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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Venous Leg Ulcers
• Intervention / Treatment: Dietary supplement: EPA+DHA; Other: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University College of Nursing

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EPA+DHA Group; 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; EPA+DHA are the n-3 polyunsaturated fatty acids contained in fish oil; Other Names: fish oil; eicosapentaenoic acid + docosahexaenoic acid
Placebo Comparator: Placebo Group; 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; placebo contains mineral oil; Other Names: mineral oil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE5	Intervention effects on plasma levels of lipid mediator of inflammation HEPE5 measured in pg/mL at Weeks 4, 8 and 12. 5-HEPE (5-hydroxy-eicosapentaenoic acid) is an eicosanoid derived from eicosapentaenoic acid (EPA) via the 5-lipoxygenase pathway. It functions as an anti-inflammatory lipid mediator, in part through the generation of reactive oxygen species. Plasma levels of 5-HEPE (also known as HEPE5) were measured using liquid chromatography-mass spectrometry.	0, 4, 8 and 12 weeks
Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE11	Intervention effects on plasma levels of lipid mediator of inflammation HEPE11 measured in pg/mL at Weeks 4, 8 and 12. 11-HEPE (11-hydroxy-5Z,8Z,12E,14Z,17Z-eicosapentaenoic acid) is a monohydroxy fatty acid derived from eicosapentaenoic acid (EPA). In research, it is commonly studied as a lipid mediator (eicosanoid) associated with anti-inflammatory processes. Plasma levels of 11-HEPE (also known as HEPE11) were quantified using liquid chromatography-mass spectrometry.	0, 4, 8 and 12 weeks
Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE12	Intervention effects on plasma levels of lipid mediator of inflammation HEPE12 at Weeks 4, 8 and 12. 12-HEPE (12-hydroxyeicosapentaenoic acid) is an omega-3 fatty acid metabolite formed from eicosapentaenoic acid (EPA) via the 12-lipoxygenase pathway. It functions as a signaling lipid that helps mediate the beneficial effects of EPA and exhibits potent anti-inflammatory properties. Plasma levels of 12-HEPE (HEPE12) were quantified using liquid chromatography-mass spectrometry.	0, 4, 8 and 12 weeks
Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE15	Intervention effects on plasma levels of lipid mediator of inflammation HEPE15 measured in pg/mL at Weeks 4, 8 and 12. 15-HEPE (15-hydroxyeicosapentaenoic acid) is an anti-inflammatory metabolite produced from the omega-3 fatty acid eicosapentaenoic acid (EPA) via the 15-lipoxygenase pathway. It functions as a pro-resolving lipid mediator, contributing to the resolution of inflammation. Plasma levels of 15-HEPE (HEPE15) were quantified using liquid chromatography-mass spectrometry.	0, 4, 8 and 12 weeks
Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE18	Intervention effects on plasma levels of lipid mediator of inflammation HEPE18 measured in pg/mL at Weeks 4, 8 and 12. 18-HEPE (18-hydroxyeicosapentaenoic acid) is an anti-inflammatory metabolite of the omega-3 fatty acid eicosapentaenoic acid (EPA) and serves as a precursor for E-series resolvins. E-series resolvins actively terminate inflammatory responses, promote the resolution of inflammation, and support tissue repair. They exert potent anti-inflammatory effects by limiting neutrophil infiltration and suppressing pro-inflammatory cytokine production. Plasma levels of 18-HEPE (HEPE18) were quantified using liquid chromatography-mass spectrometry.	0, 4, 8 and 12 weeks
Comparison of Intervention and Control Groups in IL-1β Levels (Log pg/mL)	Plasma levels of IL-1β were quantified using a commercially available V-PLEX Human Biomarker Plex Kit (Meso Scale Diagnostics). Reported values reflect the group plasma IL-1β levels expressed as log-transformed concentrations (pg/mL). The IL-1β data are presented on a logarithmic (log) scale to normalize the distribution of cytokine concentrations, which are typically right-skewed. Because log-transformed values are used, negative means can occur when the original (raw) cytokine concentrations are less than 1 (in the units of measurement, pg/mL). Thus, the negative values at baseline do not indicate 'negative' cytokine levels, but rather low concentrations on the original scale. Across time points, less negative (i.e., higher) log values indicate higher cytokine concentrations, whereas more negative values indicate lower concentrations. Therefore, changes in the mean log values over time reflect relative increases or decreases in IL-1β levels.	0, 4, 8 and 12 weeks
Comparison of Intervention and Control Groups in IL-6 Levels (Log pg/mL)	Plasma levels of IL-6 were quantified using a commercially available V-PLEX Human Biomarker Plex Kit (Meso Scale Diagnostics). Reported values reflect the group plasma IL-6 levels expressed as log-transformed concentrations (pg/mL). The data are presented on a logarithmic (log) scale to normalize the distribution of cytokine concentrations, which are typically right-skewed. Because log-transformed values are used, negative means can occur when the original (raw) cytokine concentrations are less than 1 (in the units of measurement, pg/mL). Thus, the negative values at baseline do not indicate 'negative' cytokine levels, but rather low concentrations on the original scale. Across time points, less negative (i.e., higher) log values indicate higher cytokine concentrations, whereas more negative values indicate lower concentrations. Therefore, changes in the mean log values over time reflect relative increases or decreases in IL-6 levels.	0, 4, 8 and 12 weeks
1. Comparison of Intervention and Control Groups in TNF-α Levels (Log pg/mL)	Plasma levels of TNF-α were quantified using a commercially available V-PLEX Human Biomarker Plex Kit (Meso Scale Diagnostics). Reported values reflect the group plasma TNF-α levels expressed as log-transformed concentrations (pg/mL). The data are presented on a logarithmic (log) scale to normalize the distribution of cytokine concentrations, which are typically right-skewed. Because log-transformed values are used, negative means can occur when the original (raw) cytokine concentrations are less than 1 (in the units of measurement, pg/mL). Thus, the negative values at baseline do not indicate 'negative' cytokine levels, but rather low concentrations on the original scale. Across time points, less negative (i.e., higher) log values indicate higher cytokine concentrations, whereas more negative values indicate lower concentrations. Therefore, changes in the mean log values over time reflect relative increases or decreases in TNF-α levels.	0, 4, 8 and 12 weeks
Comparison of Intervention and Control Groups in IFN-γ Levels (Log pg/mL)	Plasma levels of IFN-γ were quantified using a commercially available V-PLEX Human Biomarker Plex Kit (Meso Scale Diagnostics). Reported values reflect the group plasma IFN-γ levels expressed as log-transformed concentrations (pg/mL). The data are presented on a logarithmic (log) scale to normalize the distribution of cytokine concentrations, which are typically right-skewed. Because log-transformed values are used, negative means can occur when the original (raw) cytokine concentrations are less than 1 (in the units of measurement, pg/mL). Thus, the negative values at baseline do not indicate 'negative' cytokine levels, but rather low concentrations on the original scale. Across time points, less negative (i.e., higher) log values indicate higher cytokine concentrations, whereas more negative values indicate lower concentrations. Therefore, changes in the mean log values over time reflect relative increases or decreases in IFN-γ levels.	0, 4, 8 and 12 weeks
Intervention Effects on Polymorphonuclear Leukocyte (PMN) Activation (Log Cells/µL)	Reported values reflect PMN activation in plasma, expressed as log-transformed concentrations (cells/µL) at Weeks 4, 8, and 12.	0, 4, 8 and 12 weeks
Intervention Effects on Polymorphonuclear Leukocyte (PMN) - Derived Matrix Metalloproteinase-8 (MMP-8) Levels (Log pg/mg) in Wound Fluid	MMP-8, also known as neutrophil collagenase, is an enzyme that degrades collagen types I, II, and III and contributes to tissue remodeling and inflammatory processes. Wound fluid levels of MMP-8 were quantified using the MMP-8, neutrophil collagenase, Biotrak enzyme-linked immunosorbent assay kit (GE Healthcare Bio-Sciences Corp., Piscataway,NJ). Reported values reflect wound fluid MMP-8 levels, expressed as log-transformed concentrations (pg/mg) at Weeks 0, 4, 8, and 12.	0, 4, 8 and 12 weeks
Intervention Effects on Polymorphonuclear Leukocyte (PMN) - Derived Human Neutrophil Elastase (HNE, ELA2) Levels (Log pg/mg) in Wound Fluid	HNE is a potent serine protease stored in neutrophil granules that plays a key role in degrading bacteria and host tissue during inflammatory responses. Wound fluid levels of HNE were quantified using the InnuozymeTM Human Neutrophil Elastase Immunocapture Activity Assay Kit (Calbiochem, EMD Biosciences Inc., San Diego, CA). Reported values reflect wound fluid HNE levels, expressed as log-transformed concentrations (pg/mg) at Weeks 0, 4, 8 and 12.	0, 4, 8 and 12 weeks
Comparison of Intervention vs. Control Groups in the Percent Change in Wound Area Relative to Baseline	Percentage Area Reduction (PAR) is a valuable, widely used metric for evaluating and comparing the effectiveness of wound healing interventions in research. PAR was calculated at each follow-up time point (Weeks 4, 8, and 12) relative to the baseline. It represents the percentage change in wound size (area in cm2) from baseline, computed as: "PAR"=("Baseline Area" -"Follow-up Area" )/"Baseline Area" ×100 Positive PAR values indicate a reduction in wound area (i.e., healing), whereas negative values indicate an increase in wound size compared to baseline (i.e., the wound has enlarged).	0, 4, 8 and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Venous Insufficiency Epidemiological and Economic Study Quality Of Life/Symptom (VEINES-QOL/Sym) Questionnaire	The VEINES-QOL/Sym questionnaire consists of 26 items designed to assess both disease-specific quality of life (VEINES-QOL) and symptom severity (VEINES-Sym) in individuals with venous disorders. The instrument evaluates two separate metrics, both of which are calculated using the mean of standardized z-scores. The typical theoretical range for both is roughly 0 to 100, with a mean population standard of 50. The final score was calculated after calculating the mean of all z scores, which were multiplied by 10, and then added to 50. Higher scores indicate better quality of life and fewer symptoms (i.e., a more favorable outcome). VEINES-QOL/Sym scores are expressed as Z-scores standardized to a reference population, with a mean of 0 and standard deviation of 1. A Z-score of 0 represents the population mean. Higher Z-scores indicate better quality of life and fewer venous insufficiency symptoms, while lower Z-scores indicate worse outcomes.	0, 12 weeks
Venous Clinical Severity Score (VCSS)	The Venous Clinical Severity Score (VCSS) is a 10-item, 30-point scoring system used to assess and track the severity of chronic venous disease (CVD) and its response to treatment, ranging from 0 (none) to 3 (severe) for parameters like pain, ulcers, and edema. Scores can range from 0 to 30 with higher scores meaning more severe venous disease. The average scores at Weeks 0, 4, 8 and 12 were calculated for each treatment group.	0, 4, 8, 12 weeks

Collaborators and Investigators

• Sponsor: Ohio State University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Jodi C McDaniel, PhD, Ohio State University, College of Nursing

Publications and helpful links

General Publications

• McDaniel JC, Rausch J, Tan A. Impact of omega-3 fatty acid oral therapy on healing of chronic venous leg ulcers in older adults: Study protocol for a randomized controlled single-center trial. Trials. 2020 Jan 16;21(1):93. doi: 10.1186/s13063-019-3970-7.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2019
• Primary Completion (Actual): December 18, 2024
• Study Completion (Actual): December 18, 2024

Study Registration Dates

• First Submitted: June 13, 2018
• First Submitted That Met QC Criteria: June 22, 2018
• First Posted (Actual): July 5, 2018

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 16, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: leg ulcer, fish oil, wounds
• Additional Relevant MeSH Terms: Skin Diseases; Skin Ulcer; Skin and Connective Tissue Diseases; Leg Ulcer; Wounds and Injuries; Organic Chemicals; Fatty Acids; Lipids; Hydrocarbons; Eicosanoids; Fatty Acids, Unsaturated; Oils; Dietary Fats; Fats; Fatty Acids, Omega-3; Dietary Fats, Unsaturated; Petrolatum; Mineral Oil; Eicosapentaenoic Acid; Docosahexaenoic Acids; Fish Oils
• Other Study ID Numbers: 2018H0261; R01AG059981 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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