Chronic Venous Leg Ulcers
Conditions
Keywords
leg ulcer, fish oil, wounds
Brief summary
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
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.
Interventions
DIETARY_SUPPLEMENTEPA+DHA
EPA+DHA are the n-3 polyunsaturated fatty acids contained in fish oil
OTHERplacebo
placebo contains mineral oil
Sponsors
Ohio State University
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Investigators, participants and care providers blinded as to treatment
Intervention model description
2-group randomized, double-blind, repeated measures design
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE5 | 0, 4, 8 and 12 weeks | 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. |
| Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE11 | 0, 4, 8 and 12 weeks | 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. |
| Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE12 | 0, 4, 8 and 12 weeks | 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. |
| Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE15 | 0, 4, 8 and 12 weeks | 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. |
| Intervention Effects on Plasma Levels of Lipid Mediator of Inflammation HEPE18 | 0, 4, 8 and 12 weeks | 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. |
| Comparison of Intervention and Control Groups in IL-1β Levels (Log pg/mL) | 0, 4, 8 and 12 weeks | 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. |
| Comparison of Intervention and Control Groups in IL-6 Levels (Log pg/mL) | 0, 4, 8 and 12 weeks | 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. |
| 1. Comparison of Intervention and Control Groups in TNF-α Levels (Log pg/mL) | 0, 4, 8 and 12 weeks | 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. |
| Comparison of Intervention and Control Groups in IFN-γ Levels (Log pg/mL) | 0, 4, 8 and 12 weeks | 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. |
| Intervention Effects on Polymorphonuclear Leukocyte (PMN) Activation (Log Cells/µL) | 0, 4, 8 and 12 weeks | Reported values reflect PMN activation in plasma, expressed as log-transformed concentrations (cells/µL) at Weeks 4, 8, and 12. |
| Intervention Effects on Polymorphonuclear Leukocyte (PMN) - Derived Matrix Metalloproteinase-8 (MMP-8) Levels (Log pg/mg) in Wound Fluid | 0, 4, 8 and 12 weeks | 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. |
| Intervention Effects on Polymorphonuclear Leukocyte (PMN) - Derived Human Neutrophil Elastase (HNE, ELA2) Levels (Log pg/mg) in Wound Fluid | 0, 4, 8 and 12 weeks | 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. |
| Comparison of Intervention vs. Control Groups in the Percent Change in Wound Area Relative to Baseline | 0, 4, 8 and 12 weeks | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Venous Insufficiency Epidemiological and Economic Study Quality Of Life/Symptom (VEINES-QOL/Sym) Questionnaire | 0, 12 weeks | 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. |
| Venous Clinical Severity Score (VCSS) | 0, 4, 8, 12 weeks | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJodi C McDaniel, PhD
Ohio State University, College of Nursing
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 9.23 |
| Annual Household Income $10,000 to $14,999 | 9 Participants |
| Annual Household Income $15,000 to $19,999 | 4 Participants |
| Annual Household Income $20,000 to $24,999 | 1 Participants |
| Annual Household Income $25,000 to $29,999 | 2 Participants |
| Annual Household Income $30,000 to $34,999 | 1 Participants |
| Annual Household Income $35,000 to $39,999 | 4 Participants |
| Annual Household Income $40,000 to $44,999 | 4 Participants |
| Annual Household Income $45,000 and up | 14 Participants |
| Annual Household Income <$5000 | 1 Participants |
| Annual Household Income $5,000 to $9,999 | 5 Participants |
| Annual Household Income missing | 2 Participants |
| BMI | 41.4 kg/m^2 STANDARD_DEVIATION 12.8 |
| Comorbidities A Fib | 11 Participants |
| Comorbidities Anxiety | 2 Participants |
| Comorbidities Asthma | 3 Participants |
| Comorbidities Atherosclerosis | 1 Participants |
| Comorbidities COPD | 4 Participants |
| Comorbidities Depression | 10 Participants |
| Comorbidities Diabetes | 18 Participants |
| Comorbidities Emphysema | 0 Participants |
| Comorbidities Heart failure | 5 Participants |
| Comorbidities High blood pressure | 51 Participants |
| Comorbidities High cholesterol | 5 Participants |
| Comorbidities Osteoarthritis | 6 Participants |
| Comorbidities Pulmonary hypertension | 1 Participants |
| Comorbidities Rheumatoid arthritis | 2 Participants |
| Comorbidities Stroke | 6 Participants |
| Education College or University Graduate | 9 Participants |
| Education Graduate or professional Training | 3 Participants |
| Education High School | 11 Participants |
| Education Junior High | 1 Participants |
| Education Less than 7 years | 1 Participants |
| Education Missing | 0 Participants |
| Education Some College | 12 Participants |
| Education Some High School | 4 Participants |
| Employment status Disabled | 36 Participants |
| Employment status Full time | 9 Participants |
| Employment status missing | 1 Participants |
| Employment status Not employed | 38 Participants |
| Employment status Part time | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 27 Participants |
| Smoking status Current smoker | 14 Participants |
| Smoking status missing | 1 Participants |
| Smoking status Never | 28 Participants |
| Smoking status Past smoker | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 50 |
| other Total, other adverse events | 0 / 46 | 0 / 50 |
| serious Total, serious adverse events | 0 / 46 | 0 / 50 |
Outcome results
None listed