Immunonutrition for Diabetic Foot Ulcers

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Supplemental Immunonutrition on Healing of Chronic Non-Healing Lower Extremity Ulcers in Diabetic Patients: A Pilot Study

Conditions
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Diabetes Mellitus, Diabetic Peripheral Neuropathy, Diabetic Foot Ulcer

Intervention / Treatment
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* Drug: Lovaza
* Drug: L-Arginine Powder
* Drug: Vitamin C


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of Care Group<br>Patients will receive standard of care wound treatment as determined by a treating physician. | |
| Experimental: Immunonutrition Supplementation Group<br>Patients will receive a 6 week daily oral supply of 1.68 grams Omega-3 fatty acids, 4.5 grams L-Arginine, and 500 mg Vitamin C. | Drug: Lovaza<br>* Daily dose of 1.68grams omega-3 fatty acids, 2 Lovaza pills per day.<br>* Other names: omega-3-acid ethyl esters;Drug: L-Arginine Powder<br>* Daily dose of 4.5 grams L-Arginine, powder form.<br>* Other names: 2-amino-5-guanidinopentanoic acid;Drug: Vitamin C<br>* Daily dose of 500 mg Vitamin C, powder form.<br>* Other names: Ascorbic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | The PUSH Tool 3.0 will be used to score ulcers based on size (cm2), exudate amount, and tissue type present. The score ranges for size, exudate amount, and tissue type are 0-10, 0-3, and 0-4, respectively. For all categories, a higher score indicates a more severe ulcer. The score for each category is combined to generate a final score ranging from 0-17. A higher final score indicates a more severe ulcer. The treating physician will record ulcer scores using this tool at the time of consent and biweekly for 6 weeks for both the standard of care group and experimental group. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of supplemental immunonutrition on patient reported pain scores in patients with diabetic foot ulcers. | Patients in both the standard of care and experimental groups will report visual analog scale (VAS) pain scores at the time of consent and weekly in either office visits with the treating physician or via phone calls with a research coordinator. The VAS scale ranges from 0-10, with a higher score indicating a higher level of pain. | 6 weeks | 
| Effect of supplemental immunonutrition on patient satisfaction in patients with diabetic foot ulcers. | Patients in experimental group will complete a survey detailing their satisfaction with the supplemental immunonutrition regimen following completion study participation. Patients will be asked to rate their satisfaction from very satisfied to very unsatisfied and questions regarding their likelihood to partake in the same treatment regimen for a subsequent ulcer, recommend this treatment regimen to others, and the level of difficulty associated with taking the supplementation. | 6 weeks | 
| 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. | Study participants in both the standard of care and experimental groups will be monitored via chart review for one year following the completion of their 6 week participation in the study to assess recurrence rates of diabetic foot ulcers and to identify rate of infection, surgical intervention, and amputation. | 1 year |