Cardiovascular Disease, Inflammation
Conditions
Keywords
Cardiovascular disease, Inflammation, Fish Oil, Omega-3 Fatty Acids, LPS, Endotoxin
Brief summary
The purpose of this study is to determine the lowest effective dose of EPA + DHA (300, 600, 900 and 1,800 mg/day delivered as fish oil supplements) that significantly attenuates the inflammatory response to in vivo and ex vivo endotoxin challenge as measured by the production over time of several inflammatory markers.
Detailed description
Inflammation is an important biological process initiated by the immune system in response to injury, irritation or infection. Prolonged or chronic inflammation is involved in the etiology of several diseases such as cardiovascular disease (CVD), diabetes, rheumatoid arthritis, cancer, and neurodegenerative diseases such as Alzheimer disease. The evidence base clearly demonstrates benefits of diet in ameliorating inflammation and reducing the burden of chronic disease. With respect to marine-derived omega-3 fatty acids and various markers of inflammation related to cardiovascular disease (CVD), both population studies and randomized controlled supplementation trials have yielded mixed results. Some studies have demonstrated a dose-response relationship between dietary eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA) and increased membrane (phospholipid) EPA and DHA. Red blood cell (RBC) EPA + DHA content has been proposed as a potential, modifiable marker for coronary heart disease (CHD) risk. It is well established that these fatty acids are precursors of series-3 prostanoids, thromboxanes, 5-series leukotrienes, and novel lipid mediators such as resolvins and protectins that have anti-inflammatory effects. We hypothesize that nutritionally-relevant intakes of omega-3 fatty acids are able to blunt the usual response to an inflammatory stimulus. We propose to test this hypothesis using both in vivo (i.v. endotoxin challenge) and ex vivo (endotoxin-stimulated monocytes) models in a 6-month, dose-response study with marine-derived omega-3 fatty acid supplements in healthy volunteers.
Interventions
BIOLOGICALEicosapentaenoic Acid and Docosahexaenoic Acid (EPA + DHA)
Comparison of 4 doses of EPA+DHA on in vivo and ex vivo (monocytes) response to an inflammatory stimulus (endotoxin) following a 6 month supplementation period
Sponsors
United States Department of Agriculture (USDA)
Penn State University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men and non-pregnant/lactating women between the ages of 20 and 45 * BMI \>19.9 and \<30.0 * Able to give written informed consent and willing to comply with all study- related procedures.
Exclusion criteria
* Previous history of heart disease or diabetes * Renal Insufficiency * Chronic anti-inflammatory use * Systolic blood pressure \< 90 * Individuals currently using tobacco products or have done so in the previous 30 days * Individuals taking Omega-3 fatty acid supplements or their usual intake of fish is greater than 3-4 servings per month.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | 5 months |
| Mean Concentrations of CRP Following 5 Months of Treatment | 5 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lipid Mediators | 1, 2, 3 and 5 days post LPS administration | 0 Participants Analyzed; Lipid mediators were unable to be detected therefore there are no data to report. |
Countries
United States
Participant flow
Recruitment details
Recruitment and screened occured between September 2011 and March 2012 at the Clinical Research Center at Penn State University.
Pre-assignment details
A computer-generated randomization scheme was developed in advance. The randomization scheme was stratified by sex and age and used a balanced block size of 5 to ensure even distribution among treatment groups. Using this randomization scheme, eligible participants were assigned to blinded treatments at the baseline visit by the study coordinator.
Participants by arm
| Arm | Count |
|---|---|
| 300mg Fish Oil (EPA + DHA) Supplement Eicosapentaenoic Acid and Docosahexaenoic Acid (EPA + DHA) following a 5 month supplementation period | 23 |
| 600mg Fish Oil (EPA+DHA) Supplement Eicosapentaenoic Acid and Docosahexaenoic Acid (EPA + DHA) following a 5 month supplementation period | 21 |
| 900mg Fish Oil (EPA + DHA) Supplement Eicosapentaenoic Acid and Docosahexaenoic Acid (EPA + DHA) following a 65 month supplementation period | 24 |
| 1800mg Fish Oil (EPA + DHA) Supplement Eicosapentaenoic Acid and Docosahexaenoic Acid (EPA + DHA) following a 5 month supplementation period | 24 |
| Placebo Eicosapentaenoic Acid and Docosahexaenoic Acid (EPA + DHA) following a 5 month supplementation period | 23 |
| Total | 115 |
Baseline characteristics
| Characteristic | 300mg Fish Oil (EPA + DHA) Supplement | 600mg Fish Oil (EPA+DHA) Supplement | 900mg Fish Oil (EPA + DHA) Supplement | 1800mg Fish Oil (EPA + DHA) Supplement | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 25.8 years STANDARD_DEVIATION 7.2 | 27.1 years STANDARD_DEVIATION 7.3 | 25.8 years STANDARD_DEVIATION 6.4 | 26.0 years STANDARD_DEVIATION 5.9 | 25.7 years STANDARD_DEVIATION 6.7 | 26.1 years STANDARD_DEVIATION 6.7 |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 11 Participants | 11 Participants | 12 Participants | 55 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 13 Participants | 13 Participants | 11 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 21 | 0 / 24 | 0 / 24 | 0 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 21 | 0 / 24 | 0 / 24 | 0 / 23 |
Outcome results
Primary
Mean Concentrations of CRP Following 5 Months of Treatment
Time frame: 5 months
Population: One individual was removed from the analysis due to having very high RBC EPA+DHA content at study entry (\>8%)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 300mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of CRP Following 5 Months of Treatment | 0.6 mg/dL |
| 600mg Fish Oil (EPA+DHA) Supplement | Mean Concentrations of CRP Following 5 Months of Treatment | 0.5 mg/dL |
| 900mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of CRP Following 5 Months of Treatment | 0.6 mg/dL |
| 1800mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of CRP Following 5 Months of Treatment | 0.6 mg/dL |
| Placebo | Mean Concentrations of CRP Following 5 Months of Treatment | 0.5 mg/dL |
Primary
Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment
Time frame: 5 months
Population: One individual was removed from the analysis due to having very high RBC EPA+DHA content at study entry (\>8%)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 300mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | TNF-alpha (pg/mL) | 1.4 pg/mL |
| 300mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | IL-6 (pg/mL) | 0.9 pg/mL |
| 600mg Fish Oil (EPA+DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | TNF-alpha (pg/mL) | 1.3 pg/mL |
| 600mg Fish Oil (EPA+DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | IL-6 (pg/mL) | 1 pg/mL |
| 900mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | TNF-alpha (pg/mL) | 1.4 pg/mL |
| 900mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | IL-6 (pg/mL) | 0.9 pg/mL |
| 1800mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | IL-6 (pg/mL) | 1 pg/mL |
| 1800mg Fish Oil (EPA + DHA) Supplement | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | TNF-alpha (pg/mL) | 1.5 pg/mL |
| Placebo | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | TNF-alpha (pg/mL) | 1.4 pg/mL |
| Placebo | Mean Concentrations of Inflammatory Markers (TNF-alpha and IL-6) Following 5 Months of Treatment | IL-6 (pg/mL) | 0.9 pg/mL |
Secondary
Change in Lipid Mediators
0 Participants Analyzed; Lipid mediators were unable to be detected therefore there are no data to report.
Time frame: 1, 2, 3 and 5 days post LPS administration
Population: Lipid mediators were unable to be detected; Data were not collected.