Inflammatory Responses
Conditions
Keywords
inflammation, omega-3, fish oil
Brief summary
The purpose of this study is to assess whether the marine omega-3 fatty acids can attenuate inflammatory responses to endotoxin challenge.
Detailed description
Controlled endotoxin infusion has been used widely as a model system to evaluate anti-inflammatory mediators and therapies in a controlled, in vivo setting. It is well established that infusion of bacterial endotoxin (also known as lipopolysaccharide or LPS) in humans results in a marked increase in inflammatory cytokines, most notably TNF-α, IL-1, IL-6 and IL-8, CRP, granulocyte colony stimulating factor (GCSF); eicosanoids, such as prostaglandin (PG) E2 and other mediators. Administration of endotoxin, even at a low dose (0.6 ng/kg) elevates circulating concentrations of inflammatory cytokines, and mimics the inflammatory effects of chronic diseases. This model has been used for decades and has proved to be safe and informative for evaluating anti-inflammatory therapeutic interventions on human inflammation and downstream consequences. 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's 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. It is well established that these omega-3 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 supplementation of omega-3 fatty acids will blunt the response to an inflammatory stimulus and/or enhance the resolution phase. We propose to test this hypothesis using an in vivo endotoxin challenge with a pharmacological dose of omega-3 fatty acid ethyl esters (P-OM3, 3.4 g/d EPA + DHA) in healthy volunteers. Our proposed approach is novel in that we will provoke an in vivo inflammatory response by infusing human subjects with a low dose (0.6 ng/kg body weight) of sterile endotoxin (lipopolysaccharide \[LPS\]) in contrast to studies that have attempted to reverse established inflammatory pathology. Results from our proposed research will advance our understanding of the effect of omega-3 fatty acids on prevention/attenuation of an inflammatory response.
Interventions
DRUG4 g prescription omega-3 concentrate
4 g/d prescription omega-3 fatty acid concentrate taken orally for 8-12 weeks
DRUGPlacebo
olive oil
Sponsors
Pronova BioPharma
Penn State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Men between the ages of 20 and 45. 2. BMI ≥20 and ≤30 3. Participants who are able to give written informed consent and willing to comply with all study-related procedures. 4. Any race or ethnic background is acceptable 5. Non-smoking The specific
Exclusion criteria
are: 1. Previous history of vasovagal reactions or unprovoked fainting (I.e. fainting as a result of prolonged standing, exercise) 2. Resting heart rate \< 55 bpm 3. History of atherosclerotic cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease 4. History of diabetes mellitus (and/or a fasting glucose \>126 mg/dL at screening) 5. Chronic anti-inflammatory medication use or treatment with aspirin, NSAIDs, COX-2 inhibitors; steroids or any immunomodulatory therapy 2 weeks prior to the screening visit 6. Self-reported history of allergy to fish 7. History of a non-skin malignancy within the previous 5 years 8. Renal insufficiency as defined by creatinine outside of lab defined normal range at Screening Visit 9. History of liver disease or abnormal LFTs (AST, ALT, Alk. Phos., GGT \> 1.5x ULN; bilirubin \> 2x ULN) at Screening Visit 10. Total white blood cell count less than or equal to 3.0 THO/uL 11. Hemoglobin less than 11.0 g/dL 12. Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition or minor active infection 13. Self-reported history of HIV positive 14. Participants who have undergone any organ transplant 15. Individuals who currently use tobacco products or have done so in the previous 30 days. 16. Participants who are unwilling to discontinue use of nutritional supplements, herbs or vitamins unless approved by study staff. 17. Participants who are unwilling to eliminate omega-3 fatty acid (EPA + DHA) supplements and/or fortified food, or have a usual intake of high omega-3 fish (tuna and other non-fried fish) \> 2 servings per week 18. Elevated blood pressure (BP \> 159/99) or use of any anti-hypertensive medications. 19. Latex allergy 20. Unwillingness to refrain from blood donation for 2 months prior to and following endotoxin administration 21. Any medical condition or abnormal laboratory value that is judged clinically significant by an investigator 22. Inability to take study capsules 23. History of severe, repeated headaches 24. History of migraine 25. Medical condition that causes severe nausea or vomiting 26. Low resting blood pressure (SBP \< 90 mmHg) 27. History of atrial fibrillation/flutter 28. Abnormal coagulation parameters (platelet count, prothrombin time with INR), documented coagulation abnormality, or use of anticoagulant medication 29. High LDL-C (\> or = 160 mg/dL)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in C Reactive Protein (CRP) | 24 hours post endotoxin administration, following each 8 week intervention | Change in blood levels of CRP at 24 hours post endotoxin administration, after each 8 week intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Necrosis Factor-α (TNF-α) | 2 hours post endotoxin administration, following each 8 week intervention | Change in the plasma concentration of TNF-α at 2 hours post endotoxin administration, after each 8 week intervention |
| Interleukin-6 (IL-6) | 2 hours post endotoxin administration, following each 8 week intervention | Change in the plasma concentration of TNF-α at 2 hours post endotoxin administration, after each 8 week intervention |
Countries
United States
Participant flow
Pre-assignment details
A balanced randomization scheme was developed in advance, and subjects were assigned to a treatment sequence at enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Baseline Baseline (prior to placebo or omega-3 supplementation) | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Baseline |
|---|---|
| Age, Continuous | 27 years STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 |
Outcome results
Primary
Change in C Reactive Protein (CRP)
Change in blood levels of CRP at 24 hours post endotoxin administration, after each 8 week intervention
Time frame: 24 hours post endotoxin administration, following each 8 week intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (8 Weeks) | Change in C Reactive Protein (CRP) | 17.2 mg/L | Standard Error 1.8 |
| Omega-3 Fatty Acids (8 Weeks) | Change in C Reactive Protein (CRP) | 17.1 mg/L | Standard Error 1.8 |
Secondary
Interleukin-6 (IL-6)
Change in the plasma concentration of TNF-α at 2 hours post endotoxin administration, after each 8 week intervention
Time frame: 2 hours post endotoxin administration, following each 8 week intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (8 Weeks) | Interleukin-6 (IL-6) | 90.6 pg/mL | Standard Error 14 |
| Omega-3 Fatty Acids (8 Weeks) | Interleukin-6 (IL-6) | 99.9 pg/mL | Standard Error 14 |
Secondary
Tumor Necrosis Factor-α (TNF-α)
Change in the plasma concentration of TNF-α at 2 hours post endotoxin administration, after each 8 week intervention
Time frame: 2 hours post endotoxin administration, following each 8 week intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (8 Weeks) | Tumor Necrosis Factor-α (TNF-α) | 58.3 pg/mL | Standard Error 8.1 |
| Omega-3 Fatty Acids (8 Weeks) | Tumor Necrosis Factor-α (TNF-α) | 59.9 pg/mL | Standard Error 8.1 |