Cardiovascular Disease, Inflammationn3NCT01810003
Impact of EPA and DHA Supplementation on Plasma Biomarkers of Inflammation (n3)
A study testing High DHA and High EPA in people with Cardiovascular Disease, Inflammation, run by Laval University at 1 site in Canada.
Trial summary
Subclinical inflammation is now indisputably recognized as a key etiological factor in the development of atherosclerosis and subsequent cardiovascular disease. Obesity and related dysmetabolic states including metabolic syndrome (MetS) are highly prevalent causes of subclinical inflammation. Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Cardiovascular Disease, Inflammation
- What is being tested?
- High DHA and High EPA
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 170 participants
- Where
- 1 siteCanada
- Study dates
- Mar 2013to Dec 2017
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Men and women aged between 18 and 70 years with abdominal obesity as defined by the International Diabetes Federation criteria and a measure of plasma CRP >1 mg/L
- Stable body weight for at least 3 months prior to randomization.
- Pre-menopausal women with regular menstrual cycle (25-35 days)
Who cannot join
- Plasma CRP > 10 mg/L at screening
- Extreme dyslipidemias such as familial hypercholesterolemia
- Previous history of cardiovascular disease (coronary heart disease, cerebrovascular disease or peripheral arterial disease)
- Subjects taking medications known to affect inflammation (e.g. steroids, binging alcohol)
- Subjects taking LCn-3PUFA supplements within 2 months of study onset.
Trial locations and contacts
1 site in 1 country.
Canada1 site
Institute of Nutrition and Functional Foods (INAF), Laval University
Québec, Quebec, G1V 0A6
About this study
Official title: Impact of EPA and DHA Supplementation on Plasma Biomarkers of Inflammation in Men and Women With Metabolic Syndrome
Subclinical inflammation is now indisputably recognized as a key etiological factor in the development of atherosclerosis and subsequent cardiovascular disease. Obesity and related dysmetabolic states including metabolic syndrome (MetS) are highly prevalent causes of subclinical inflammation. Obesity and MetS are both diet and lifestyle-related and there is a growing body of literature suggesting that specific nutrients, such as long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA), may attenuate the pro-inflammatory state associated with these conditions. However, careful review of existing literature on this topic reveals important gaps in knowledge, the purported anti-inflammatory effects of LCn-3PUFA even being questioned by many. Significant confounding attributable to study design, sample size and biomarker selection may be responsible in part for inconsistencies in the literature on LCn-3PUFA and inflammation. We also found that evidence available to date (for and against) is based primarily on secondary analyses, as most of the studies published were not primarily designed to investigate inflammation as a primary outcome. It remains unclear whether the different LCn-3PUFA, primarily docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), have similar effects on pro-inflammatory processes as almost all studies were undertaken using a mix of LCn-3PUFA. Whether efficacy of EPA and DHA is influenced by sex/gender is also unknown. Finally, a better understanding of the systemic and tissue-specific mechanisms underlying the anticipated anti-inflammatory effects of different LCn-3PUFA in MetS would also be of great value. Addressing these gaps has important public health implications, considering that LCn-3PUFA supplements are broadly and indiscriminately recommended for the prevention of cardiovascular disease.
The overarching objective of the proposed research is to compare the anti-inflammatory effects of EPA and DHA in men and women with MetS.
Read the detailed description
The proposed study will be undertaken according to a double-blind randomized placebo controlled cross-over design with 3 treatment phases: 1- high DHA, 2- High EPA, 3- Control. Each treatment phase will last 10 weeks and will be separated by 8-week washouts. Participants will be randomized to one of 6 treatment sequences while stratifying for sex. Treatments will provide 3 identical 1g capsules per day. During the 3 treatment periods, subjects will receive in random order 0g/d EPA+DHA (3g corn oil placebo), 3g/d EPA (>90% EPA), and 3g/d DHA (>90% DHA). Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) will be provided in their re-esterified triacylglycerol form as studies have shown that bioavailability was greater when EPA and DHA were consumed as TG rather than as ethyl esters. The therapeutic dose that maximizes the anti-inflammatory effects of LCn-3PUFA in patients with inflammation has not been established, although data suggest that they may be dose-dependent. However, studies in healthy human volunteers suggest that an intake > 2 g EPA + DHA/day is required to affect inflammatory processes. Many of the available studies have used a dose of EPA+DHA that was lower than 2g/d, with no apparent anti-inflammatory effects. A study has shown that a dose of 1.8g/d of EPA+DHA induced significant changes in peripheral blood cell (PBC) inflammation gene expression, with no change in plasma CRP concentrations. In the present study, we propose to use a dose of 3 g/d for each individual LCn-3PUFA tested, which is at the higher end of the recommended intake for patients with high plasma TG, but which will maximize our chance to observe changes in inflammatory markers and to differentiate the effects of EPA and DHA, if they exist. Participants will be instructed to maintain a constant body weight during the course of the study. They will also be counselled on how to exclude fatty fish meals (including salmon, tuna, mackerel, and herring), fish-oil supplements, flax products, walnuts, and omega-3-enriched eggs during the study. Vitamin supplements and natural health products will be strictly forbidden during the entire experimental period, with the exception of calcium and vitamin D, which will be allowed at a stable dose. Although alcohol consumption will be permitted during the study with intakes not exceeding one serving (12-15 g alcohol) per day, it will be forbidden for the 4 days that precede the various tests at the end of each treatment phase. Subjects will also be instructed to maintain their usual physical activity except for the 4 days that precede blood sampling at the various stages of the study, during which they will be asked to remain sedentary.
- Conditions
- Cardiovascular Disease, Inflammation
- Being tested
- High DHA, High EPA, Placebo
- Keywords
- Cardiovascular disease, Inflammation, EPA/DHA supplementation
- Medical subject headings
- Cardiovascular Diseases, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High DHADietary supplement
10 week supplementation period
High EPADietary supplement
10 week supplementation period
PlaceboDietary supplement
10 week supplementation period
| Study group | Role | What they receive |
|---|---|---|
| High DHA | Experimental | High DHA supplementation (3g/day) Receives: Dietary Supplement: High DHA |
| High EPA | Experimental | EPA supplementation (3g/day) Receives: Dietary Supplement: High EPA |
| Placebo | Placebo comparator | Placebo (3g corn oil/day) Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in plasma biomarkers of inflammation (CRP, Interleukin (IL)-6, IL-18 and Tumor necrosis factor-α)
Change between treatments based on post-treatment values, adjusting for treatment-specific baseline values
Measured: At the beginning and the end of each 10-week period
Secondary outcomes (5)
Change in lipid concentrations (LDL-C, HDL-C, TG)
Change between treatments based on post-treatment values, adjusting for treatment-specific baseline values
Measured: At the beginning and the end of each 10-week period
Change in blood pressure
Change between treatments based on post-treatment values, adjusting for treatment-specific baseline values
Measured: At the beginning and the end of each 10-week period
Change in endogenous production and clearance rate of CRP (in a subsample of the entire study population)
Change between treatments based on post-treatment values
Measured: At the end of the three 10-week periods
Change in expression of inflammation genes in peripheral blood cells (in a subsample of the entire study population)
Change between treatments based on post-treatment values
Measured: At the end of the three 10-week periods
Change in anthropometric measures (waist and hip circumference)
Change between treatments based on post-treatment values, adjusting for treatment-specific baseline values
Measured: At the beginning and the end of each 10-week period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2013 (estimated)
- Study startMar 2013
- Primary completionJul 2015
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Cardiovascular Disease, InflammationStudies of the same condition, open and under way.
- More trials run by Laval UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 170 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Laval University
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Responsible party
- Principal investigator, Benoit Lamarche, Laval University
- Investigators
- Benoît Lamarche, PhD, Principal investigator, Laval University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01810003
- Sponsor's protocol ID
- INAF-2012-143
- Acronym
- n3
- Status last verified
- Feb 2018
- First submitted
- 4 Mar 2013
- Last updated
- 22 Feb 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
Vallee Marcotte B, Allaire J, Guenard F, de Toro-Martin J, Couture P, Lamarche B, Vohl MC. Genetic risk prediction of the plasma triglyceride response to independent supplementations with eicosapentaenoic and docosahexaenoic acids: the ComparED Study. Genes Nutr. 2020 Jun 15;15(1):10. doi: 10.1186/s12263-020-00669-x.
PubMed 32539794Allaire J, Vors C, Tremblay AJ, Marin J, Charest A, Tchernof A, Couture P, Lamarche B. High-Dose DHA Has More Profound Effects on LDL-Related Features Than High-Dose EPA: The ComparED Study. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2909-2917. doi: 10.1210/jc.2017-02745.
PubMed 29846653Vors C, Allaire J, Marin J, Lepine MC, Charest A, Tchernof A, Couture P, Lamarche B. Inflammatory gene expression in whole blood cells after EPA vs. DHA supplementation: Results from the ComparED study. Atherosclerosis. 2017 Feb;257:116-122. doi: 10.1016/j.atherosclerosis.2017.01.025. Epub 2017 Jan 20.
PubMed 28131045Allaire J, Couture P, Leclerc M, Charest A, Marin J, Lepine MC, Talbot D, Tchernof A, Lamarche B. A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the Comparing EPA to DHA (ComparED) Study. Am J Clin Nutr. 2016 Aug;104(2):280-7. doi: 10.3945/ajcn.116.131896. Epub 2016 Jun 8.
PubMed 27281302
Study at a glance
From the registry record, last updated by the sponsor on 22 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of EPA and DHA Supplementation on Plasma Biomarkers of Inflammation in Men and Women With Metabolic Syndrome
- ClinicalTrials.gov ID
- NCT01810003
- Acronym / sponsor ID
- n3 / INAF-2012-143
- Conditions
- Cardiovascular Disease, Inflammation
- Keywords
- Cardiovascular disease, Inflammation, EPA/DHA supplementation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 170 participants (estimated)
- Lead sponsor
- Laval UniversityUniversity, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Study start
- Mar 2013 (actual)
- Primary completion
- Jul 2015 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 13 Mar 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Subclinical inflammation is now indisputably recognized as a key etiological factor in the development of atherosclerosis and subsequent cardiovascular disease. Obesity and related dysmetabolic states including metabolic syndrome (MetS) are highly prevalent causes of subclinical inflammation. Obesity and MetS are both diet and lifestyle-related and there is a growing body of literature suggesting that specific nutrients, such as long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA), may attenuate the pro-inflammatory state associated with these conditions. However, careful review of existing literature on this topic reveals important gaps in knowledge, the purported anti-inflammatory effects of LCn-3PUFA even being questioned by many. Significant confounding attributable to study design, sample size and biomarker selection may be responsible in part for inconsistencies in the literature on LCn-3PUFA and inflammation. We also found that evidence available to date (for and against) is based primarily on secondary analyses, as most of the studies published were not primarily designed to investigate inflammation as a primary outcome. It remains unclear whether the different LCn-3PUFA, primarily docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), have similar effects on pro-inflammatory processes as almost all studies were undertaken using a mix of LCn-3PUFA. Whether efficacy of EPA and DHA is influenced by sex/gender is also unknown. Finally, a better understanding of the systemic and tissue-specific mechanisms underlying the anticipated anti-inflammatory effects of different LCn-3PUFA in MetS would also be of great value. Addressing these gaps has important public health implications, considering that LCn-3PUFA supplements are broadly and indiscriminately recommended for the prevention of cardiovascular disease.
The overarching objective of the proposed research is to compare the anti-inflammatory effects of EPA and DHA in men and women with MetS.
Detailed description
The proposed study will be undertaken according to a double-blind randomized placebo controlled cross-over design with 3 treatment phases: 1- high DHA, 2- High EPA, 3- Control. Each treatment phase will last 10 weeks and will be separated by 8-week washouts. Participants will be randomized to one of 6 treatment sequences while stratifying for sex. Treatments will provide 3 identical 1g capsules per day. During the 3 treatment periods, subjects will receive in random order 0g/d EPA+DHA (3g corn oil placebo), 3g/d EPA (>90% EPA), and 3g/d DHA (>90% DHA). Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) will be provided in their re-esterified triacylglycerol form as studies have shown that bioavailability was greater when EPA and DHA were consumed as TG rather than as ethyl esters. The therapeutic dose that maximizes the anti-inflammatory effects of LCn-3PUFA in patients with inflammation has not been established, although data suggest that they may be dose-dependent. However, studies in healthy human volunteers suggest that an intake > 2 g EPA + DHA/day is required to affect inflammatory processes. Many of the available studies have used a dose of EPA+DHA that was lower than 2g/d, with no apparent anti-inflammatory effects. A study has shown that a dose of 1.8g/d of EPA+DHA induced significant changes in peripheral blood cell (PBC) inflammation gene expression, with no change in plasma CRP concentrations. In the present study, we propose to use a dose of 3 g/d for each individual LCn-3PUFA tested, which is at the higher end of the recommended intake for patients with high plasma TG, but which will maximize our chance to observe changes in inflammatory markers and to differentiate the effects of EPA and DHA, if they exist. Participants will be instructed to maintain a constant body weight during the course of the study. They will also be counselled on how to exclude fatty fish meals (including salmon, tuna, mackerel, and herring), fish-oil supplements, flax products, walnuts, and omega-3-enriched eggs during the study. Vitamin supplements and natural health products will be strictly forbidden during the entire experimental period, with the exception of calcium and vitamin D, which will be allowed at a stable dose. Although alcohol consumption will be permitted during the study with intakes not exceeding one serving (12-15 g alcohol) per day, it will be forbidden for the 4 days that precede the various tests at the end of each treatment phase. Subjects will also be instructed to maintain their usual physical activity except for the 4 days that precede blood sampling at the various stages of the study, during which they will be asked to remain sedentary.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| High DHA | Experimental | Dietary Supplement: High DHAHigh DHA supplementation (3g/day) |
| High EPA | Experimental | Dietary Supplement: High EPAEPA supplementation (3g/day) |
| Placebo | Placebo comparator | Dietary Supplement: PlaceboPlacebo (3g corn oil/day) |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Men and women aged between 18 and 70 years with abdominal obesity as defined by the International Diabetes Federation criteria and a measure of plasma CRP >1 mg/L
- Stable body weight for at least 3 months prior to randomization.
- Pre-menopausal women with regular menstrual cycle (25-35 days)
Key exclusion criteria (5 listed)
- Plasma CRP > 10 mg/L at screening
- Extreme dyslipidemias such as familial hypercholesterolemia
- Previous history of cardiovascular disease (coronary heart disease, cerebrovascular disease or peripheral arterial disease)
- Subjects taking medications known to affect inflammation (e.g. steroids, binging alcohol)
- Subjects taking LCn-3PUFA supplements within 2 months of study onset.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High DHA10 week supplementation period | Dietary supplement | High DHA |
| High EPA10 week supplementation period | Dietary supplement | High EPA |
| Placebo10 week supplementation period | Dietary supplement | Placebo |
Primary outcome
Change in plasma biomarkers of inflammation (CRP, Interleukin (IL)-6, IL-18 and Tumor necrosis factor-α)
Time frame: At the beginning and the end of each 10-week period
Change between treatments based on post-treatment values, adjusting for treatment-specific baseline values
5 secondary outcomes
Change in lipid concentrations (LDL-C, HDL-C, TG)
Time frame: At the beginning and the end of each 10-week period
Change in blood pressure
Time frame: At the beginning and the end of each 10-week period
Change in endogenous production and clearance rate of CRP (in a subsample of the entire study population)
Time frame: At the end of the three 10-week periods
Change in expression of inflammation genes in peripheral blood cells (in a subsample of the entire study population)
Time frame: At the end of the three 10-week periods
Change in anthropometric measures (waist and hip circumference)
Time frame: At the beginning and the end of each 10-week period
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Feb 2018.
- Derived from this study: PubMed 32539794Vallee Marcotte B, Allaire J, Guenard F, de Toro-Martin J, Couture P, Lamarche B, Vohl MC. Genetic risk prediction of the plasma triglyceride response to independent supplementations with eicosapentaenoic and docosahexaenoic acids: the ComparED Study. Genes Nutr. 2020 Jun 15;15(1):10. doi: 10.1186/s12263-020-00669-x.
- Derived from this study: PubMed 29846653Allaire J, Vors C, Tremblay AJ, Marin J, Charest A, Tchernof A, Couture P, Lamarche B. High-Dose DHA Has More Profound Effects on LDL-Related Features Than High-Dose EPA: The ComparED Study. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2909-2917. doi: 10.1210/jc.2017-02745.
- Derived from this study: PubMed 28131045Vors C, Allaire J, Marin J, Lepine MC, Charest A, Tchernof A, Couture P, Lamarche B. Inflammatory gene expression in whole blood cells after EPA vs. DHA supplementation: Results from the ComparED study. Atherosclerosis. 2017 Feb;257:116-122. doi: 10.1016/j.atherosclerosis.2017.01.025. Epub 2017 Jan 20.
- Derived from this study: PubMed 27281302Allaire J, Couture P, Leclerc M, Charest A, Marin J, Lepine MC, Talbot D, Tchernof A, Lamarche B. A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the Comparing EPA to DHA (ComparED) Study. Am J Clin Nutr. 2016 Aug;104(2):280-7. doi: 10.3945/ajcn.116.131896. Epub 2016 Jun 8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Benoît Lamarche, PhD principal investigator
Laval University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing High DHA and High EPA in people with Cardiovascular Disease, Inflammation, run by Laval University at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in plasma biomarkers of inflammation (CRP, Interleukin (IL)-6, IL-18 and Tumor necrosis factor-α) (time frame: At the beginning and the end of each 10-week period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01810003, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2018.