ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12614000762651

Ethics application status

Approved

Date submitted

9/07/2014

Date registered

17/07/2014

Date last updated

16/06/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

Effects of long-chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) supplementation on cerebral circulation and cognitive function

Scientific title

A 20-week randomised, double-blind, placebo controlled parallel study to evaluate the effects of LCn-3PUFA supplementation on cerebrovascular function, mood and cognitive performance in adults with borderline hypertension.

Secondary ID [1]

nil

Universal Trial Number (UTN)

U1111-1158-4352

Trial acronym

n-3 brain health study

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cerebrovascular function

Cognitive performance

Mood

Condition category

Condition code

Cardiovascular

Other cardiovascular diseases

Mental Health

Studies of normal psychology, cognitive function and behaviour

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Suitable participants will be required to attend the CNRC 5 times over the period of 20 weeks.

Participants will arrive at the Clinical Nutrition Research Centre (CNRC) following an 8 h overnight fast for further screening to determine study eligibility. Anthropometric measurements of height, weight and waist circumference will be obtained before clinic blood pressure (BP) and arterial compliance (AC) measurements are assessed. Those with clinic BP not within the study inclusion range will be excluded. Participants will be fitted with a transcranial doppler (TCD) headpiece supporting an ultrasound probe on each temporal region. An investigator will adjust the probes until a measurable blood flow signal is obtained in each middle cerebral artery (MCA) and posterior cerebral artery (PCA). If the investigator is unable to obtain a blood flow signal in the PCA, the procedure for cerebrovascular responsiveness (CVR) to photic stimulation will not commence. However, if no measureable blood flow signal is detected in the MCA for the measure of CVR to hypercapnia, the participant will be excluded from the study.

The dementia status of the participants will be determined using the Australian Version of the Modified Mini Mental State Examination (3MS). Participants scoring below 78/100 (considered an indicator of suspected dementia) will be excluded from this study. A blood sample analysis for the measure of Omega-3 index, pro-inflammatory biomarkers and blood lipids will be obtained from the participant. Due to the long fasting duration in the physiological assessment protocol (Part A), the psychological assessments (Part B) will be scheduled for the following day or within 7 days of completing the physiological assessments. This is to minimize the risk of hypoglycemia, which would affect the neuropsychometric test performance. Participants will return for neuropsychological testing following a 4 h fast (no food/beverage, except water). The TCD headpiece will be refitted on the participants and probes adjusted to obtain a measurable blood flow signal in each MCA. Continuous recordings of changes in mean blood flow velocities during the neuropsychological test battery will be obtained.

At the conclusion of the test battery, participants will be asked to complete a scale to assess mood states. In addition, a short questionnaire of one’s dietary intake of long-chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) and the Self-reported Assessment of Subjective Cognitive Impairment (as previously captured in the Health, Diet & Lifestyle Questionnaire) will be administered at Visit 2 or 5 and for the purpose of determining test-retest reliability coefficients. Duration of the visit will last approximately 90 min. Light refreshments will be served at the conclusion of each visit.

Participants will be randomly assigned to a treatment arm using allocation by minimization (Altman DG, Bland JM. Treatment allocation by minimisation. Brit Med J. 2005 Apr 9;330(7495):843-.). They will be required to consume 4 supplement capsules per day for 20 weeks, preferably at the same time each day. To assist with compliance, participants will note down the time of capsule consumption in their supplement diary. A study investigator will contact the participants every 4 weeks during the intervention to check participants’ well-being and to remind them to consume their supplements. Participants will return at week 10 to be reassessed for Part A of the protocol. To minimize learning effects, Part B will not be assessed at week 10. The purpose of this visit is to maintain participant-investigator contact and to assess treatment compliance, as assessed by erythrocyte LCn-3PUFA levels. Measuring cerebrovascular function mid-way in the intervention will provide insight into the trajectory of improvement. Participants will continue taking their allocated supplement from week 10 to 20 before returning for reassessment physiological and psychometric assessments.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo (corn oil)
Mode – taken orally with water
Frequency – daily with morning or evening meal
Duration = 4 oral capsules of placebo (corn oil) per day for 20 weeks.

Control group

Placebo

Outcomes

Primary outcome [1]

Cerebrovascular responsiveness (CVR) to hypercapnia is assessed using transcranial doppler ultrasound (Doppler Box X). Increases in blood flow velocity in the MCA in response to vasodilator stimuli (i.e. hypercapnia) reflect endothelial dilatation in downstream vascular beds. Basal cerebral blood flow velocities for 10 cardiac cycles will first be recorded to determine the blood flow velocity (peak systolic, end diastolic and mean) at rest. The measures of cerebral pulsatility and resistive indexes will also be recorded simultaneously. During CVR to hypercapnia, participants breathe carbogen (5% CO2, 95% O2) for 150 seconds and the peak increase of blood flow velocity is recorded. This is performed 3 times with a 2-min interval.

Timepoint [1]

Baseline at week 0, and at week 10 and week 20 after intervention commencement.

Secondary outcome [1]

Seated clinic blood pressure and arterial compliance will be measured by automated oscillometry with a Cardiovascular Profiler (Trademark) (HDI Cardiovascular Profiler CR2000).

Timepoint [1]

Baseline at week 0, and at week 10 and week 20 after intervention commencement.

Secondary outcome [2]

Cerebrovascular responsiveness (CVR) to photic stimulation will be assessed using transcranial doppler ultrasound. Increase in blood flow velocity in the posterior cerebral arteries (PCA) in response to photic stimulation is a robust activation paradigm that allows for the assessment of the relationship between local neuronal activities and regional blood flow in the cortex (neurovascular coupling capacity) (20). Protocol will take place in a quiet, dark room and a computer monitor will be placed 0.3m in front of the seated participant. The screen will occupy approximately 80% of the participant’s visual field. Mean blood flow velocities in the PCA will be recorded continuously during stimulation period.

After a baseline recording of 1 min eyes open and 1 min eyes closed, CVR to photic stimulation protocol will consist of alternating between 60s eyes closed and 40s eyes open whilst (a) looking at the monitor with a white lighted and (b) looking at an image of complex scenery. Transition between eyes open and close will be signal by an acoustic tone. Previous literature found that the blood flow velocity in the PCA will peak within 20s of photic stimulation. Discarding the first 5 s during the eyes closed, an averaged velocity of the reminding 30s will be the baseline. The vasomotor reaction time will be recorded as the time taken to reach peak velocity after opening eyes. CVR to photic stimulation will be calculated as the percentage increase of peak velocity over baseline velocity.

Timepoint [2]

Baseline at week 0, and at week 10 and week 20 after intervention commencement.

Secondary outcome [3]

Cerebrovascular responsiveness to neuropsychological tests will be recorded continuously using transcranial doppler ultrasound to monitor the changes in mean blood flow velocity in the middle cerebral artery (MCA) during cognitive assessments. To minimise the potential influence of artefact, CVR will be assessed only in the non-verbal tasks of the cognitive battery, i.e. all except the dual-task conditions. The order of tests will be as follows:
- Choice reaction time test
- N-back task
- Computerised multi-tasking test battery
- Trail-making task

Timepoint [3]

Baseline at week 0 and at the end of the intervention phase at week 20.

Secondary outcome [4]

Neuropsychological test performance on the choice reaction time test, N-back task, computerised multi-tasking test battery, trail making task and dual tasking conditions.

Timepoint [4]

Baseline at week 0 and at the end of the 20-week intervention phase.

Secondary outcome [5]

Mood states will be measured using a Profile of Mood States (POMS) questionnaire consisting of 65-adjectives that participants will rate on a 5-point scale. This will be administered on paper at the conclusion of the neuropsychological test battery. Participants will be required to rate the level at which they have been feeling in the last week and including today according to the 1-5 Likert Scale (1 being “not at all” and 5 being “extremely).

Timepoint [5]

Baseline at week 0 and at the end of the 20-week intervention phase.

Secondary outcome [6]

Omega 3 index which is the percentage of EPA+DHA in the red blood cell fatty acids. This will be determined by gas chromotography. Fasting venous blood will be obtained from participants/ Red blood cells will be seperated from plasma and frozen for analysis if omega-3 index.

Timepoint [6]

Baseline at week 0 and at the end of the 20-week intervention phase.

Secondary outcome [7]

Fasting total, HDL, LDL cholestrol and triglycerides. Participants will be asked to attend the Hunter Area Pathology Service (HAPS) collection centre on campusl to provide a blood sample. Blood collection and biochemical analysis will be collected and provided Hunter Area Pathology Services (HAPS).

Timepoint [7]

Baseline at week 0 and at the end of the 20-week intervention phase

Secondary outcome [8]

Inflammatory biomarkers of IL-6, TNF-alpha, NF-kappa beta, HS-CRP and ESM-1. Participants will be asked to attend the Hunter Area Pathology Service (HAPS) collection centre on campusl to provide a blood sample. Blood collection and biochemical analysis will be collected and provided Hunter Area Pathology Services (HAPS).

Timepoint [8]

Baseline at week 0 and at the end of the 20-week intervention phase.

Eligibility

Key inclusion criteria

-Clinic SBP between 130-160mmHg or DBP between 85-100mmHg (determined at screening)
-Consuming less than 2 fish/seafood meals per week
-Consuming equal to 300mg/day of long-chained LCn-3PUFA from fish oil supplements or enriched foods
-Unlikely to change medication/supplements during the intervention
-Competent in using computer mouse and keyboard.

Minimum age

40 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

-Suspected dementia (3MS score of < 78/100)
-Smokers or currently on nicotine therapy
- Neurological conditions
- Kidney/liver disease
- Diabetes
- Major depression as diagnosed by a health care professional
- Visual problems
- Unable to obtain a measurable signal in the MCA
- Unwilling to or have intolerance to fish or vegetable oil
- Unwilling to provide a blood sample
- Unwilling to maintain pre-enrolment physical activity levels and dietary habits for the duration of the trial.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

- Participants will receive and return a completed health and lifestyle questionnaire and consent form,
- Participants will then attend the research clinic for their screening/baseline visit
- Participants who meet the inclusion criteria will be randomly assigned to a treatment arm either active or placebo using allocation by minimization (Altman & Bland BMJ 2005;330;843).
- The supplement bottles will be labelled with their assigned participant ID. Both the study investigator and the participant will not know whether they are on the ‘active’ or the ‘inactive’ supplement.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be allocated their initial treatment accordingly to the randomisation by minimisation process (Altman & Bland BMJ 2005;330;843), where gender and body mass index will be the primary determinant. The initial allocation of the first participant will be determined by a coin toss.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

In the intention-to-treat analysis, effects of LCn-3PUFA supplementation on primary and secondary outcomes will be analysed by two-way, repeated measures ANOVA with factors of time (baseline, post-dose) and treatment (placebo, LCn-3PUFA). Significant interactions (with appropriate correction for multiple comparisons) will be further explored by pre-planned comparisons of treatments at each time point using t-tests for independent samples.
Baseline measures will be used as covariates. We will match groups by stratification of age and gender and other potentially confounding variables such as IQ, years of education and socioeconomic status will be added as covariates.
Relationships between changes in circulatory parameters and cognitive parameters will be analysed by linear regression with appropriate pre-planned Bonferroni comparisons and the effect of biomarker status will be determined using biomarkers as covariates in a mixed model analysis.
48 participants in a two-treatment parallel design will give 80% power to detect a 7.5% change in CVR to hypercapnia (relative increase ~25%) at alpha = 0.05, based on a 9% SD observed previously (Wong RHX, Howe PRC, Coates AM, Buckley JD, Berry NM. Chronic consumption of a wild green oat extract (Neuravena) improves brachial flow-mediated dilatation and cerebrovascular responsiveness in older adults. J Hypertens. 2013 Jan;31(1):192-200.). We will recruit a total of 60 participants to allow for a 20% attrition.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

10/09/2014

Actual

26/09/2014

Date of last participant enrolment

Anticipated

Actual

15/06/2016

Date of last data collection

Anticipated

Actual

22/11/2016

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Funding & Sponsors

Funding source category [1]

University

Name [1]

The University of Newcastle

Address [1]

The University of Newcastle, University Drive, Callaghan, New South Wales 2308

Country [1]

Australia

Primary sponsor type

University

Name

The University of Newcastle

Address

The University of Newcastle, University Drive, Callaghan, New South Wales 2308

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

Professor Peter Howe

Address [1]

Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
The University of Newcastle,
University Drive,
MS 304
Callaghan, NSW 2308

Country [1]

Australia

Other collaborator category [2]

University

Name [2]

Dr Rachel Wong

Address [2]

Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
The University of Newcastle,
University Drive,
MS 514
Callaghan, NSW 2308

Country [2]

Australia

Other collaborator category [3]

University

Name [3]

Professor Manohar Garg

Address [3]

Nutraceuticals Research Group
305C Medical Science Building
University of Newcastle
University Drive,
Callaghan, NSW 2308

Country [3]

Australia

Other collaborator category [4]

University

Name [4]

Ms Melissa Fry

Address [4]

Nutraceuticals Research Group
305 Medical Science Building
University of Newcastle
University Drive,
Callaghan, NSW 2308

Country [4]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee

Ethics committee address [1]

Human Research Ethics Committee
The Chancellery
The University of Newcastle,
University Drive
Callaghan, NSW 2308

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/06/2014

Approval date [1]

17/07/2014

Ethics approval number [1]

H-2014-0152

Summary

Brief summary

It is postulated that impairments in circulatory function are central to the association between hypertension and declining cognition and mood. Regular long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) supplementation has the potential to enhance cerebral arterial function which may in turn enhance mood and cognition. This project aims to evaluate benefits of supplementing the diet with LCn-3PUFA on cerebrovascular function, mood and cognitive performance in hypertensive adults with low habitual intake of LCn-3PUFA. Sixty dementia-free adults aged 40-65 years with elevated blood pressure (BP) (130-160 mmHg systolic and 85-100 mmHg diastolic) at screening will undertake a 20-wk randomised, double-blind, placebo-controlled, parallel design omega-3 supplementation trial at the University of Newcastle. Eligible volunteers will undergo further baseline assessment of systemic artery compliance (AC) (pulse wave analysis), cerebral AC (pulsatility index), cerebrovascular responsiveness (CVR) to hypercapnic and cognitive stimuli (assessed by transcranial Doppler ultrasound), cognitive performance and mood. Participants will then be randomised to consume 4 capsules delivering 2g LCn-3PUFA or placebo daily for 20 wk before returning for reassessment. We expect that LCn-3PUFA supplementation will improve cerebrovascular perfusion and thereby enhance mood and cognition. Findings will advocate the use of LCn-3PUFA in hypertension management.

Trial website

Trial related presentations / publications

There are no publications related to this study.

Public notes

Attachments [1]

/AnzctrAttachments/366604-BC04 Expedited Approval 17 july 2014.pdf

Contacts

Principal investigator

Name

Prof Peter Howe

Address

Clinical Nutrition Research Centre School of Biomedical Sciences & Pharmacy MS 304 University of Newcastle University Drive, Callaghan NSW 2308

Country

Australia

Phone

+61 2 4921 7309

Fax

[email protected]

Contact person for public queries

Name

Dr Rachel Wong

Address

Clinical Nutrition Research Centre School of Biomedical Sciences & Pharmacy MS 514 University of Newcastle University Drive, Callaghan NSW 2308

Country

Australia

Phone

+61 2 4921 6408

Fax

[email protected]

Contact person for scientific queries

Name

Prof Peter Howe

Address

Clinical Nutrition Research Centre School of Biomedical Sciences & Pharmacy MS 304 University of Newcastle University Drive, Callaghan NSW 2308

Country

Australia

Phone

+61 2 4921 7309

Fax

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Effects of long chain omega-3 polyunsaturated fatty acids on brain function in mildly hypertensive older adults.	2018	https://dx.doi.org/10.3390/nu10101413

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically