function plays a role in wound healing outcomes among Alzheimer's Disease and Related Dementias (AD/ADRD) patients.

The primary parent study will address molecular mechanisms implicated in biofilm-induced loss of skin epithelial barrier integrity in DFU patients. Within the parent study, an additional cohort of patients with a chronic wound that are diagnosed with Alzheimer's Disease and Related Dementias (AD/ADRD) will be studied to better understand the similarities and differences in molecular mechanisms and wound healing trajectory between this group and the parent cohort.

Study Design

Study Type:

Observational

Anticipated Enrollment :

420 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Diabetic Foot Ulcer (DFU) Biofilm Infection and Recurrence

Actual Study Start Date :

Jan 31, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Diabetic Foot Ulcer parent study 405 clinically diagnosed Diabetic Foot Ulcer (DFU) patients who are suspected to be infected will be recruited . Wound swab for culture obtained. Baseline digital imaging of target wound(s). SF-12 Health survey, Visual Analogue Pain scale, Cardiff wound impact questionnaires. Wound site evaluation including TcOM/TBI/ankle brachial index (ABI) will be completed for subjects with wounds below the knee, if not already completed per standard of care within the previous 12 months. Hemoglobin A1c point of care testing will be drawn for diabetic subjects who do not have an A1c available within 90 days prior to enrollment; 3mm biopsy tissue or debrided tissue will be collected. Ideally, two tissue samples will be obtained; the subject's medical records will be reviewed and followed for up to 16 weeks or until their wound has closed, whichever comes first. The research staff will also call the patient or care facility as needed to check for wound closure.	Procedure: Observation of wound infection and time to wound closure Observational: collecting data on length of time to wound closure
Imaging sub study- 30 subjects All of the above items will be performed in this arm in addition to the below: Wound perfusion will also be measured by laser speckle imaging (LSI) using the Pericam PSI-NR instrument (Perimed Inc.). PeriCam PSI is a non-invasive non-contact device providing two-dimensional imaging of peripheral tissue blood perfusion. Reduced blood flow may lead to insufficient tissue oxygenation and, thus, assessment of peripheral vascular function has several clinical applications. The PeriCam PSI System is FDA 510(k) (#K063586) approved instrument imaging of peripheral tissue blood perfusion. The additional Pericam imaging for perfusion will be performed only in a small pilot cohort of n=40 patients at an IU site to compare this imaging modality with established modalities such as TcOM/TBI/ABI measurements performed within this study.	Procedure: Observation of wound infection and time to wound closure Observational: collecting data on length of time to wound closure Device: Pericam PSI-NR Laser Speckle imaging non-invasive non-contact device providing two-dimensional imaging of peripheral tissue blood perfusion. Reduced blood flow may lead to insufficient tissue oxygenation and, thus, assessment of peripheral vascular function has several clinical applications.
Alzheimer and/or related dementia All items in the group: Diabetic Foot Ulcer Parent study will be performed plus: 15 patients that currently have an open chronic wound and are clinically diagnosed with Alzheimer's Disease or Related Dementias (AD/ADRD) will be recruited for this additional cohort.	Procedure: Observation of wound infection and time to wound closure Observational: collecting data on length of time to wound closure

Arm

Intervention/Treatment

Diabetic Foot Ulcer parent study

405 clinically diagnosed Diabetic Foot Ulcer (DFU) patients who are suspected to be infected will be recruited . Wound swab for culture obtained. Baseline digital imaging of target wound(s). SF-12 Health survey, Visual Analogue Pain scale, Cardiff wound impact questionnaires. Wound site evaluation including TcOM/TBI/ankle brachial index (ABI) will be completed for subjects with wounds below the knee, if not already completed per standard of care within the previous 12 months. Hemoglobin A1c point of care testing will be drawn for diabetic subjects who do not have an A1c available within 90 days prior to enrollment; 3mm biopsy tissue or debrided tissue will be collected. Ideally, two tissue samples will be obtained; the subject's medical records will be reviewed and followed for up to 16 weeks or until their wound has closed, whichever comes first. The research staff will also call the patient or care facility as needed to check for wound closure.

Procedure: Observation of wound infection and time to wound closure

Observational: collecting data on length of time to wound closure

Imaging sub study- 30 subjects

All of the above items will be performed in this arm in addition to the below: Wound perfusion will also be measured by laser speckle imaging (LSI) using the Pericam PSI-NR instrument (Perimed Inc.). PeriCam PSI is a non-invasive non-contact device providing two-dimensional imaging of peripheral tissue blood perfusion. Reduced blood flow may lead to insufficient tissue oxygenation and, thus, assessment of peripheral vascular function has several clinical applications. The PeriCam PSI System is FDA 510(k) (#K063586) approved instrument imaging of peripheral tissue blood perfusion. The additional Pericam imaging for perfusion will be performed only in a small pilot cohort of n=40 patients at an IU site to compare this imaging modality with established modalities such as TcOM/TBI/ABI measurements performed within this study.

Procedure: Observation of wound infection and time to wound closure

Observational: collecting data on length of time to wound closure

Device: Pericam PSI-NR Laser Speckle imaging

non-invasive non-contact device providing two-dimensional imaging of peripheral tissue blood perfusion. Reduced blood flow may lead to insufficient tissue oxygenation and, thus, assessment of peripheral vascular function has several clinical applications.

Alzheimer and/or related dementia

All items in the group: Diabetic Foot Ulcer Parent study will be performed plus: 15 patients that currently have an open chronic wound and are clinically diagnosed with Alzheimer's Disease or Related Dementias (AD/ADRD) will be recruited for this additional cohort.

Procedure: Observation of wound infection and time to wound closure

Observational: collecting data on length of time to wound closure

Outcome Measures

Primary Outcome Measures

Aim 1 [16 weeks]
Determine how biofilm-induced DFU tissue microRNA's disrupt barrier function of the repairing DFU
Aim 2 [16 weeks]
Test the incidence of wound biofilm infection at initial visit and test its association with deficient skin barrier function at the closed DFU-site
Aim 3 [12 weeks]
Test whether closed DFU with deficient barrier function is associated with higher rate of recidivism
Aim 4 [28 weeks]
Identify the predictors and patterns of wound healing outcomes and wound recurrences among AD/ADRD and non-AD/ADRD patients

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or Female, Age ≥ 18
Willing to comply with protocol instructions, including all study visits and study activities.
Patient with an open Diabetic Foot Ulcer
Adequate arterial blood flow as evidenced by at least one of the following (for wounds below the knee):
TcOM >30 mmHg
Ankle-brachial index ≥0.7-1.20
Toe pressure > 30 mmHg
TBI > 0.6 mmHg

Exclusion Criteria:

Individuals who are deemed unable to understand the procedures, risks, and benefits of the study.
Wounds closed or to be surgically closed by flap or graft coverage
Subjects with marked immunodeficiency (HIV/AIDS, or on immunosuppressive medications.
TcOM < 30mmHg
Diabetics with a hemoglobin A1c > 12 within 3 months prior to enrollment
Subject with autoimmune connective tissue disease
Ulcer size and location that does not allow the TEWL measurement per SOP
Pregnant women
Prisoners
Unable to comply with study procedures and/or complete study visits

AIM 4 Inclusion

Inclusion Criteria:

Male or Female, Age ≥ 18 with a clinical diagnosis of Alzheimer's Disease or Related Dementias (AD/ADRD), or any similar cognitive impairment.
An available Legally Authorized Representative (LAR), as needed, to provide consent
Willing to comply with protocol instructions, including all study visits and study activities.
Clinically diagnosed with diabetes as defined by the American Diabetes Association
Chronic would defined as any ulcer that has been open for ≥ 30 days
Adequate arterial blood flow as evidenced by at least one of the following (for wounds below the knee):
TcOM >30 mmHg
Ankle-brachial index ≥0.7-1.20
Toe pressure > 30 mmHg
TBI > 0.6 mmHg

AIM 4 Exclusion

Exclusion Criteria:

Wounds closed or to be surgically closed by flap or graft coverage
Subjects with marked immunodeficiency (HIV/AIDS, or on immunosuppressive medications.
TcOM < 30mmHg
Diabetics with a hemoglobin A1c > 12 within 3 months prior to enrollment
Subject with autoimmune connective tissue disease
Ulcer size and location that does not allow the TEWL measurement per SOP
Pregnant women
Prisoners
Unable to comply with study procedures and/or complete study visits

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85724
2	Aiyan Diabetes Center	Augusta	Georgia	United States	30907
3	IU Health Wound Healing Center	Bloomington	Indiana	United States	47403
4	Rosewalk	Indianapolis	Indiana	United States	46219
5	American Village	Indianapolis	Indiana	United States	46220
6	Bethany Village	Indianapolis	Indiana	United States	46227
7	Indiana University Health Methodist Hospital	Indianapolis	Indiana	United States	46228