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Fish Oil-derived N-3 Polyunsaturated Fatty Acids and Extracellular Vesicles (HI-FIVE)

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ClinicalTrials.gov Identifier: NCT03203512
Recruitment Status : Recruiting
First Posted : June 29, 2017
Last Update Posted : October 11, 2018
Sponsor:
Collaborator:
Biotechnology and Biological Sciences Research Council
Information provided by (Responsible Party):
Professor Parveen Yaqoob, MA, DPhil, RNutr, FAfN, University of Reading

Brief Summary:
N-3 polyunsaturated fatty acids (n-3 PUFA), which are abundant in oily fish and fish oils, have been suggested to play a role in reducing the risk of cardiovascular diseases (CVDs) by modifying a wide range of risk factors, such as blood fats, blood clotting, blood vessel function and inflammation. Extracellular vesicles (EVs) are small particles released from various cells when they are activated or damaged. High numbers of EVs in the blood have been associated with a higher risk of CVDs, and it is thought that this is because they carry 'bioactive' components which can affect many processes involved in CVDs. However, very few clinical trials have investigated the relationships between the consumption of n-3 PUFA and circulating EVs. This study aims to investigate the effects of dietary n-3 PUFA on the generation and functional activities of EVs, which would provide new insight into the benefits of n-3 PUFA on cardiovascular health.

Condition or disease Intervention/treatment Phase
Extracellular Vesicles; Generation and Function Dietary Supplement: Fish oil capsules Dietary Supplement: High-oleic safflower oil capsules Not Applicable

Detailed Description:
The proposed study will be a randomised, double-blind, placebo-controlled crossover intervention. Subjects (40-70y) at moderate CVDs risk will be supplemented with either fish oil (1.8 g/d n-3 PUFA) or placebo (high-oleic safflower oil) for 12 weeks. After a 12-week washout and then cross-over to the other intervention for another 12 weeks. Blood samples will be collected before and after each intervention. A food frequency questionnaire will be administered to assess the subject's habitual intake of n-3 PUFA. Subjects will also be expected to maintain a low consumption of n-3 fatty acids, refrain from the use of all supplements, and maintain their body weight during the study. The dose is based on our previous work, which demonstrated a reduction in numbers of endothelial-derived EVs (EEVs) and a trend for reduced numbers of platelet-derived EVs (PEVs), and a dose at which beneficial effects of n-3 PUFA on plaque stability are reported. The experimental work will follow two main strands. The first strand will examine the influence of n-3 PUFA supplementation on the characteristics and functional activities of total EVs from plasma. The second strand will examine the influence of n-3 PUFA on the generation of PEVs from platelets taken from subjects and stimulated in vitro; the PEVs generated will subsequently be assessed for their composition and functional activity. This experimental design will allow simultaneous investigation of both the composition and activity of total EVs taken directly from blood, and the generation and activity of PEVs. Based on our previous work, 27 subjects are required to detect a 10% reduction in numbers of EVs following fish oil supplementation with a two-sided significance level of 5% and a power of 90%, and 34 subjects are required for a power of 95%. Also based on previous data, 22 subjects would give 95% power to detect 10% differences in thrombus formation and 30 subjects are required to detect a significant effect of n-3 PUFA on platelet aggregation and phosphatidylserine (PS) exposure. Allowing for a 15% dropout rate, and aiming for 95% power based on a 10% reduction in EVs numbers, we will therefore recruit 40 subjects in total.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Effects of Fish Oil-derived N-3 Polyunsaturated Fatty Acids on the Generation and Functional Activities of Extracellular Vesicles
Actual Study Start Date : February 16, 2018
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Intervention
Fish oil capsules
Dietary Supplement: Fish oil capsules
Each serving contains 360mg eicosapentaenoic acid (EPA), 270mg docosahexaenoic acid (DHA) and total supplement is 1.8 g per day n-3 PUFA for 12 weeks

Placebo Comparator: Placebo
High-oleic safflower oil capsules
Dietary Supplement: High-oleic safflower oil capsules
High-oleic safflower oil capsules for 12 weeks




Primary Outcome Measures :
  1. Concentrations of total circulating EVs in platelet-free plasma (PFP) detected by flow cytometry [ Time Frame: Change of total circulating EVs concentrations in PFP detected by flow cytometry after intake period of 12 weeks ]
  2. Concentrations of total circulating EVs in platelet-free plasma (PFP) detected by nanoparticle tracking analysis (NTA) [ Time Frame: Change of total circulating EVs concentrations in PFP detected by NTA after intake period of 12 weeks ]
  3. Pro-thrombotic activities of circulating EVs in PFP [ Time Frame: Change of pro-thrombotic activities of circulating EVs in PFP after intake period of 12 weeks ]
    Including: platelet activation; thrombin generation; thrombus formation ex vivo activities


Secondary Outcome Measures :
  1. Characterisation of circulating EVs in PFP and serum detected by fluorescence flow cytometry [ Time Frame: Change in EV phenotype in PFP and serum by fluorescence flow cytometry after intake period of 12 weeks ]
  2. Characterisation of circulating EVs in PFP and serum detected by fluorescence NTA [ Time Frame: Change in EV phenotype in PFP and serum detected by fluorescence NTA after intake period of 12 weeks ]
  3. Ex vivo agonist-stimulated platelet activation detected by plate-based platelet activation and aggregation assays [ Time Frame: Change in ex vivo platelet activation after intake period of 12 weeks ]
  4. Pro-thrombotic activities of platelet-derived extracellular vesicles (PEVs) prepared from the supernatants of stimulated platelets [ Time Frame: Change in pro-thrombotic activities of PEVs prepared from the supernatants of stimulated platelets after intake period of 12 weeks ]
    Including: thrombus formation in response to PEVs

  5. Fatty acid composition analysis [ Time Frame: Change in fatty acid composition and n-3 PUFA content of blood components after intake period of 12 weeks ]
    Fatty acid composition analysis of plasma, red blood cells, platelets, blood-derived EVs, PEVs prepared from the supernatants of stimulated platelets

  6. Blood pressure [ Time Frame: Change in blood pressure after intake period of 12 weeks ]
    Blood pressure measurement

  7. Concentrations of total triglyceride and cholesterol in plasma [ Time Frame: Change in concentrations of total triglyceride and cholesterol in plasma after intake period of 12 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Aged 40-70 years
  • Non-smoker
  • At moderate risk of cardiovascular diseases

    • The risk will be evaluated by an online calculator called "QRISK2". This online calculator (https://qrisk.org/2016/), which use traditional risk factors (age, systolic blood pressure, smoking status and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with body mass index, ethnicity, measures of deprivation, family history, will provide a percentage of risk of having a heart attack or stroke within the next 10 years.
    • Subjects with 10%-20% will be regarded as being at moderate risk

Exclusion Criteria:

  • BMI: <18.5 kg/m2
  • Anaemia (haemoglobin concentration <12.5 g/L in men and<11.5 g/L in women)
  • Hyperlipidaemia (total cholesterol concentration >8 mmol/L)
  • Diabetes (diagnosed or fasting glucose concentration >7 mmol/L) or other endocrine disorders
  • Angina, stroke, or any vascular disease in the past 12 months
  • Renal, gastrointestinal, respiratory, liver or bowel disease
  • Inflammatory disease
  • Take drug treatment for hypertension, hyperlipidaemia, inflammation, depression or thyropathy.
  • Take aspirin, ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs) > 4 times per month, or once in the week preceding the study
  • Take any other anti-platelet or anti-coagulant drugs, like triflusal, clopidogrel and warfarin.
  • Have allergies
  • Smoking (including e-cigarettes and nicotine products)
  • Alcohol misuse or intakes >21 units/wk for men and >15 units/wk for women or have a history of alcohol misuse
  • Regularly consume oily fish and/or dietary supplements
  • Planning to start or on a weight reducing regimen
  • Intense aerobic exercise (>20 min, three times a week)
  • Females who are pregnant, lactating, or if of reproductive age and not using a reliable form of contraception (including abstinence)
  • Have participated in another clinical trial within the last three months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03203512


Contacts
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Contact: Parveen Yaqoob, MA, DPhil, RNutr 0118 378 8720 p.yaqoob@reading.ac.uk
Contact: Ruihan Zhou ruihan.zhou@pgr.reading.ac.uk

Locations
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United Kingdom
University of Reading Recruiting
Reading, United Kingdom, RG6 6AP
Contact: Parveen Yaqoob    +44 (0)118 378 8720    p.yaqoob@reading.ac.uk   
Contact: Ruihan Zhou       ruihan.zhou@pgr.reading.ac.uk   
Sponsors and Collaborators
University of Reading
Biotechnology and Biological Sciences Research Council
Investigators
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Principal Investigator: Parveen Yaqoob, MA, DPhil, RNutr University of Reading

Additional Information:
QRISK2  This link exits the ClinicalTrials.gov site

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Responsible Party: Professor Parveen Yaqoob, MA, DPhil, RNutr, FAfN, Professor Parveen Yaqoob, University of Reading
ClinicalTrials.gov Identifier: NCT03203512     History of Changes
Other Study ID Numbers: UREC 17/18
First Posted: June 29, 2017    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Professor Parveen Yaqoob, MA, DPhil, RNutr, FAfN, University of Reading:
Fish oil; N-3 polyunsaturated fatty acids

Additional relevant MeSH terms:
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Blister
Skin Diseases, Vesiculobullous
Skin Diseases
Pathological Conditions, Anatomical