Trial Review

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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] 284871 0
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 292437 0
Cognitive performance 292438 0
Mood 292439 0
Condition category
Condition code
Cardiovascular 292748 292748 0 0
Other cardiovascular diseases
Mental Health 292749 292749 0 0
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] 289781 0
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] 292599 0
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] 292599 0
Baseline at week 0, and at week 10 and week 20 after intervention commencement.
Secondary outcome [1] 309305 0
Seated clinic blood pressure and arterial compliance will be measured by automated oscillometry with a Cardiovascular Profiler (Trademark) (HDI Cardiovascular Profiler CR2000).
Timepoint [1] 309305 0
Baseline at week 0, and at week 10 and week 20 after intervention commencement.
Secondary outcome [2] 309306 0
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] 309306 0
Baseline at week 0, and at week 10 and week 20 after intervention commencement.
Secondary outcome [3] 309307 0
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] 309307 0
Baseline at week 0 and at the end of the intervention phase at week 20.
Secondary outcome [4] 309308 0
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] 309308 0
Baseline at week 0 and at the end of the 20-week intervention phase.
Secondary outcome [5] 309309 0
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] 309309 0
Baseline at week 0 and at the end of the 20-week intervention phase.
Secondary outcome [6] 309310 0
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] 309310 0
Baseline at week 0 and at the end of the 20-week intervention phase.
Secondary outcome [7] 309311 0
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] 309311 0
Baseline at week 0 and at the end of the 20-week intervention phase
Secondary outcome [8] 309312 0
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] 309312 0
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?
No
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
60
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 289575 0
University
Name [1] 289575 0
The University of Newcastle
Country [1] 289575 0
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] 288259 0
None
Name [1] 288259 0
Address [1] 288259 0
Country [1] 288259 0
Other collaborator category [1] 278046 0
University
Name [1] 278046 0
Professor Peter Howe
Address [1] 278046 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
The University of Newcastle,
University Drive,
MS 304
Callaghan, NSW 2308
Country [1] 278046 0
Australia
Other collaborator category [2] 278047 0
University
Name [2] 278047 0
Dr Rachel Wong
Address [2] 278047 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
The University of Newcastle,
University Drive,
MS 514
Callaghan, NSW 2308
Country [2] 278047 0
Australia
Other collaborator category [3] 278048 0
University
Name [3] 278048 0
Professor Manohar Garg
Address [3] 278048 0
Nutraceuticals Research Group
305C Medical Science Building
University of Newcastle
University Drive,
Callaghan, NSW 2308
Country [3] 278048 0
Australia
Other collaborator category [4] 278049 0
University
Name [4] 278049 0
Ms Melissa Fry
Address [4] 278049 0
Nutraceuticals Research Group
305 Medical Science Building
University of Newcastle
University Drive,
Callaghan, NSW 2308
Country [4] 278049 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291312 0
Human Research Ethics Committee
Ethics committee address [1] 291312 0
Ethics committee country [1] 291312 0
Australia
Date submitted for ethics approval [1] 291312 0
30/06/2014
Approval date [1] 291312 0
17/07/2014
Ethics approval number [1] 291312 0
H-2014-0152

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 166 166 0 0
/AnzctrAttachments/366604-BC04 Expedited Approval 17 july 2014.pdf

Contacts
Principal investigator
Name 49474 0
Prof Peter Howe
Address 49474 0
Clinical Nutrition Research Centre School of Biomedical Sciences & Pharmacy MS 304 University of Newcastle University Drive, Callaghan NSW 2308
Country 49474 0
Australia
Phone 49474 0
+61 2 4921 7309
Fax 49474 0
Email 49474 0
[email protected]
Contact person for public queries
Name 49475 0
Rachel Wong
Address 49475 0
Clinical Nutrition Research Centre School of Biomedical Sciences & Pharmacy MS 514 University of Newcastle University Drive, Callaghan NSW 2308
Country 49475 0
Australia
Phone 49475 0
+61 2 4921 6408
Fax 49475 0
Email 49475 0
[email protected]
Contact person for scientific queries
Name 49476 0
Peter Howe
Address 49476 0
Clinical Nutrition Research Centre School of Biomedical Sciences & Pharmacy MS 304 University of Newcastle University Drive, Callaghan NSW 2308
Country 49476 0
Australia
Phone 49476 0
+61 2 4921 7309
Fax 49476 0
Email 49476 0
[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
SourceTitleYear of PublicationDOI
EmbaseEffects of long chain omega-3 polyunsaturated fatty acids on brain function in mildly hypertensive older adults.2018https://dx.doi.org/10.3390/nu10101413
N.B. These documents automatically identified may not have been verified by the study sponsor.