Clinical trial NCT05281562: Immunonutrition for Diabetic Foot Ulcers
Official title: Effects of Supplemental Immunonutrition on Healing of Chronic Non-Healing Lower Extremity Ulcers in Diabetic Patients: A Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Diabetes Mellitus
Diabetic Peripheral Neuropathy
Diabetic Foot Ulcer
Lead sponsor: Prisma Health-Midlands
Sponsor class: OTHER
First posted: 2022-03-16
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized to receive 6 weeks of oral immunonutrition supplementation, consisting of L-Arginine, Vitamin C, and Omega-3 fatty acids, in addition to standard of care for wound treatment or standard of care alone.
Primary purpose: TREATMENT

Brief summary: Diabetes-induced peripheral neuropathy can lead to the development of diabetic foot ulcers (DFUs), which can have a devastating effect on patients' lives and can lead to life threatening infection, amputations, and even death. Conventional treatment of DFUs are time consuming, burdensome, costly, and often do not treat the root cause of the problem. Even with proper care, ulcers can take a significantly longer time to heal in diabetic patients due to the altered physiology which does not allow for the proper nutrients and healing factors to mobilize to the site of injury, leaving these ulcers with a poor chance of healing and at high risk for infection and possible amputation. Supplemental immunonutrition therapy may offer a viable, low cost, rapidly scalable, and widely available approach to enhance the body's ability to heal itself. This prospective, randomized pilot study will evaluate the effect of a 6-week daily oral course of a specific combination of immunonutrients, L-Arginine, Omega-3 fatty acids, and Vitamin C, on wound healing in diabetic patients with chronic lower extremity ulcers compared to traditional standard of care. The deliverables of this clinical project will serve to advance a cost-effective added strategy to address a significant unmet clinical need in treatment for the diabetic patient population. Study outcomes will lay the foundation for a multi-site clinical trial to establish the efficacy and cost-effectiveness of this strategy across the health care system.

Detailed description: Diabetes mellitus is one of the most prevalent chronic diseases in the world and its incidence is expected to increase over the next 20 years. Historically there are three described types of diabetes mellitus: Type 1, Type 2, and Gestational. The etiology of disease may vary between types, and our current understanding notes overlap of these types, yet the resulting pathophysiology is the same: poor peripheral blood flow, decreased cellular response at the injury site, elevated glucose levels, and poor nutrient transport. Despite many of these patients having an elevated Body Mass Index (BMI), they are functionally under or malnourished. In addition, some patients develop progressive neurologic dysfunction, called peripheral neuropathy (PN). A common complication of diabetes induced PN is the development of diabetic foot ulcers (DFUs), which can have a devastating effect on patients' lives and can lead to life threatening infection, amputations, and even death.

Conventional treatment of DFUs includes shoe wear modification, self-monitoring, local wound care, brace and shoe offloading, and surgical intervention as well as more sophisticated treatments such as bioengineered cellular technologies and hyperbaric oxygen therapy. These modalities are time consuming, burdensome, costly, and often do not treat the root cause of the problem. Additionally, even with proper care, ulcers can take a significantly longer time to heal in diabetic patients due to the altered physiology which does not allow for the proper nutrients and healing factors to mobilize to the site of injury, leaving these ulcers with a poor chance of healing and at high risk for infection and possible amputation. In contrast to traditional treatment modalities, nutrition therapy has been shown to aide in healing of chronic wounds by providing essential nutrients which were not previously present in necessary amounts in diabetic patients. Nutrition therapy has proven useful in modulating inflammation and the immune response, optimizing glucose control, and attenuating the hypermetabolic response to ulcers, ultimately improving healing and recovery. Thus, supplemental immunonutrition therapy may offer a viable, low cost, rapidly scalable, and widely available approach to enhance the body's ability to heal itself.

This prospective, randomized pilot study will evaluate the effect of a 6-week daily oral course of a specific combination of immunonutrients, L-Arginine, Omega-3 fatty acids, and Vitamin C, on wound healing in diabetic patients with chronic lower extremity ulcers compared to traditional standard of care. Wound characteristics and clinical photographs will be documented throughout the course of the study. Patient-reported pain scores, side effects, and unscheduled visits to emergency departments/urgent care centers will be recorded. Patients randomized to receive immunonutrition supplementation will complete an additional survey detailing their satisfaction with the treatment plan upon completion of their participation in the study. The deliverables of this clinical project will serve to advance a cost-effective added strategy to address a significant unmet clinical need in treatment for the diabetic patient population. Study outcomes will lay the foundation for a multi-site clinical trial to establish the efficacy and cost-effectiveness of this strategy across the health care system.

Eligibility criteria: Inclusion Criteria:

* ≥ 18 years of age at the time of informed consent
* Toe blood pressure (TBP) \>40 mmHg
* Hemoglobin A1c \<10% (measured within the previous 6 months)
* Diagnosis of diabetes mellitus
* Presence of at least one new chronic, non-healing (present for ≥4 weeks), lower extremity wound (Werner stage 2-3)
* Documented lipid panel within 3 months of study enrollment
* Documented CMP within 3 months of study enrollment
* Documented ECG within 3 months of study enrollment
* Receiving standard or care defined as sharps debridement, appropriate dressing, and offloading.

Exclusion Criteria:

* Allergy to fish
* Current smoker
* Currently taking any OTC supplements containing Omega-3 fatty acids, L-Arginine, or Vitamin C, or antibiotics
* Presence of at least one of the following diseases or conditions: End stage renal disease as defined by patients who have been diagnosed with Stage 4 kidney disease and are not on hemodialysis or who are on hemodialysis with a GFR consistently \< 15L/min and BUN \> 60, Untreated deep bone infection (osteomyelitis), Currently pregnant or breastfeeding
* Women of child-bearing potential
* Prisoners and other institutionalized individuals
* Any patients who have a legal representative to make medical decisions on their behalf or any individuals who are otherwise deemed as medically incompetent.

Primary outcomes:
measure: Effect of Supplemental Immunonutrition on Wound Healing in Patients With Diabetic Foot Ulcers as Assessed by the Pressure Ulcer Scale for Healing (PUSH) Tool 3.0.
timeFrame: 6 weeks
measure: Effect of Supplemental Immunonutrition on Patient Reported Pain Scores in Patients With Diabetic Foot Ulcers.
timeFrame: 6 weeks
Secondary outcomes:
measure: Effect of Supplemental Immunonutrition on Patient Satisfaction in Patients With Diabetic Foot Ulcers.
timeFrame: 6 weeks
measure: Long Term Effect of Supplemental Immunonutrition on Wound Healing in Patients With Diabetic Foot Ulcers on Rates of Ulcer Recurrence, Infection, Surgical Intervention, and Amputation.
timeFrame: 1 year
Other outcomes:
Locations:
city: Columbia
country: United States
facility: Prisma Health
state: South Carolina
Study officials:
affiliation: Prisma Health-Midlands
name: J. Benjamin Jackson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther. 2008 Nov;88(11):1254-64. doi: 10.2522/ptj.20080020. Epub 2008 Sep 18.
citation: Allen L, Powell-Cope G, Mbah A, Bulat T, Njoh E. A Retrospective Review of Adverse Events Related to Diabetic Foot Ulcers. Ostomy Wound Manage. 2017 Jun;63(6):30-33.
citation: Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013 Dec;13(6):805-13. doi: 10.1007/s11892-013-0425-5.
citation: Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep. 2019 Aug 27;19(10):86. doi: 10.1007/s11892-019-1212-8.
citation: Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers. Diabetes Care. 2014;37(3):651-8. doi: 10.2337/dc13-2176. Epub 2013 Nov 1.
citation: Evans DC, Martindale RG, Kiraly LN, Jones CM. Nutrition optimization prior to surgery. Nutr Clin Pract. 2014 Feb;29(1):10-21. doi: 10.1177/0884533613517006. Epub 2013 Dec 17.
citation: Alexander JW, Supp DM. Role of Arginine and Omega-3 Fatty Acids in Wound Healing and Infection. Adv Wound Care (New Rochelle). 2014 Nov 1;3(11):682-690. doi: 10.1089/wound.2013.0469.
citation: Zhang XJ, Chinkes DL, Wolfe RR. The anabolic effect of arginine on proteins in skin wound and muscle is independent of nitric oxide production. Clin Nutr. 2008 Aug;27(4):649-56. doi: 10.1016/j.clnu.2008.01.006. Epub 2008 Mar 7.
citation: Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011 Sep 1;51(5):1000-13. doi: 10.1016/j.freeradbiomed.2011.05.017. Epub 2011 May 25.
citation: Cereda E, Klersy C, Serioli M, Crespi A, D'Andrea F; OligoElement Sore Trial Study Group. A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015 Feb 3;162(3):167-74. doi: 10.7326/M14-0696.
citation: Leigh B, Desneves K, Rafferty J, Pearce L, King S, Woodward MC, Brown D, Martin R, Crowe TC. The effect of different doses of an arginine-containing supplement on the healing of pressure ulcers. J Wound Care. 2012 Mar;21(3):150-6. doi: 10.12968/jowc.2012.21.3.150.
citation: Desneves KJ, Todorovic BE, Cassar A, Crowe TC. Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial. Clin Nutr. 2005 Dec;24(6):979-87. doi: 10.1016/j.clnu.2005.06.011. Epub 2005 Nov 15.
citation: Theilla M, Schwartz B, Cohen J, Shapiro H, Anbar R, Singer P. Impact of a nutritional formula enriched in fish oil and micronutrients on pressure ulcers in critical care patients. Am J Crit Care. 2012 Jul;21(4):e102-9. doi: 10.4037/ajcc2012187.