Evaluation of Personalized Nutritional Intervention on Wound Healing of Cutaneous Ulcers in Diabetics

Evaluation of Personalized Nutritional Intervention Together With the Application of MSC-derived Exosomes on the Regenerative Capacity and Wound Healing of Cutaneous Ulcers in Diabetics

The ageing population and the increase in diabetes raise the prevalence of chronic skin ulcers (CCU). In diabetics, precursor cell mobilization decreases. In wounds, the inflammation is prolonged and oxidative stress increases. This is an unfavorable microenvironment for healing. A major risk factor in the development of CCU is nutritional deficiency. Healing needs energy and nutrients for regeneration. In diabetics the malnutrition can be more than 60%. However, although the provision of certain nutrients can improve the healing capacity, it is not a common clinical practice to nutritionally evaluate diabetic with CCU. Exosomes are extracellular vesicles that reflect the physiological state of the cells producing them. Stem cell derivatives exosomes are rich in factors, that can provide a favorable microenvironment for tissue regeneration.

The aim of this project is to develop a therapeutic process to accelerate the healing of diabetic CCU, based on the correction of nutritional deficiencies, to improve the regenerative capacity, together with the application of exosomes from mesenchymal stem-cell (MSC) in the wound, creating a microenvironment that favors tissue regeneration. For this, a pilot clinical trial with diabetic patients with CCU is proposed, to evaluate the effect of personalized nutritional supplementation on healing and regenerative capacity.

Study Overview

• Status: Recruiting
• Conditions: Foot, Diabetic
• Intervention / Treatment: Dietary supplement: Personalized Nutritional Intervention

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marta Camacho-Cardenosa, PhD; Email: marta.camacho@imibic.org
• Study Contact Backup: Name: Antonio Casado-Díaz, PhD; Phone Number: 957213814; Email: bb1cadia@uco.es

Study Locations

• Spain
  • Andalucía
    • Córdoba, Andalucía, Spain, 14004
      • Recruiting
      • Hospital Universitario Reina Sofía de Córdoba
      • Contact: Alfonso Calañas, PhD; Phone Number: 957010000; Email: alfonso.calanas.sspa@juntadeandalucia.es

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signature of the informed consent
• Age between 50 and 80 years
• Diagnosis of Diabetes Mellitus for more than 1 year
• Documented diagnosis of peripheral artery disease
• HbA1c < 9%
• Category 5 in the Rutherford-Becker classification

Exclusion Criteria:

• Poor cognitive function, dementia or psychiatric conditions
• Osteomyelitis, gangrene, malignancy or immunocompromised disease
• Thromboangiitis obliterans or Buerger's disease
• Clinical evidence of invasive infection in the target limb requiring IV antibiotherapy
• Presence of neuropathic ulcers only
• Human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) positive.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nutritional Intervention (NI); In addition to the usual treatment, will receive dietary advice and a nutritional supplement, according to the results of their evaluation in the Endocrinology Service	Dietary supplement: Personalized Nutritional Intervention; Those with malnutrition criteria will also receive a nutritional supplement (e.g. fortimel cubitan, advanced or extra, Nutricia) or another of similar composition, in case of intolerance to the first option. The aim will be to provide at least 50% of the recommended intakes for the main nutrients related to wound healing.
No Intervention: Control (C); Who will continue with their usual treatments in the Diabetic Foot Unit and they will receive dietary advice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ulcer evaluation	Change from baseline in size ulcer assessed by picture, including ruler to measure their size	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite measure of markers of nutritional status	Change from baseline in nutritional status assessed from blood samples	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Composite measure of haemogram	Change from baseline in haemogram assessed from blood samples	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Hemoglobin A1c (HbA1c) Test for Diabetes	Change from baseline in HbA1c (%) assessed from blood samples	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Measure of markers of nutritional status, include to thyrotropin	Change from baseline in thyrotropin (mlU/L) assessed from blood samples	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Ultrasensitive C-reactive Protein (CRP) test	Change from baseline in CRP (mg/L) assessed from blood samples	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Quantification of circulating endothelial progenitor cells (EPC)	Change from baseline in total CD34+ or CD133+ cells expressing vascular endothelial growth factor receptor 2 (VEGFR2) analyzed by flow cytometry	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Concentration of stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor A (VEGFA)	Change from baseline in concentration of SDF-1 and VEGFA factors in serum by ELISA	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nutritional Risk	Change from baseline in nutritional risk assessed by Malnutrition Universal Screening Tool (MUST)	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Diagnosis of malnutrition	Change from baseline in diagnosis of malnutrition assessed by Global Leadership Initiative on malnutrition (GLIM criteria)	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Sarcopenia	Change from baseline in sarcopenia assessed by SARC-F	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Handgrip Strength	Change from baseline in handgrip strength assessed by dynamometry	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Body weight and height	Body weight and height will be combined to report body mass index (BMI) in kg/m^2. Change from baseline in BMI	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Tricipital skinfold	Change from baseline in tricipital skinfold using a skinfold caliper	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Waist and hip circumferences	waist and hip circumferences (cm) will be combined to report Waist and Hip Ratio (WHR). Change from baseline in WHR	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Body Fat	Change from baseline in body fat assessed by multifrequency bioimpedaciometry and bioelectrical impedance vector analysis	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Muscle Mass	Change from baseline in muscle mass assessed by multifrequency bioimpedaciometry and bioelectrical impedance vector analysis	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Hydration status	Change from baseline in hydration status assessed by multifrequency bioimpedaciometry and bioelectrical impedance vector analysis	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation
Arm circumference	Change from baseline in arm circumference in centimeters (cm)	Baseline, 30 days after treatment initiation, 60 days after treatment initiation and 90 days after treatment initiation

Collaborators and Investigators

• Sponsor: Maimónides Biomedical Research Institute of Córdoba
• Collaborators: Instituto de Salud Carlos III; Hospital Universitario Reina Sofia de Cordoba
• Investigators: Principal Investigator: Alfonso Calañas, PhD, Hospital Universitario Reina Sofia; Principal Investigator: Antonio Casado-Díaz, PhD, Maimónides Biomedical Research Institute of Córdoba

Publications and helpful links

General Publications

• Cederholm T, Jensen GL, Correia MITD, Gonzalez MC, Fukushima R, Higashiguchi T, Baptista G, Barazzoni R, Blaauw R, Coats A, Crivelli A, Evans DC, Gramlich L, Fuchs-Tarlovsky V, Keller H, Llido L, Malone A, Mogensen KM, Morley JE, Muscaritoli M, Nyulasi I, Pirlich M, Pisprasert V, de van der Schueren MAE, Siltharm S, Singer P, Tappenden K, Velasco N, Waitzberg D, Yamwong P, Yu J, Van Gossum A, Compher C; GLIM Core Leadership Committee; GLIM Working Group. GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community. Clin Nutr. 2019 Feb;38(1):1-9. doi: 10.1016/j.clnu.2018.08.002. Epub 2018 Sep 3.
• Malmstrom TK, Morley JE. SARC-F: a simple questionnaire to rapidly diagnose sarcopenia. J Am Med Dir Assoc. 2013 Aug;14(8):531-2. doi: 10.1016/j.jamda.2013.05.018. Epub 2013 Jun 25. No abstract available.
• Armstrong DG, Hanft JR, Driver VR, Smith AP, Lazaro-Martinez JL, Reyzelman AM, Furst GJ, Vayser DJ, Cervantes HL, Snyder RJ, Moore MF, May PE, Nelson JL, Baggs GE, Voss AC; Diabetic Foot Nutrition Study Group. Effect of oral nutritional supplementation on wound healing in diabetic foot ulcers: a prospective randomized controlled trial. Diabet Med. 2014 Sep;31(9):1069-77. doi: 10.1111/dme.12509. Epub 2014 Jun 19.
• Basiri R, Spicer MT, Levenson CW, Ormsbee MJ, Ledermann T, Arjmandi BH. Nutritional Supplementation Concurrent with Nutrition Education Accelerates the Wound Healing Process in Patients with Diabetic Foot Ulcers. Biomedicines. 2020 Aug 3;8(8):263. doi: 10.3390/biomedicines8080263.
• Haughey L, Barbul A. Nutrition and Lower Extremity Ulcers: Causality and/or Treatment. Int J Low Extrem Wounds. 2017 Dec;16(4):238-243. doi: 10.1177/1534734617737639. Epub 2017 Nov 16.
• Kurian SJ, Miraj SS, Benson R, Munisamy M, Saravu K, Rodrigues GS, Rao M. Vitamin D Supplementation in Diabetic Foot Ulcers: A Current Perspective. Curr Diabetes Rev. 2021;17(4):512-521. doi: 10.2174/1573399816999201012195735.
• Zhang SS, Tang ZY, Fang P, Qian HJ, Xu L, Ning G. Nutritional status deteriorates as the severity of diabetic foot ulcers increases and independently associates with prognosis. Exp Ther Med. 2013 Jan;5(1):215-222. doi: 10.3892/etm.2012.780. Epub 2012 Oct 30.

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2023
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 20, 2022
• First Submitted That Met QC Criteria: February 14, 2022
• First Posted (Actual): February 17, 2022

Study Record Updates

• Last Update Posted (Actual): October 25, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Wound Healing; Malnutrition; Dietary Supplementations
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Ulcer; Diabetic Foot; Skin Ulcer
• Other Study ID Numbers: PI21/01935

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No