Clinical trial NCT05281562
Conditions: Diabetes Mellitus Diabetic Peripheral Neuropathy Diabetic Foot Ulcer
Sponsor: Prisma Health-Midlands
Start date: 2023-02-08; Completion date: 2023-03-20
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Patients will receive standard of care wound treatment as determined by a treating physician. arm 2: 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.
Interventions: intervention 1: Lovaza intervention 2: L-Arginine Powder intervention 3: Vitamin C
Intervention descriptions: intervention 1: Daily dose of 1.68grams omega-3 fatty acids, 2 Lovaza pills per day. intervention 2: Daily dose of 4.5 grams L-Arginine, powder form. intervention 3: Daily dose of 500 mg Vitamin C, powder form.

Protocol documents:
Prot_SAP_001.pdf: 
Effects of Supplemental Immunonutrition on Healing of Chronic Non-Healing Lower 
Extremity Ulcers in Diabetic Patients: A Pilot Study 
Principal Investigators: 
Rachel Glenn, MD 
J. Benjamin Jackson III, MD, MBA
Co-Investigators: 
James Hardin, PhD 
Tyler Gonzalez, MD, MBA 
Poornema Ramasamy, MD 
Study Coordinator: 
Cindy Earley 
NCT Number: 
NCT05281562 
Document Date: 
02/20/2023 


1) Background/Justification for Study 
 
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. In 2018, approximately 34.2 million Americans 
(~10%) were affected with the disease. By 2050, the number of Americans diagnosed with diabetes 
is expected to exceed 48 million.1,2 Diabetes mellitus represents a group of metabolic disorders 
characterized by hyperglycemia and changes in the metabolism of other macronutrients. There are 
three main types of diabetes mellitus: Type 1, Type 2, and Gestational. Type 1 diabetics are unable 
to make insulin and are considered insulin-dependent, Type 2 diabetics are insensitive to insulin, 
and gestational diabetics develop insulin insensitivity, transiently, during or shortly after 
pregnancy.2 The etiology of disease may vary between 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.3 In addition, due to these mechanisms, some patients 
develop progressive neurologic dysfunction, called peripheral neuropathy, which affects the most 
distal nerves first. The late effects of peripheral neuropathy can lead to an insensate foot that is 
prone to ulceration and subsequent infection.4,5  
 
A common complication of diabetes-induced peripheral neuropathy is the development of diabetic 
foot ulcers (DFUs). While estimates vary, studies suggest that the average annual incidence of 
DFUs among diabetic patients may be as high as 6%.6,7 DFUs can have a devastating effect on 
patients’ lives, often leading to debilitating injuries, amputations, and even death. It is estimated 
that foot ulcers are one of the major sources for hospitalization among diabetic patients and 
precedes up to 84% of lower limb amputations in these patients. In addition to the drastic impact 
to affected patients, DFUs represent a significant economic burden to the health care system 
and payers. Estimates place the total cost for management of diabetic foot ulcers between $9-
$13 billion in addition to treatment and management of diabetes mellitus alone.6  
 
Conventional treatment of DFUs including shoe wear modification, self-monitoring, local wound 
care, brace and shoe offloading, and surgical intervention. More sophisticated treatments including 
bioengineered cellular technologies and hyperbaric oxygen therapy have been used with limited 
success. However, these modalities are time consuming, burdensome, costly, and often do not treat 
the root cause of the problem. Additionally, even with proper care, wounds can take a significantly 
longer time to heal in diabetic patients. This is due to the altered physiology which does not allow 
for the proper nutrients and factors to mobilize to the site of injury, leaving wounds at high risk 
for infection and possible amputation.6   
 
In contrast to traditional treatment modalities, nutrition therapy has recently been shown to aide in 
healing of chronic wounds by providing essential nutrients which were not previously present in 
necessary amounts. Nutrition therapy has proven useful in modulating inflammation and the 
immune response, optimizing glucose control, and attenuating the hypermetabolic response to 
injuries, ultimately improving healing and recovery.8 Multiple studies have produced strong 
evidence that nutrition therapy reduces the incidence of complications including poor healing, 
infections, and development of hypertrophic scars.9 Thus, supplemental immunonutrition may 
offer a viable, low cost, rapidly scalable, and widely available approach to enhance the body’s 
ability to heal itself. 
 


Common immunonutrients include arginine, Omega-3 fatty acids, and vitamin C, each of which 
offer unique properties to enhance self-healing. Arginine is an amino acid that is important for 
protein metabolism and nitric oxide production; during times of extreme physiologic stress or 
malnutrition, it is considered an essential amino acid. Studies have suggested that arginine 
supplementation should be implemented to maintain a proper nitrogen balance for regulation of 
protein synthesis and to regulate nitric oxide levels for appropriate cellular signaling.8,10 Most 
commonly found in fish, Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and 
docosahexaenoic acid (DHA), are long chain polyunsaturated fats not produced in the human body, 
making their dietary intake essential. In addition to their well-known cardioprotective effects, 
Omega-3s compete with arachidonic acid as a substrate for cyclooxygenase and therefore serve as 
regulators of immune function.11 Vitamin C is a water-soluble vitamin and a potent antioxidant 
and has an essential role in collagen biosynthesis. The antioxidant properties of vitamin C help to 
decrease the release of reactive oxygen and nitrogen species, contributing to the attenuation of a 
cell’s inflammatory state. Vitamin C is also a key cofactor in collagen cross-linking, the process 
that gives collagen its strength.12 
 
Various studies have been conducted with the described nutrients to evaluate their effects in 
specific patient populations. A multicenter, randomized, controlled, blinded trial evaluated the 
effect of a nutritional formula enriched with arginine, zinc, and antioxidants in 200 adult 
malnourished patients with stage 2-4 pressure ulcers. Improved wound healing was observed in 
patients who received up to 6 grams of arginine daily for 8 weeks compared to the control group.13 
A 2012 study examining various doses of arginine supplementation on wound healing 
demonstrated that patients with stage 2-4 pressure ulcers receiving either  4.5 or 9 grams of a daily 
arginine supplement achieved a 2-fold improvement on healing time compared to the control 
group, illustrating that a lower dose of arginine supplementation is sufficient to elicit clinical 
benefit.14 A combination of arginine and vitamin C was shown to be effective for wound healing 
in a 2005 study involving inpatients with stage 2-4 pressure ulcers. Patients who were randomized 
to receive a standard diet plus two high-protein/energy supplements containing additional arginine 
(9 grams), vitamin C (500 mg), and zinc (30 mg) demonstrated a clinically significant 
improvement in pressure ulcer healing compared to a control group who did not receive the 
additional supplementation.15 Additionally, vitamin C (500 mg), in conjunction with vitamin E, 
has been shown to reverse oxidative stress-induced morphological changes in RBCs, improve 
anemia, and reduce blood flow to the ulcer area in a randomized trial including 60 adult patients 
with diabetic foot ulcers following 12 weeks of daily supplementation.16 The effects of omega-3 
fatty acids, specifically 10 grams per day of EPA for 4 weeks, were illustrated in a 2012 study in 
which patients with pressure ulcers stage 2 or higher were randomized to receive a nutritional 
formula enriched with fish oil and other antioxidants versus an isonitrogenous nutritional formula. 
Patients receiving the formula enriched with fish oil and other antioxidants showed decreased 
progression of pressure ulcers and a decrease in concentrations of C-reactive protein.17  
 
While several studies have been conducted on the beneficial effects of L-arginine, omega-3 fatty 
acids, and vitamin C over a range of subjects and disease conditions, there has yet to be a study 
involving a combination of these specific nutrients to help better heal chronic wounds in the 
diabetic population.13-18 This study is designed to address this knowledge gap by assessing and 
comparing the effectiveness of oral immunonutrition versus standard of care wound therapies on 
diabetic patients, using nutrients that have already been proven to improve wound healing in other 


patient populations. If proven to have significant effects, this study will provide an added strategy 
that may decrease rates of infections, wound complication, amputations, and possibly death in the 
diabetic population. Additionally, this treatment strategy may decrease resource utilization and 
cost of care for the treatment of DFUs. Positive results, given the wide availability of these 
nutrients, would be rapidly translatable, scalable, and deployable in other healthcare centers around 
the country.  
 
2) Objectives / Research Aims 
 
Chronic, non-healing foot ulcers are a common complication of diabetes that can threaten loss of 
limbs, shorten life expectancy, and require resource-intensive treatment. Patients who exhibit these 
late effects of diabetes are often medically complex and have not only a shortened life expectancy 
but also a lower quality of life than their non-ulcer peers.2,3 Despite the prevalence of obesity in 
these patients, many exhibit metabolic signs of malnutrition, malabsorption, or both. Even when 
direct treatment for the ulcer is ideal, if the patient does not have the metabolic building blocks or 
the correct macronutrient healing environment, then treatment will be futile.  
 
To this end, we believe focused immunonutrition supplementation consisting of L-Arginine, 
Omega-3 fatty acids, and Vitamin C combined with quality wound care will lead to an 
improvement in treatment success, satisfaction, patient reported outcome measures, and limb 
salvage.  
 
Specific Aim 1: To compare the healing process of diabetic patients with chronic, non-healing, 
lower-extremity wounds receiving oral immunonutrition supplementation to patients receiving 
traditional care.  
 
a.  This will be addressed by performing a prospective, randomized pilot study including 30 
diabetic patients with chronic lower extremity wounds, Wagner stages 1-2. Fifteen patients 
will receive oral immunonutrition supplementation (2 grams omega-3 fatty acids + 500 mg 
vitamin C + 4.5 grams L-arginine per day) in addition to current standard of care and 15 
patients will receive the current standard of care only. Study participation will continue for 
6 weeks. 
 
b. Effect of wound healing will be assessed utilizing the Pressure Ulcer Scale for Healing 
(PUSH) Tool 3.0 which scores ulcers based on size (cm2), exudate amount, and tissue type 
present. Plantar pressure profiles will be recorded using a Tekscan Pressure Mat and plantar 
weight-bearing foot images will be recorded. Additionally, patient charts will be monitored 
over the course of the study to identify rate of infection, surgical intervention, and 
amputation and for one year following completion of the study to assess ulcer recurrence 
rates. 
 
 
 
 


Specific Aim 2: To assess compliance and patient satisfaction with an oral immunonutrition 
supplementation regimen in diabetic patients with chronic, non-healing, lower-extremity wounds.  
 
a. Patients randomized to receive the oral immunonutrition supplementation in addition to 
standard of care will complete a daily compliance log documenting their intake of the 
provided supplements. 
b. All patients will complete a weekly survey rating their pain score (VAS) and any 
symptoms/side effects experienced during their study participation.  
c. At the final visit, subjects randomized to receive the oral immunonutrition 
supplementation will complete a satisfaction survey in which they detail their thoughts 
on their treatment plan.  
3) Setting 
 
Subjects visiting the Prisma Health Wound Healing Center – Richland will be recruited to 
participate in this study.  
 
4) Resources Available 
 
Documentation will be comprised of demographic information, medical histories, rates of 
infection/surgical intervention/amputation included in patient electronic medical records. 
Additionally, patient reported outcome measurements and compliance logs provided by the 
participants and PUSH Tool 3.0 assessments recorded by the provider will be analyzed.  
 
A fellowship trained foot and ankle surgeon will lead the research team. 
 
The research team will be comprised of practicing orthopaedic surgeons, wound center 
physicians and staff, research staff, orthopedic residents, and medical students.  
 
5) Prior Approvals 
None 
6) Study Design 
a. Recruitment Methods 
 
Study participants will be recruited from the pool of patients visiting the Prisma Health Wound 
Healing Center – Richland. A research coordinator within the Prisma Health Orthopedics 
department will review weekly clinic schedules of participating providers at the Wound 
Healing Center to flag patients who may qualify for the study and are scheduled for an office 
visit. The provider who sees the patient will inform the patient of the research study during 
their office visit, screen to ensure eligibility criteria are met, and, if appropriate, consent the 
patient to participate in the study.  
 
 


b. Inclusion and Exclusion 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). If a patient has not had 
an A1c within 6 months of study enrollment, one will be performed at the time of 
enrollment to confirm study eligibility.  
• Diagnosis of diabetes mellitus 
• Presence of at least one new chronic, non-healing (present for ≥4 weeks), lower extremity 
wound (Wagner stage 1-2) 
• Documented lipid panel within 3 months of study enrollment. If a patient has not had a 
lipid panel within 3 months of study enrollment, one will be performed at the time of 
enrollment to confirm study eligibility.  
• Documented CMP within 3 months of study enrollment. If a patient has not had a CMP 
within 3 months of study enrollment, one will be performed at the time of enrollment to 
confirm study eligibility.  
• Documented INR/PT within 3 months of study enrollment. If a patient has not had an 
INR/PT within 3 months of study enrollment, one will be performed at the time of 
enrollment to confirm study eligibility.  
• Documented normal ECG within 3 months of study enrollment. If a patient has not had an 
ECG within 3 months of study enrollment, one will be performed at the time of enrollment 
to confirm study eligibility.  
• Receiving standard of care defined as sharps debridement, appropriate dressing, and 
offloading.  
 
Exclusion Criteria: 
• Allergy to fish 
• History of hypersensitivity reactions to LOVAZA or any of its components 
• 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: 
o 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.  
o Hepatic impairment as defined by patients with a Child-Turcotte-Pugh score ≥2 based 
on a CMP/INR/PT performed within 3 months of study enrollment.  
o Paroxysmal or persistent atrial fibrillation 
o Untreated deep bone infection (osteomyelitis)  
o 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.  


 
 
c. Local Number of Subjects 
 
This is a pilot study which aims to enroll 30 patients locally, 15 per arm.  
 
d. Study Timelines 
 
We expect this study to be completed within one year of receiving IRB approval. We aim to 
achieve complete enrollment of 30 participants in a 6- to 9-month period. Following the 
completion of participant enrollment and data collection, the obtained results will be reviewed 
and statistically analyzed over a 3-month period. Finally, a manuscript detailing the study 
results will be written and submitted for publication.  
 
e. Study Endpoints 
Primary Outcome: Complete wound closure of a chronic, non-healing wound at 6 
weeks.  
a. Complete wound closure will be defined as skin reepithelialization without 
drainage or dressing requirements confirmed at two consecutive study visits 2 
weeks apart. Incidence of complete wound closure in the control group will be 
compared to that of the treatment group. 
Secondary Outcome: Rate of wound closure over 6-week study period. 
a. PUSH Tool 3.0 scores and clinical photos will be compared between the control 
group and treatment group to evaluate the rate of wound closure over the course 
of the 6-week study period.  
Tertiary Outcome: Compliance and patient satisfaction with immunonutrition 
supplementation regimen. 
a. Patient satisfaction surveys and compliance logs will be evaluated to assess 
feasibility of implementing an immunonutrition regimen into standard wound 
care.  
f. Procedures Involved 
 
1. A research coordinator within the Prisma Health Orthopedics department will review 
weekly clinic schedules of participating providers at the Wound Healing Center to flag 
patients who may qualify for the study and are scheduled for an upcoming office visit. 
The provider scheduled to see the patient will be informed of potential subjects for 
inclusion.  
 
2. At the office visit, the provider seeing the patient will inform the patient of the research 
study, screen to ensure eligibility criteria are met, and, if appropriate, consent the patient 
to participate in the study. The study will be thoroughly explained to the subject and all 
questions/concerns will be addressed. Research team members will be available to assist 
if the patient agrees to participate with the provider. 


a. Note: If the patient has not had an ECG (within 3 months of study enrollment), a lipid 
panel (within 3 months of study enrollment), a CMP (within 3 months of study 
enrollment, an INR/PT (within 3 months of study enrollment), and/or an A1c lab (within 
6 months of study enrollment) these will be performed to confirm normal parameters 
prior to continuation of study activities.  If any labs or ECG are required, results will be 
reviewed by the provider and the patient will resume study activities at their next 
scheduled visit.  
 
3. The provider will document wound characteristics via the PUSH Tool 3.0 (Appendix 2). 
Plantar pressure profile readings will be obtained using a Tekscan Pressure Mat and 
clinical plantar weight-bearing images will be captured. The provider will verify and 
document concomitant medications in the patient’s chart. The provider will visualize and 
evaluate any additional wounds that are present and record characteristics in the patient’s 
chart.  
 
4. The patient will be randomized to the control group or treatment group via a pre-defined 
randomization table in which subject IDs are already assigned as belonging to either 
group. 
a. If randomized to the control group (SOC only), patients will receive standard of care 
defined as sharps debridement, appropriate dressing, and offloading. If randomized to 
the treatment group (SOC + Immunonutrition), subjects will receive standard of care 
defined as sharps debridement, appropriate dressing, and offloading in addition to aa 6-
week supply of Omega-3 fatty acids (soft gel form, 2 pills per day, total of 1.68 grams) 
and L-Arginine/Vitamin C (powder form, to be mixed with 8 oz liquid, 1 scoop once 
daily, total of 4.5 grams L-arginine and 500 mg vitamin C). Subjects will also be 
provided a compliance log with detailed instructions for taking and tracking 
supplements.  
 
5. Patients will be scheduled for biweekly wound checks with their provider (weeks 2, 4, 6). 
Wound characteristics will be documented at each follow up visit using the PUSH Tool 
3.0, images of the wound will be obtained, and an interval history and physical exam will 
be documented. The provider will verify and document concomitant medications in the 
patient’s chart. The provider will visualize and evaluate any additional wounds that are 
present (new or present at time of enrollment) and record characteristics in the patient’s 
chart. Patients will complete a questionnaire detailing their pain level (VAS), symptoms 
experienced during the treatment phase, and any unscheduled visits to emergency 
departments/urgent care centers. This will be completed via a paper survey in clinic during 
their office visit (Appendix 4). On weeks where an office visit is not scheduled (weeks 1, 
3, 5), a research coordinator will call the patient and collect survey responses (Appendix 
3).  
 
6. At the final office visit (week 6), plantar pressure profiles will be recorded via the Tekscan 
Pressure Mat, and clinical plantar weight-bearing images will be captured. Patients 
randomized to receive the oral immunonutrition supplementation will complete an 
additional survey detailing their satisfaction with the treatment plan and any additional 
thoughts they would like to share (Appendix 5) and return the completed compliance log 


(Appendix 6). Patients in the treatment arm will have CMP and lipid panel labs drawn at 
this timepoint or within 3 months of study completion.  
 
7. A follow-up safety visit will be conducted by the provider for patients randomized to the 
treatment group 6-8 weeks after the week 6 office visit. This visit is more than 5 half-lives 
after supplementation discontinuation and will allow for capture of adverse events that 
may occur after completion of dosing. The wound will be visualized during this visit. 
Adverse events and wound details will be documented in the patient’s chart. This visit 
will be conducted in-office if the patient is already scheduled to see their provider within 
the visit window. If the patient is not scheduled to see their provider, this visit may be 
conducted virtually through EPIC.  
 
8. Patient charts will be monitored throughout the patient’s participation in the study for any 
signs of infection, unscheduled visits, calls to the provider, and/or onset of severe adverse 
events. Patient charts will continue to be monitored for one year following the completion 
of the study to assess ulcer recurrence rates.  
 
The schedule of events is outlined below and is pictured in Appendix 1: 
 
 Visit 0: Previously scheduled office visit: 
• Provider reviews study with patient, confirms that inclusion/exclusion criteria are met, 
and obtains informed consent. 
a. Note: If any labs or ECG are required, results will be reviewed by the provider and the 
patient will resume study activities at their next scheduled visit.  
• Provider documents characteristics of wound via PUSH Tool 3.0, obtains plantar pressure 
profile reading, and captures clinical photos. 
• Provider verifies and documents concomitant medications in the patient’s chart. 
• Provider visualizes and evaluates any additional wounds that are present and records 
characteristics in the patient’s chart. 
• Patient is randomized to receive either oral immunonutrition supplementation with 
standard of care or standard of care alone. 
• Patient is provided oral immunonutrition supplements and compliance log, if appropriate. 
 
Phone Call 1: (1 Week Call, first call after completing 7 days of oral immunonutrition): 
• Patient completes questionnaire over phone with research coordinator (VAS, 
experienced symptoms since enrollment, review of supplement compliance). 
 
Visit 1: 2 Week Follow-up (First visit after completing 14 days of oral immunonutrition): 
• Provider documents characteristics of wound via PUSH Tool 3.0, captures clinical photos, 
obtains interval history, performs interval physical exam, and verifies and documents 
concomitant medications in the patient’s chart. 
• Provider visualizes and evaluates any additional wounds that are present and records 
characteristics in the patient’s chart. 
• Patient completes questionnaire in clinic (VAS, experienced symptoms since enrollment, 
review of supplement compliance).  


 
Phone Call 2: (3 Week Call, second call after completing 21 days of oral 
Immunonutrition): 
• Patient completes questionnaire over phone with research coordinator (VAS, 
experienced symptoms since enrollment, review of supplement compliance). 
 
Visit 2: 4 Week Follow-up (Second visit after completing 28 days of oral 
immunonutrition): 
• Provider documents characteristics of wound via PUSH Tool 3.0, captures clinical photos, 
obtains interval history, performs interval physical exam, and verifies and documents 
concomitant medications. 
• Provider visualizes and evaluates any additional wounds that are present and records 
characteristics in the patient’s chart. 
• Patient completes questionnaire in clinic (VAS, experienced symptoms since enrollment, 
review of supplement compliance).  
 
Phone Call 3: (5 Week Call, third call after completing 36 days of oral 
immunonutrition): 
• Patient completes questionnaire over phone with research coordinator (VAS, 
experienced symptoms since enrollment, review of supplement compliance). 
 
Visit 3: 6 Week Follow-up/Completion Visit (Third visit after completing 42 days of oral 
immunonutrition): 
• Provider documents characteristics of wound via PUSH Tool 3.0, obtains plantar pressure 
profile reading, captures clinical photos, obtains interval history, performs interval 
physical exam, and verifies and documents concomitant medications. 
• Provider visualizes and evaluates any additional wounds that are present and records 
characteristics in the patient’s chart. 
• Patient completes questionnaire in clinic (VAS, experienced symptoms since enrollment, 
review of supplement compliance).  
• Patient completes satisfaction survey detailing their experience with supplementation (if 
applicable). 
• Patient returns compliance log (if applicable). 
• Provider orders CMP and lipid panel labs to be drawn at this timepoint or within 3 months 
of study completion. 
 
Phone Call 4: (Final Safety Follow-up, 6-8 weeks after completing oral immunonutrition, 
if randomized to treatment group): 
• Provider reviews and records adverse events experienced after supplement 
discontinuation and visualizes wound.  
 
 
g. Data and Specimen Banking 
 


Data collected from this study will be stored in the Prisma Health REDCap. Images 
will be stored on a password-protected network. No specimens will be collected as part 
of this research study. Only authorized research members of this study can access this 
information.  
 
h. Statistical Analysis 
 
Summary statistics will be used to summarize measurements and assessed for unadjusted 
differences across treatment condition. Student’s t-tests will be used for continuous 
measures, exact binomial tests for dichotomous measures, and chi-square tests for 
categorical measures.  
 
The main outcome of interest is the proportion of wound closed at the end of 6 weeks which 
we will model in a generalized linear models framework15 
 
𝐸𝐸[𝑔𝑔(𝑦𝑦𝑖𝑖)] = 𝛽𝛽0 + 𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖𝛽𝛽1 + 𝑍𝑍𝑖𝑖𝛾𝛾  
 
where 𝑦𝑦𝑖𝑖 is the outcome measure of interest of the 𝑖𝑖th participant, 𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖 is an indicator 
variable of whether the participant was assigned to the treatment condition, 𝑍𝑍𝑖𝑖 is a vector 
of covariates for which we will adjust the model (i.e., initial wound size, diabetes 
etiology, sex, race, and age), and 𝛾𝛾 is a vector of regression parameters.  We have written 
the outcome in terms of a link function (𝑦𝑦𝑖𝑖) to emphasize that we will estimate a linear 
regression model (identity function) as well as a zero-one augmented beta regression 
model for which we will choose from among several link functions (logit, log, log-log, 
and complementary log-log). Anticipating that we will have outcomes of exactly 0% or 
100% reduction of the wound size, we will model the transformed outcome16  
 
𝑦𝑦𝑖𝑖
∗= 99𝑦𝑦+ 0.5
100
 
 
Our focus is on the null hypothesis 𝐻𝐻0: 𝛽𝛽1 = 0.  We will evaluate this null hypothesis 
using a Wald test of the parameter based on an appropriate variance estimate – chosen 
from model-based, sandwich, or sandwich based on an evaluation of the implied 
dispersion properties of the model-based variance estimator. 
 
Other secondary outcome variables to be modeled include the time to complete healing 
(Cox proportional hazards regression), rate of closure (Cox proportional hazards 
regression), presence of infection (binary regression), and need for surgery (binary 
regression).  Cox proportional hazards models will be used to interpret the relative 
hazards between treatment conditions.  The proportional hazards assumption will be 
checeked using Schoenfeld residuals and accelerated failure time (parametric) regression 
models will also be evaluated.  Binary outcomes will be modeled using various link 
functions (logit and log).  Exponentiated coefficients for logit-link models will be 
interpreted as odds ratios, and exponentiated coefficients from log-link models will be 
interpreted as risk ratios.  Binary outcomes may be relatively rare, and so we will also 


estimated binary models using exact statistics.  In addition, we will investigate bias 
through estimation of bias-corrected models.17 
 
i. Data Management  
 
Data will be maintained in the Prisma Health REDCap and on a secure server with 
password protection. Study data and signed consent documents will be stored in a 
locked office in Prisma Health Orthopedics. Only authorized research members of this 
study can access this information. The researchers involved in this study commit to 
handle all information with care and to protect research subjects’ identities. Study data 
will be de-identified after data collection and before sending to the biostatistician for 
data analysis. No PHI data will be published or presented. 
Key data points include:  
• BMI 
• Demographic info (age, gender, race, ethnicity) 
• ABI 
• Hb-A1c 
• Diabetes mellitus diagnosis 
• Wound characteristics such as size, exudate amount, and tissue type (as documented 
by PUSH Tool 3.0) and Wagner stage 
• Lab results (CMP, lipid panel, INR/PT) 
• ECG results 
• Plantar pressure profile readings 
• Clinical photos of wound 
• Current medications (throughout study participation) 
• Treatment received as standard of care 
• Rate of infection 
• Rate of surgical intervention 
• Rate of amputation 
• Rate of ulcer recurrence 
• Comorbidities 
• VAS scores 
• Compliance with supplementation 
• Supplementation side effects 
 
j. Confidentiality 
Signed consent documents will be stored in a locked office at Prisma Health 
Orthopedics. Data will be maintained in the Prisma Health REDCap and on a secure 
server with password protection. Only authorized research members of this study can 
access this information. The researchers involved in this study commit to handle all 
information with care and to protect research subjects’ identities. Study data will be de-
identified after data collection and before sending to a biostatistician for data analysis. 
No PHI data will be published or presented. 


 
k. Withdrawal of Subjects 
 
Subjects may withdraw from the study at any time. All data recorded to that point may be kept 
and used for data analysis. 
 
The provider has the authority to remove any subject from the study at his/her discretion, at 
which time the provider will inform the subject of withdraw. Circumstances for withdraw 
include, but are not limited to: 
a. Failure to meet inclusion/exclusion criteria (labs, A1c, ECG parameters) 
b. Lack of compliance with supplementation 
b. Rapid progression of wound(s) which is expected to result in surgery during the 6-week 
study period 
c. Severe adverse effects which are possibly related to supplementation 
 
All data recorded to the point of withdraw may be kept and used for data analysis.  
 
l. Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
Data will be maintained on the Prisma Health REDCap and a secure server with 
password protection. Study data and signed consent documents will be stored in a 
locked office in Prisma Health Orthopedics. Only authorized research members of this 
study can access this information. The researchers involved in this study commit to 
handle all information with care and to protect research subjects’ identities.  
 
7) Risks to Subjects 
 
Potential risks to subjects include adverse reactions to the oral immunonutrition 
supplementation: 
 
Omega-3 fatty acids (LOVAZA), 1.68 grams/day: 
The FDA states that ≤3.0 grams/day of EPA + DHA is safe for humans. The daily 
supplementation provided to patients per this protocol is 1.68 grams/day (0.93 grams/day EPA 
+ 0.75 grams/day DHA), well below the tolerable threshold.  
Possible side effects associated with omega-3 fatty acid supplementation (LOVAZA) include 
eructation, dyspepsia, taste perversion, constipation, gastrointestinal disorder, vomiting, 
increased ALT, increased AST, pruritus, rash, hemorrhagic diathesis, urticaria. 
 
Vitamin C, 500 mg/day: 
The upper limit suggested for daily vitamin C intake is 2,000 mg/day. The daily 
supplementation provided to patients per this protocol is 500 mg/day, well below the upper 
threshold.  
Possible side effects associated with vitamin C supplementation include diarrhea, nausea, 
vomiting, heartburn, abdominal cramps, headache, insomnia. 
 


L-Arginine, 4.5 grams/day: 
There is no recommended daily amount established for arginine supplementation. The 
observed safe level for oral administration is 9 grams/day and levels used in research vary from 
2 to 30 grams/day. The daily supplementation provided to patients per this protocol is 4.5 
grams/day, well below the upper threshold.  
Possible side effects associated with L-arginine supplementation include abdominal pain, 
nausea, diarrhea, dyspepsia, palpitations, headache, numbness, bitter taste, and hypotension. 
 
Noted above are the known side effects of the individual supplements. However, this specific 
combination of supplements has not been studied together in humans and therefore, the risks 
are unknown.  
 
8) Potential Benefits to Subjects 
 
Patients in either treatment arm may benefit from increased monitoring by research staff with 
no additional expense to the patient. Research staff will be in constant contact with providers, 
meaning that providers will be alerted of changes in the patient’s medical status potentially 
sooner than if the patient was not enrolled in the study.  
 
Patients who are randomized to receive the oral immunonutrition supplementation may 
potentially benefit by receiving a new regimen of medical care for diabetic foot ulcers in 
addition to standard of care.  
 
Indirectly, patients may benefit by providing new information for medical professionals to 
better treat similar patients in the future.  
 
9) Safety Monitoring Plan 
 
Laboratory Monitoring:  
Periodic laboratory and ECG monitoring will be performed to assess safety of the oral 
supplement as detailed below: 
 
Lipid panel monitoring: patients are eligible for study participation if they have had a lipid 
panel performed within 3 months of study enrollment. An additional lipid panel will be 
performed at study conclusion (6-week timepoint or within 3 months of study completion) for 
patients enrolled in the treatment arm.  
 
Blood glucose monitoring: blood glucose is routinely monitored in diabetic patients at our 
institution. This data will be reviewed in the patients’ charts as they become available, and the 
investigators will be alerted to any abnormalities.  
 
Serum chemistry parameters and hepatic enzymes: patients are eligible for study 
participation if they have had a CMP performed within 3 months of study enrollment. An 
additional CMP will be performed at study conclusion (6-week timepoint or within 3 months 
of study completion) for patients enrolled in the treatment arm. Patients will have an INR/PT 


performed at the time of study enrolled (if not within the past 3 months) to confirm no hepatic 
impairment.  
 
Continuous Patient Monitoring:  
Patients enrolled in this study will be flagged in EPIC as a participant in a research study. If a 
patient presents to an Emergency Department and/or is admitted to a Prisma Health hospital, 
the study team will be notified via EPIC. The patient’s chart will be reviewed to determine the 
cause of the admission and promptly reported to the study investigators.  
 
Adverse Event (AE) and Serious Adverse Event (SAE) Reporting:  
Adverse events will be recorded at in-office visits, via study coordinator phone calls, and 
through manual chart review. All AEs will be reported to the wound care provider, if they are 
not already aware of the event. Serious adverse events will be immediately reported to all study 
investigators.  
 
Patients who experience an adverse event (AE) assessed as ≥ Grade 3 (and ≥ Grade 2 for bone 
marrow and cardiovascular events) per NCI-CTCAE version 5.019 will discontinue use of the 
oral supplement, if in the treatment arm. These subjects will continue to be monitored until the 
AE resolves or stabilizes. AEs and SAEs will be promptly reported to the IRB and FDA, as 
required.  
 
Adverse Event/Outcomes Scheduled Monitoring:  
An independent Data Safety Committee has been assembled for scheduled monitoring of 
adverse events. The committee is comprised of: 
 
Nicholas Strasser, MD 
Assistant Professor, Department of Orthopedic Surgery  
Foot and Ankle Surgeon 
Vanderbilt University Medical Center 
 
Samuel E. Ford, MD 
Foot and Ankle Surgeon 
OrthoCarolina 
 
William Huntington, MD 
Foot and Ankle Surgeon 
Prisma Health - Upstate 
Steadman Hawkins Clinic of the Carolinas 
 
Following enrollment of 5 subjects to the study (17%), the Data Safety Committee will meet 
to review data collected to date, including an in-depth review of all recorded AEs and SAEs. 
The Data Safety Committee will make a determination on the continuation of the study at this 
point. If the study is allowed to proceed, the Data Safety Committee will continue to meet 
following the enrollment of each set of 5 patients to repeat this process. If the Data Safety 
Committee determines that the study should not proceed, all study activities will be 


immediately halted. Patients in the treatment arm will be instructed to immediately discontinue 
the immunonutrition supplements.  
 
Plan for management of unplanned and/or emergent surgery:  
If a wound of a patient enrolled in the treatment arm is progressing more rapidly than expected, 
as determined by the wound care provider, the provider will withdraw the patient and instruct 
them to discontinue supplementation immediately in preparation for surgery. Additionally, all 
patients will be flagged as participating in this research study in EPIC with details on the 
supplements involved. There will be an explicit note that the PI of the study should be 
contacted prior to any surgical procedure to discuss the timing of the surgery and 
discontinuation of the supplements. If it is not possible for the patient to discontinue the 
supplementation 2 weeks prior to surgery, all relevant parties (PI, surgeon, anesthesia) will be 
notified of the patient’s involvement in the study and discuss additional potential risks of 
surgery and a patient-specific strategy for management of these risks. The study coordinator 
will review the charts of patients included in the supplement arm daily and will facilitate this 
communication between parties, if necessary. 
 
 
10) Provisions to Protect the Privacy Interests of Subjects 
Members of the research team will have access to data contained in medical records 
and data provided by the patients. Only authorized members of the research team will 
be able to access this information. The research study will be thoroughly explained to 
potential subjects in a private manner. Consenting will be done also in a private setting, 
away from other subjects.  
 
11) Compensation for Research-Related Injury 
There is no compensation for research-related injury in this study.  
 
12) Economic Burden to Subjects 
There will be no additional economic burden to subjects outside of the typical costs for 
treatment of chronic, non-healing, lower extremity wounds in the diabetic population.  
Patients will attend bi-weekly visits with their provider, which is the current standard 
of care for patients meeting eligibility requirements of this study and is billable to 
insurance.  
Study funds will cover an ECG, A1c lab, CMP, INR/PT, and/or lipid panel lab if needed 
at the time of enrollment.  
 
The oral immunonutrition supplements will be covered by study funds and provided to 
subjects free of charge. Study funds will cover a CMP and a lipid panel (at 6-week 
timepoint or within 3 months of study completion) for study participants in the 
treatment arm.  
 


If the final safety follow-up visit is an additional visit solely for the purposes of 
participating in the research study, then study funds will cover the cost of this visit.   
 
13) Consent Process 
 
Subjects who meet eligibility criteria will be consented during their previously scheduled 
office visit by a participating provider. The study will be thoroughly explained to the subject 
and all questions/concerns will be addressed. Research team members will be available to 
assist if the patient agrees to participate with the surgeon. Signed consent documents will be 
stored in a locked office within Prisma Health Orthopedics and a copy will be uploaded to the 
subject’s electronic medical record.  
 
Subjects must speak English and understand instructions. Subjects that do not speak English 
will not be enrolled in this study. We will follow the IRB Written Documentation of Consent.  
 
14) Process to Document Consent in Writing 
We will follow the IRB Written Documentation of Consent. 
 
15) References 
 
1. National Diabetes Statistics Report, 2020. CDC. 
https://www.cdc.gov/diabetes/library/features/diabetes-stat-report.html 
2. Deshpande, Anjali D et al. “Epidemiology of diabetes and diabetes-related complications.” Physical 
therapy vol. 88,11 (2008): 1254-64. doi:10.2522/ptj.20080020 
3. 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. PMID: 28657897. 
4. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in 
the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-813. 
doi:10.1007/s11892-013-0425-5 
5. Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in 
Diabetes. Curr Diab Rep. 2019;19(10):86. Published 2019 Aug 27. doi:10.1007/s11892-019-1212-8 
6. Rice, J Bradford et al. “Burden of diabetic foot ulcers for medicare and private insurers.” Diabetes 
care vol. 37,3 (2014): 651-8. doi:10.2337/dc13-2176 
7. Margolis DJ, Malay DS, Hoffstad OJ, et al. Incidence of diabetic foot ulcer and lower extremity 
amputation among Medicare beneficiaries, 2006 to 2008: Data Points #2. 2011 Feb 17. In: Data 
Points Publication Series [Internet]. Rockville (MD): Agency for Healthcare Research and Quality 
(US); 2011-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK65149/ 
8. Evans, David C et al. “Nutrition optimization prior to surgery.” Nutrition in clinical practice : official 
publication of the American Society for Parenteral and Enteral Nutrition vol. 29,1 (2014): 10-21. 
doi:10.1177/0884533613517006 
9. Alexander JW, Supp DM. Role of Arginine and Omega-3 Fatty Acids in Wound Healing and 
Infection. Adv Wound Care (New Rochelle). 2014;3(11):682-690. doi:10.1089/wound.2013.0469 
10. Zhang, Xiao-jun et al. “The anabolic effect of arginine on proteins in skin wound and muscle is 
independent of nitric oxide production.” Clinical nutrition (Edinburgh, Scotland) vol. 27,4 (2008): 
649-56. doi:10.1016/j.clnu.2008.01.006 


11. Meredith, Dennis S., et al. “Erratum to: The effect of omega-3 fatty-Acid supplements on 
perioperative bleeding following posterior spinal arthrodesis.” European Spine Journal, vol. 21, no. 
12, 12 May 2012, pp. 2664–2664., doi:10.1007/s00586-012-2412-y. 
12. Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free 
Radic Biol Med. 2011;51(5):1000-1013. doi:10.1016/j.freeradbiomed.2011.05.017 
13. Cereda, Emanuele et al. “A nutritional formula enriched with arginine, zinc, and antioxidants for the 
healing of pressure ulcers: a randomized trial.” Annals of internal medicine vol. 162,3 (2015): 167-74. 
doi:10.7326/M14-0696 
14. Leigh, B et al. “The effect of different doses of an arginine-containing supplement on the healing of 
pressure ulcers.” Journal of wound care vol. 21,3 (2012): 150-6. doi:10.12968/jowc.2012.21.3.150 
15. Desneves, Katherine J et al. “Treatment with supplementary arginine, vitamin C and zinc in patients 
with pressure ulcers: a randomised controlled trial.” Clinical nutrition (Edinburgh, Scotland) vol. 
24,6 (2005): 979-87. doi:10.1016/j.clnu.2005.06.011 
16. B., Vasanthi; T. J., Ainsy Goldlin. Efficacy of Vitamin C and Vitamin E as an add on therapy in 
diabetic foot ulcer and red blood cell morphology as a biomarker of oxidative stress: a randomized, 
open label, comparative pilot study. International Journal of Basic & Clinical Pharmacology, [S.l.], v. 
7, n. 3, p. 548-555, feb. 2018. ISSN 2279-0780. Available at: 
<https://www.ijbcp.com/index.php/ijbcp/article/view/2329>. Date accessed: 12 aug. 2021. 
doi:http://dx.doi.org/10.18203/2319-2003.ijbcp20180672. 
17. Theilla, M., Schwartz, B., Cohen, J., Shapiro, H., Anbar, R., & Singer, P. (2012). Impact of a 
nutritional formula enriched in fish oil and micronutrients on pressure ulcers in critical care 
patients. American journal of critical care : an official publication, American Association of Critical-
Care Nurses, 21 4, e102-9 . 
18. J.C.L. Neyens, E. Cereda, E.P. Meijer, C. Lindholm, J.M.G.A. Schols. Arginine-enriched oral 
nutritional supplementation in the treatment of pressure ulcers: A literature review. Wound Medicine, 
Volume 16, 2017, Pages 46-51, ISSN 2213-9095.  
19. NCI-CTCAE v5.0 Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_5x7.pdf 
 
 
 
 
 


Appendix 1: Schedule of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 0: Previously scheduled office visit 
•
Provider reviews study with patient, confirms that inclusion/exclusion criteria are met, and obtains 
informed consent 
a.
Note: If the patient has not had an ECG (within 3 months of study enrollment), a lipid panel (within 3 months of study enrollment), 
a CMP/INR/PT (within 3 months of study enrollment), and/or an A1c lab (within 6 months of study enrollment) these will be 
performed to confirm normal parameters prior to continuation of study activities.  If any labs or ECG are required, results will be 
reviewed by the provider and the patient will resume study activities at their next scheduled visit.  
•
Provider documents characteristics of wound via PUSH Tool 3.0, obtains plantar pressure profile readings 
via Tekscan Pressure Mat, and captures clinical photos 
•
Provider verifies and documents concomitant medications.   
•
Provider visualizes and evaluates any additional wounds that are present and records characteristics in the 
patient’s chart. 
•
Patient is randomized to receive either oral immunonutrition supplementation or standard care 
•
Patient is provided oral immunonutrition supplements and compliance log, if appropriate 
  
Biweekly Office Visits 
•
Document characteristics of wound via PUSH Tool 3.0, obtain 
pressure profile reading (visits 0 and week 6), capture clinical 
photos, obtain interval history, perform interval physical exam, 
verify and document concomitant medications, visualize and 
record characteristics of additional wounds present. 
•
 Patient completes questionnaire (VAS, experienced symptoms 
since enrollment, review of supplement compliance (if 
applicable))  
Biweekly Phone Calls 
•
Patient completes questionnaire over phone 
with research coordinator (VAS, experienced 
symptoms since enrollment, review of 
supplement compliance (if applicable))  
 
Office Visit 1 
Week 2 
After 14 days of oral 
immunonutrition   
Office Visit 2 
Week 4 
After 28 days of oral 
immunonutrition   
Office Visit 3 
Week 6/Completion visit 
After 42 days of oral immunonutrition   
*Patients in treatment arm return compliance log, 
complete satisfaction survey, and have lipid panel 
and CMP labs drawn (or within 3 months of study 
completion) * 
Phone Call #1 
Week 1 
After 7 days of oral 
immunonutrition   
Phone Call #2 
Week 3 
After 21 days of oral 
immunonutrition   
Phone Call #3 
Week 5 
After 35 days of oral 
immunonutrition   
Final Safety Follow-up Visit 
6-8 Weeks after Office Visit 
3/discontinuation of 
supplement 


Appendix 2: PUSH Tool 3.0 
 
 


 
 


Appendix 3: Biweekly Clinic Survey (Weeks 2, 4, 6) 
 
Effects of Supplemental Immunonutrition on Healing of Chronic Non-Healing Lower Extremity 
Ulcers in Diabetic Patients: Clinic Survey 
 
Name: _________________________________Date:  ______________________ 
 
1. Which follow-up visit are you being seen for today?  
 2-week visit 
 4-week visit 
 6-week visit 
 
2. Did you receive immunonutrition supplements (Omega-3 fatty acids, Vitamin C, L-Arginine)? 
 Yes (proceed to question 3) _________________________________________ 
 No (proceed to question 4) 
 
3. Have you experienced any difficulty taking the supplementation according to the instructions? 
 Yes, please explain: _______________________________________________ 
 No 
 
4. Have you experienced any of the following symptoms since your surgery? Check all that apply:  
 Abdominal Pain 
 Heartburn 
 Nausea 
 Vomiting 
 Diarrhea 
 Headache 
 Insomnia 
 Rash 
 Indigestion 
 Palpitations 
 Numbness 
 Bitter Taste 
 Low Blood Pressure 
 Burping 
 Taste Perversion 
 Constipation 
 Gastrointestinal Disorder 
 Itchy Skin 
 Easy bleeding or bruising 
 Red, itchy welts 
 Other, please explain: ________ 
__________________________ 
 
 
5. Have you made any trips to Emergency Departments/Urgent Care Centers since your last visit 
related to your foot ulcer? 
 Yes, please explain: ___________________________________________________ 
 No 
 
6. Circle your current level of pain related to your foot ulcer on the scale below: 
 
 
 
 
 
 
 
 
 


 
 
Page 23 of 26 
 
Appendix 4: Biweekly Phone Survey (Weeks 1, 3, 5) 
 
Effects of Supplemental Immunonutrition on Healing of Chronic Non-Healing Lower Extremity 
Ulcers in Diabetic Patients: Phone Survey 
 
1) Intro: “Hello (Patient’s Name), this is (research staff member’s name) calling from the office 
of______________________. I am calling regarding the research study you previously agreed to be 
enrolled in. Is now an okay time to speak?” 
1. If No: “Okay, when would be an acceptable time to call you back?” 
2. If Yes: proceed to number 2 
 
2) VAS Pain score: “On a scale of 0-10, with 0 being no pain, and 10 being the worst pain possible, 
how would you rate your foot ulcer pain currently?” 
 
If the subject is enrolled in the treatment arm (received oral immunonutrition 
supplementation), proceed with questions 3 and 4. If not, skip to question 5: 
 
3) Verification of supplementation: “Did you receive supplementation and instructions on how it 
should be taken? 
1. If No: “May I ask why not?” 
2. If Yes: proceed to number 3 
 
4) Medication compliance: “Have you been able to take the supplementation daily as instructed?” 
1. If No: “May I ask why not?” 
2. If Yes: proceed to number 3 
 
5) Experienced symptoms: 
1. “Have you experienced any of the following symptoms during your participation in the study. 
Please answer yes or no to each” 
 Abdominal pain, heartburn, nausea, vomiting, diarrhea, headache, insomnia, rash, 
indigenstion, palpitations, numbness, bitter taste, low blood pressure, burping, taste 
perversion, constipation, gastrointestinal disorger, itchy skin, easy bleeding or bruising, red 
itchy welts 
 “Have you experienced any other symptoms” 
 If yes: “can you please explain?” 
 If no: proceed to number 5 
 
6) Emergency Department / Urgent Care Visits: “Since beginning this study, have you had any 
unscheduled office visits, or have you been to any emergency departments or urgent care centers 
related to your foot ulcer?” 
1. If Yes: “Can you please explain?” 
2. If No: proceed to number 6 
 
 
 “Thank you for your time (Patient name), I hope you have a good day.” 
 


 
 
Page 24 of 26 
 
Appendix 5: Patient Satisfaction/Completion Survey 
 
Effects of Supplemental Immunonutrition on Healing of Chronic Non-Healing Lower 
Extremity Ulcers in Diabetic Patients: Completion Survey 
 
*This survey should only be completed at the 6-week follow-up visit if you received the 
immunonutrition supplementation as a part of the research study*  
 
Name: ___________________________    
 
Date: __________________ 
 
1. How satisfied were you with the immunonutrition therapy? 
 Very Unsatisfied 
 Unsatisfied 
 Neutral 
 Satisfied 
 Very Satisfied 
 
2. Would you choose to follow the same therapy plan again, if you were to development another 
foot ulcer? 
 Yes 
 No 
 
3. Would you recommend this therapy to friends/family? 
 Yes 
 No 
 
4. Do you feel the therapy aided in the healing of your ulcer? 
 Yes 
 No 
 
5. How would you rate the difficulty in taking the supplementation? 
 Very Difficult 
 Somewhat Difficult 
 Neutral 
 Easy 
 Very Easy 
 
6. How often did you forget to take the supplementation? 
 Never 
 Sometimes 
 Often 
 Almost Always 
 
7. Did you experience any negative side effects from the supplementation therapy? 
 Yes, please explain: ____________________________________ 
 No 
 
8. Is there anything else you would like us to know about your experience with this therapy? 
____________________________________________________________________ 


 
 
Page 25 of 26 
 
Date Consented:
Date Supplement Received:
(Record the date that you were provided your 
supplements from Hawthorne Pharmacy)
Day 1
Date:__________________
Day 2
Date:__________________
Day 3
Date:__________________
Day 4
Date:__________________
Day 5
Date:__________________
Day 6
Date:__________________
Day 7
Date:__________________
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Day 1
Date:__________________
Day 2
Date:__________________
Day 3
Date:__________________
Day 4
Date:__________________
Day 5
Date:__________________
Day 6
Date:__________________
Day 7
Date:__________________
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Day 1
Date:__________________
Day 2
Date:__________________
Day 3
Date:__________________
Day 4
Date:__________________
Day 5
Date:__________________
Day 6
Date:__________________
Day 7
Date:__________________
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Effects of Supplemental Immunonutrition on Healing of Chronic Non-healing Lower Extremity Ulcers in Diabetic Patients
Compliance Log
Week 1
Week 2
Week 3
Supplement Instructions: 
Lovaza capsules
Take 2 gel capsules by mouth daily.
Arginine/Vitamin C Powder
Mix one scoop of powder into 8 oz water, juice, or gatorade and drink 
once daily.
Instructions for completing compliance log: Week 1, Day 1 should be recorded as the first day 
AFTER you receive your supplements from Hawthorne Pharmacy. Indicate with a check mark 
when you take each supplement (2 Lovaza capsules and 1 Arginine/Vitamin C scoop) daily. 
Days should be consecutive. Do not skip days between doses. You will take these supplements 
every day for 6 weeks. Please be accurate in your reporting - ex. If you only take 1 Lovaza 
capsule on day 3, only record one check mark for this supplement. 
Appendix 6: Supplement Compliance Log 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 26 of 26 
 
 
 
 
 
 
 
Day 1
Date:__________________
Day 2
Date:__________________
Day 3
Date:__________________
Day 4
Date:__________________
Day 5
Date:__________________
Day 6
Date:__________________
Day 7
Date:__________________
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Day 1
Date:__________________
Day 2
Date:__________________
Day 3
Date:__________________
Day 4
Date:__________________
Day 5
Date:__________________
Day 6
Date:__________________
Day 7
Date:__________________
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Day 1
Date:__________________
Day 2
Date:__________________
Day 3
Date:__________________
Day 4
Date:__________________
Day 5
Date:__________________
Day 6
Date:__________________
Day 7
Date:__________________
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Lovaza capsule (2 capsules/day): 
____   ____
Arginine/Vitamin C Powder (1 scoops/day): 
____
Week 6
Week 4
Week 5