Impact of Omega-3 Fatty Acid Oral Therapy on Healing of Chronic Venous Leg Ulcers in Older Adults

Study Overview
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Brief Summary
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The purpose of this study is to test the efficacy of an oral, nutrient intervention containing the bioactive components of fish oil to promote healing of chronic venous leg ulcers (CVLUs) by reducing the chronic inflammation at wound sites that prevents healing progression. If this systemic, nutrient intervention is found to alter the microenvironment of CVLUs, the science of wound healing and care of patients with CVLUs will be vastly improved.

Detailed Description
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The pathogenesis of CVLU involves high numbers of activated polymorphonuclear leukocytes (PMN) that are associated with persistent inflammation in the wound bed. The proposed research is to test the efficacy of an oral, nutrient intervention containing the bioactive components of fish oil (eicosapentaenoic acid - EPA + docosahexaenoic acid - DHA) to assuage PMN activity and promote healing. The study plans to include 248 successive eligible adults ≥ 55 years of age with CVLUs who continue to receive standard care at two university out-patient wound clinics. Participants will be randomized to 2 groups: 12 weeks of daily oral therapy with EPA+DHA (1.87 g/d of EPA + 1.0 g/d of DHA) or daily oral therapy with placebo. At 0, 4, 8 and 12 weeks, across the 2 groups, three specific aims will be pursued: Aim 1. Compare levels of EPA+DHA-derived lipid mediators, and inflammatory cytokines in blood and CVLU fluid. Subaim 1a. Compare inflammatory cytokine gene expression by PMNs in blood (neutrophils and monocytes). Aim 2. Compare PMN activation (blood, CVLU fluid), and PMN-derived protease levels (CVLU fluid). Aim 3. Compare reduction in wound area, controlling for key factors known to affect healing, and determine relationships with lipid mediators, cytokines and PMN activation. Subaim 3a. Compare frequency of CVLU recurrence and levels of study variables in blood between 2 subgroups within the EPA+DHA group with healed CVLUs (after 3 additional months of EPA+DHA therapy versus placebo therapy beyond Week 12 time point). Subaim 3b. Compare the symptom of pain at all time points and quality of life at first and last study visits across the 2 groups and 2 subgroups.

Official Title
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Impact of Omega-3 Fatty Acid Oral Therapy on Healing of Chronic Venous Leg Ulcers in Older Adults

Conditions
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Chronic Venous Leg Ulcers

Intervention / Treatment
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* Dietary Supplement: EPA+DHA
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men ≥ 55 years of age with: A CVLU between the ankle and knee that has been present for at least 4 weeks, but not longer than 12 months, prescribed compression therapy with 1-4 layer bandaging; Ankle brachial pressure index (ABPI) between 0.7 and 1.2; Target wound area of 2-60 cm2 who can Read and understand English or Spanish, and Provide consent. Exclusion Criteria: Fish allergy; Corticosteroids or selective cyclooxygenase (COX)-2 inhibitors (e.g., Celebrex); non- steroidal anti-inflammatory drugs (NSAIDS) > 2x/week (exception: aspirin 81 mg/day); Autoimmune diseases; Chemotherapy within 6 months of Week 0; Diabetes if HbA1c > 12% or ulcer complicated by cellulitis, exposed tendon or bone.

Ages Eligible for Study
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Minimum Age: 55 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: 2-group randomized, double-blind, repeated measures design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPA+DHA Group<br>12 weeks of daily oral therapy with EPA+DHA (three opaque softgels to provide a total daily intake of 1.87 g of EPA + 1.0 g of DHA) | Dietary Supplement: EPA+DHA<br>* EPA+DHA are the n-3 polyunsaturated fatty acids contained in fish oil<br>* Other names: fish oil;|
| Placebo Comparator: Placebo Group<br>12 weeks of daily oral therapy with placebo (three opaque softgels to provide a total daily intake of 2.5 mL of mineral oil) | Other: placebo<br>* placebo contains mineral oil<br>* Other names: mineral oil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EPA+DHA-derived lipid mediators | plasma and wound fluid levels of EPA+DHA-derived lipid mediators of inflammation | 0, 4, 8 and 12 weeks | 
| Change in inflammatory cytokines | plasma and wound fluid levels of pro- and anti-inflammatory cytokines | 0, 4, 8 and 12 weeks | 
| Change in polymorphonuclear leukocyte (PMN) activation | blood and wound fluid levels of PMN activation | 0, 4, 8 and 12 weeks | 
| Change in PMN-derived proteases | wound fluid levels of PMN-derived proteases | 0, 4, 8 and 12 weeks | 
| Change in reduction in wound area | reduction in wound area measured in cm2 | 0, 4, 8 and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| inflammatory cytokine gene expression | inflammatory cytokine gene expression by neutrophils and monocytes from blood | 0, 4, 8 and 12 weeks | 
| recurrence of chronic venous leg ulcers | frequency of recurrence of chronic venous leg ulcers after healing | 3 months beyond Week 12 time point in participants whose leg ulcers have healed by Week 12 | 
| Change in symptom of pain | pain related to venous leg ulcer measured using the Venous Clinical Severity Score (VCSS) | 0, 4, 8 and 12 weeks (and at 3 month timepoint beyond Week 12 in participants in extended study - with healed leg ulcers by Week 12) | 
| quality of life using the VEINES-QOL/Sym questionnaire | quality of life related to venous leg ulcer measured using the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms questionnaire | 0, 12 weeks ((and at 3 month timepoint beyond Week 12 in participants in extended study - with healed leg ulcers by Week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leg ulcer, fish oil, wounds