SPM Regulation by Fish Oil Supplements in Healthy Volunteers

Study Overview
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Brief Summary
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A randomised, double-blind, placebo-controlled study to determine whether fish oil supplementation regulates peripheral levels of specialized pro-resolving mediators and white blood cell responses in healthy volunteers

Detailed Description
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Rationale for the study The relationship between omega-3 essential fatty acid supplementation, and specifically fish oil supplementation, and SPM production in humans is very poorly understood. Given that the body produces SPM from omega-3 essential fatty acids to regulate inflammation and also to repair damaged tissues, it is critical to gain further insights on how the body utilizes dietary supplementation of omega-3 fatty acids from fish oils for SPM formation. With the availability of a mass spectrometry based platform developed by the investigators the scientific community is now in a unique position to better understand the biology of fish oil supplementation by monitoring the levels of SPM in plasma. This understanding may in turn shed light into the beneficial actions of omega-3 supplementation. It may also provide new leads for the control of excessive inflammation, as found in chronic inflammatory disorders, via dietary supplementation to exploit the body's own defense systems. Rationale for choice of doses Given that in a study using a different fish oil source and formulation the investigators found that 1 g of essential fatty acids gave a mild but significant increase in plasma SPM levels (25) the investigators chose the lowest dose in the study to be of 1.5g. with the other two doses being within the European Food Safety Authority's Tolerable Upper Intake Level for supplements containing both EPA and DHA. Given that this limit is of 5 g and previous study with both healthy volunteers and patients demonstrated that doses up to 4 g are well tolerated (22-24), the investigators chose the remaining 2 doses to be 3.0 g and 4.5 g. In addition, this supplement was awarded a Generally Recognized as Safe Status (see appendix 1) in the for a dose of up to 5 g. Similar doses of the emulsion from of the fish oil supplement are also being used in an ongoing clinical study in the USA (ClinicalTrials.gov Identifier: NCT02719665) measuring different outcomes to those being investigated in the present study. Aim of research The aim of this research is to investigate whether fish oil supplementation increases the peripheral blood levels of SPM and whether fish oil supplementation also regulates peripheral white blood cell responses (including neutrophils, monocytes and platelets) to inflammatory stimuli. Original hypothesis Given that fish oils are rich in omega-3 essential fatty acids that are precursors in the biosynthesis of SPM the hypothesis underlying the present study is: Fish oil supplementation increase peripheral blood levels of SPM precursors that may be converted to bioactive mediators which in turn will regulate white blood cell responses.

Official Title
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Exploratory Double Blind Placebo Controlled Study Investigating the Regulation of Proresolving Mediators and White Blood Cell Responses by Fish Oil Supplements in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Dietary Supplement: SPM Active


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For participants to be included in the study they will need to meet the following criteria: Able to provide informed consent Men and women between the age of 18 and 45 Declare not to be taking aspirin, other NSAIDS, other form of medication or omega-3 fatty acid supplements for more than 2 weeks prior to screening and the duration of the participation. Willingness to abstain from eating fish for 2 days before each study visit Willingness to abstain from alcohol consumption for at least 24h prior to each study visit Willingness to abstain from caffeine as directed before and during study Exclusion Criteria: 1) History of, chronic disorders, cardiovascular disease (e.g., heart disease, stroke), cancer, or diabetes or significant genetically inherited conditions. 2) Pregnancy or breast-feeding. 3) Hypothyroidism in the opinion of the investigator. 4) Liver disease in the opinion of the investigator. 5) Any abnormality or pre-existing disease which, in the opinion of the investigator, might either expose the subject to risk, or influence the validity of the results. 6) Women of childbearing potential not taking adequate methods of contraception 7) Inability to read and write in English 8) Participation in a clinical study of a new chemical entity, biological product or a prescription medicine, or loss of more than 400 mL blood, within the previous 3 months 9) Anyone who is currently smoking or used to smoke 10) Presence or history of drug or alcohol abuse or intake of more than the amount of alcohol in the current guidelines on alcohol consumption

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: SPM Active is the supplement tested in this study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo control | Dietary Supplement: SPM Active<br>* Supplement or placebo will be administered orally between 9 am to 9:30 am. Each participant will give a baseline blood sample then they will be given one of the randomly allocated three doses of fish oil supplement, or a matching placebo in one of 8 study groups [this will be on a 1:1:1:1:1:1:1:1 ratio]. Blood will be collected again at 2h, 4h, 6h and 24h after supplementation/placebo, 12ml per time interval.<br>|
| Experimental: Dose 1<br>1.5 g of omega-3 supplement | Dietary Supplement: SPM Active<br>* Supplement or placebo will be administered orally between 9 am to 9:30 am. Each participant will give a baseline blood sample then they will be given one of the randomly allocated three doses of fish oil supplement, or a matching placebo in one of 8 study groups [this will be on a 1:1:1:1:1:1:1:1 ratio]. Blood will be collected again at 2h, 4h, 6h and 24h after supplementation/placebo, 12ml per time interval.<br>|
| Experimental: Dose 2<br>3.0 g of omega-3 supplement | Dietary Supplement: SPM Active<br>* Supplement or placebo will be administered orally between 9 am to 9:30 am. Each participant will give a baseline blood sample then they will be given one of the randomly allocated three doses of fish oil supplement, or a matching placebo in one of 8 study groups [this will be on a 1:1:1:1:1:1:1:1 ratio]. Blood will be collected again at 2h, 4h, 6h and 24h after supplementation/placebo, 12ml per time interval.<br>|
| Experimental: Dose 3<br>4.5 g of omega-3 supplement | Dietary Supplement: SPM Active<br>* Supplement or placebo will be administered orally between 9 am to 9:30 am. Each participant will give a baseline blood sample then they will be given one of the randomly allocated three doses of fish oil supplement, or a matching placebo in one of 8 study groups [this will be on a 1:1:1:1:1:1:1:1 ratio]. Blood will be collected again at 2h, 4h, 6h and 24h after supplementation/placebo, 12ml per time interval.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regulation of peripheral blood pro-resolving mediator levels | The Primary endpoint of the study will be an increase in peripheral blood SPM levels that will be measured using established liquid chromatography tandem mass spectrometry based approach | compared to baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regulation of bacterial phagocytosis by peripheral blood leukocytes | An increase in ex vivo phagocytosis of Escherichia coli by peripheral white blood cells | compared to baseline | 
| Regulation of peripheral blood platelet and leukocyte responses | A decrease in white blood cell activation when cells are incubated with an inflammatory stimulus | compared to baseline |