Diabetic Foot Ulcer (DFU) Biofilm Infection and Recurrence

Diabetic Foot Clinical Trial

— DFUBiofilm  

Official title:

Diabetic Foot Ulcer (DFU) Biofilm Infection and Recurrence

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05172089
• Other study ID #: STUDY23050116
• Secondary ID: 3R01DK125835-02S
• Status: Recruiting
• Start date: April 2, 2024
• Est. completion date: June 27, 2029

Study information

• Verified date: April 2024
• Source: University of Pittsburgh
• Contact: Bryce Hockman, CCRP
• Phone: 317 278 2715
• Email: bbhockma[@]iu.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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. Our prior study identified miR-9 is a biofilm induced microRNA that targets adherens junction protein E-cadherin. We propose that miR-9 can target CTNND1 (Aim 1). 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 studies22. This proposal rests on such mechanisms that have been reported by us in pre-clinical large animal studies18-20. The primary parent study will address molecular mechanisms implicated in biofilm-induced loss of skin epithelial barrier integrity in DFU patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 405
• Est. completion date: June 27, 2029
• Est. primary completion date: June 27, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Wounds
• Communicable Diseases
• Diabetic Foot
• Diabetic Foot Infection
• Foot Ulcer
• Infections
• Recurrence

Intervention

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.

Locations

Country	Name	City	State
United States	UPMC Wound Healing Services at UPMC Passavant	Cranberry Township	Pennsylvania
United States	University of Arizona	Tucson	Arizona

Sponsors (3)

Lead Sponsor	Collaborator
University of Pittsburgh	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of Arizona

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Aim 1	Determine how biofilm-induced DFU tissue microRNA's disrupt barrier function of the repairing DFU	16 weeks
Primary	Aim 2	Test the incidence of wound biofilm infection at initial visit and test its association with deficient skin barrier function at the closed DFU-site	16 weeks
Primary	Aim 3	Test whether closed DFU with deficient barrier function is associated with higher rate of recidivism	12 weeks