Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000017628
Ethics application status
Approved
Date submitted
20/12/2013
Date registered
7/01/2014
Date last updated
27/11/2018
Date data sharing statement initially provided
27/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Does Manipulation of Arterial Shear Stress Enhance Cerebrovascular Function and Cognition in the Aging Brain?
Scientific title
The Preventia Study: A randomised controlled study of the effects of a 6 month land-based walking or water walking or an ageing education program on brain blood flow and cognition in older adults.
Secondary ID [1] 283728 0
Nil
Universal Trial Number (UTN)
Trial acronym
PREVENTIA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Risk of cognitive decline 290693 0
Vascular health 290696 0
Physical inactivity 290697 0
Condition category
Condition code
Neurological 291063 291063 0 0
Alzheimer's disease
Cardiovascular 291064 291064 0 0
Diseases of the vasculature and circulation including the lymphatic system
Public Health 291065 291065 0 0
Health promotion/education

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 1: Land-based exercise training.
Participants will attend a centre-based program 3 times weekly for 1hour. Supervised land-based walking will be undertaken in surrounding parkland or on treadmills in a laboratory or gymnasium. Initial exercise intensity will be set individually according to results of a preliminary exercise test (i.e. 55-65%VO2peak) and regular measures of intensity (heart rate (HR) using a HR monitor and Rate of Perceived Exertion (RPE, Borg Scale) will be collected and recorded during each session to ensure compliance. Exercise intensity will be progressed throughout the 6-month program.

Group 2: Water-based exercise training.
Participants will attend a centre-based program 3 times weekly for 1hour per visit, and will participate in a water-walking program undertaken in a shallow heated 30x25m pool. The intensity of each session (55-65%VO2peak) will be matched to that undertaken by Group 1 using comparative oxygen uptake assessment as well as HR monitoring. The exercise-training program will be similarly progressed over the 6-month period.
Intervention code [1] 288421 0
Prevention
Intervention code [2] 288422 0
Lifestyle
Intervention code [3] 288423 0
Behaviour
Comparator / control treatment
Group 3: Educational Seminar Group This group will be asked to continue with their usual physical activities for the 6-month duration of the trial. During this time they will receive a centre-based education program (4 sessions of 1 hour conducted every 6 weeks) providing information including healthy lifestyles in older age, to minimize any Hawthorne effect. The education program will be delivered by study investigators and trained research assistants.
Control group
Active

Outcomes
Primary outcome [1] 291060 0
Cerebral blood flow (CBF) velocity (cm/sec) assessed by transcranial Doppler (TCD)
CBF will be assessed by combining bilateral measures of anterior (ACA), middle (MCA) and posterior cerebral artery (PCA) flow velocities at rest and in response to various physiological stimuli.

1. Cerebrovascular carbon dioxide (CO2) reactivity
2. Dynamic cerebral auto-regulation
3. Neurovascular coupling:
Timepoint [1] 291060 0
Baseline, 12 weeks, 24 weeks (6 months) and 48 weeks (12 months) after the intervention commencement.
Primary outcome [2] 291063 0
Peripheral vascular function
Peripheral vascular function will be assessed via ultrasound scans of the carotid, brachial and superficial femoral arteries at baseline and following assessment of brachial and superficial femoral artery flow mediated dilation (FMD); brachial artery peak blood flow and dilation responses to ischaemic exercise (iEx). Bilateral brachial endothelium-independent vasodilation will be measured after sublingual administration of a nitric oxide (NO)-donor (GTN).
Measurements will be collected for the assessment of wall thickness and % change in arterial diameter.
Timepoint [2] 291063 0
Baseline, 12 weeks, 24 weeks (6 months) and 48 weeks (12 months) after the intervention commencement.
Secondary outcome [1] 305912 0
Cognition
Cognitive function will be assessed using the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status); the TOTAL score and 5 INDEX scores for individual cognitive domains (Language, Attention, Visuospatial, Immediate Memory, Delayed Memory).
Timepoint [1] 305912 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [2] 305913 0
Other cognitive measures will include:
1) MMSE total score
2) Trail making test score
3) MAC-Q
Timepoint [2] 305913 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [3] 305914 0
Mood, emotion and wellbeing will be measured using:
1) Hospital Anxiety and Depression Scale (HADS)
2) World Health Organisation -Five Wellbeing index (WHO-5)
Timepoint [3] 305914 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [4] 305915 0
Resting Blood pressure
Resting blood pressure and heart rate will be assessed in 2 ways.
1. Mean clinic resting blood pressure and heart rate measured supine for 20 minutes at 2-minutely intervals on 2 visits.
2. Mean self-monitored resting blood pressure and heart rate measured sitting at 2-minutely intervals for 5 measures on 2 weekdays and 1 weekend day .
Timepoint [4] 305915 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [5] 305917 0
BDNF
Mean brain-derived neurotrophic factor (BDNF) will be determined from a blood sample.
Timepoint [5] 305917 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [6] 305918 0
Blood Lipids
Blood will be sampled after an overnight fast and mean measures cholesterol, triglyceride, High-Density Lipoprotein Cholesterol (HDL-C) and Low-Density Lipoprotein Cholesterol (LDL-C) determined.
Timepoint [6] 305918 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [7] 305919 0
Glucose and Insulin Metabolism
Mean fasted basal blood glucose, insulin and HbA1c will be measured.
Timepoint [7] 305919 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [8] 305920 0
Inflammatory Markers
Blood will also be analysed for a range of inflammatory markers (e.g. hs-CRP, IGF1 and the myokine IL-6, IL-10 and IL-1ra and TNF?).
Timepoint [8] 305920 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [9] 305921 0
Platelet Function
Platelet Function will be measured using flow cytometry to assess platelet activation and monocyte platelet aggregates. Serum CD40L (thrombo-inflammatory marker) and soluble P-selectin (shed from activated platelets) will also be measured.
Timepoint [9] 305921 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [10] 305922 0
Cardiovascular fitness
Peak oxygen consumption will be assessed utilising a 12-lead ECG monitored, graded walking exercise test, while assessing VO2. The test will be a walking test, involving 3 minutes workload whereby walking speed will be maintained while elevation (grade) will be increased by 3.5% every 3 minutes. The test will end once the participant has reached volitional exhaustion or if any relative or absolute contraindications to exercise are determined.
Timepoint [10] 305922 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [11] 305923 0
Body Composition
Mean waist and hip circumferences will be measured. Body composition, specifically total fat mass, total lean mass, % body fat and bone mineral content as well as the regional components, will be measured using dual energy x-ray absorptiometry (DEXA).
Timepoint [11] 305923 0
Baseline, 6 months and 12 months after the intervention commencement.
Secondary outcome [12] 305924 0
Mean weekly (mins/week) physical activity will be assessed using the Stage of Change Questionnaire.
Accelerometry (using an actigraph monitor) over a 7-day period will be used to determine mean daily minutes of sedentary, light, moderate, vigorous, and a composite of moderate-to-vigorous intensity physical activity.
Timepoint [12] 305924 0
Baseline, 6 months and 12 months after the intervention commencement.

Eligibility
Key inclusion criteria
Healthy men
Healthy post-menopausal women, (stable HRT included)
Aged 50 years and over
Memory complainer
Inactive lifestyle (equal or less than 60 minutes/week moderate intensity exercise for at least 3 months)
Non-smoker for at least 12 months
Available for 12 –15 month duration
Prepared to participate in an centre-based exercise program; complete 150 minutes of moderate physical activity per week (3x50 minutes/week).
Systolic BP less than 160mmHg or Diastolic BP less than 100mmHg. (blood pressure lowering medication if on stable therapy medications and if the blood pressure is within the criteria)
total cholesterol less than or equal to 7mmol/L (cholesterol lowering medication if on stable therapy)
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
No medical details from General Practitioner (GP)
Smoker (smoked in the last 12 months)
Systolic BP greater than 160mmHg or Diastolic BP greater than 100mmHg
Total cholesterol greater than 7mmol/L
weekly alcohol intake greater than 280gm/week and/or drinking more than 40gms ethanol in one session?
greater than 60 minutes/week of regular moderate (or higher) intensity exercise per week
BMI greater than 40 kg/m2
Modified Telephone Interview Cognitive Status (Tics-M) less than 32
Geriatric Depression Scale- (GDS) greater than 6
Standardised Mini-Mental State Examination (sMMSE) - score less than 24
Repeatable Battery for the Assessment of Neuropsychological Status
(RBANS) greater than 1.5 SD below the age-related means for delayed memory index
Diagnosis of mild cognitive impairment, dementia or Alzheimer’s disease
Psychiatric medications such as cognitive enhancers or anti-epileptics, lithium
Intermittent use of NSAIDS (non-steroidal anti-inflammatory drugs)
not able to meet the requirement of moderate physical activity.
Not confident of exercising in chest deep water
Present or past history of :
- ischemic heart disease (myocardial infarction, coronary artery disease)
- angina
- intermittent claudication
- stroke
- diabetes mellitus
- persistent or frequent arrhythmias
- atrial fibrillation (chronic and on warfarin)
- regular medication for asthma or chronic obstructive airways disease
- epilepsy/epilepsy medication
- severe mental illness (anxiety, psychosis, schizophrenia)
- liver disease
- kidney disease
- any joint, muscular or spinal disorders including arthritis that prohibits moderate exercise.
- other serious illness medical conditions likely to compromise survival (cancer)
Possible hospital admission or period of treatment/rehabilitation, in the next 6 months
Not able to communicate in English.
Simultaneous participation in another research study

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
1. Telephone screening to determine initial eligibility
2. Screening visit with further eligibility criteria screened
3. Confirmation from the participant’s general practitioner
4. Completion of 4 baseline visits
5. Randomisation. Allocation is concealed using sealed opaque envelopes drawn by a person independent to the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified block randomisation will be used to minimise the effects of gender so that the resulting sample will have very close to a 1:1 ratio of men and women. Other known risk factors such as age will be controlled in the analysis. The block randomisation will be done using a database based on the ‘ralloc’ package within strata. The randomisation will use three randomised block sizes and simple randomisation within blocks to ensure a ratio of study : control participants close to unity within strata and overall. The randomisation will use a 2x3 design so there are six strata (from one stratification variable and three blocks). The order of the block size will be randomised.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size
No published study has investigated the impact of exercise training on cerebrovascular function, our primary outcome measure. However, based on our previous published work, and recent feasibility (pilot) work from our laboratory which demonstrated that CBF is increased in older individuals (n=9, age 65-78 years) by 10% following 12 weeks of training. A sample size of 35 will provide 80% power, assuming a two-tailed alpha of 0.05. We will recruit 45 subjects to each group to allow for a withdrawal rate of around 10-15% which we have found in our experience of centre-based interventions to be sufficient.
Data analysis
The normality of data will be assessed graphically by using histograms and box plots. Continuous variables with normal distribution will be described using means and standard deviations; median and inter-quartile range will be used for those without a normal distribution. Categorical variables will be described using frequency tables.
Outcome measures will be primarily assessed with an intention-to-treat analysis at the end of the intervention with secondary analysis for the 12- month time point. This effect will be tested as the interaction between the allocation group (land-based walking; water-based walking and control) and time, on the primary and secondary outcomes. We will apply multilevel regression models (mixed models) given the repeated measures design. The baseline value of each outcome will be included in the model as a covariate. Alpha will be set at 0.05 and all statistical tests reported will be two-tailed.


Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/02/2014
Actual
28/03/2014
Date of last participant enrolment
Anticipated
1/06/2016
Actual
31/03/2016
Date of last data collection
Anticipated
Actual
31/05/2017
Sample size
Target
150
Accrual to date
Final
72
Recruitment in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 7642 0
6009 - Crawley

Funding & Sponsors
Funding source category [1] 288437 0
Government body
Name [1] 288437 0
National Health and Medical Research Council
Country [1] 288437 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
35 Stirling Hwy
Crawley.

Western Australia 6009.
Country
Australia
Secondary sponsor category [1] 287139 0
University
Name [1] 287139 0
University of Melbourne
Address [1] 287139 0
Melbourne Research Office
Level 5, Allan Gilbert Building
The University of Melbourne
Vic. 3010
Country [1] 287139 0
Australia
Other collaborator category [1] 277732 0
University
Name [1] 277732 0
University of British Columbia
Okanagan
Address [1] 277732 0
School of Health and Exercise Sciences
The University of British Columbia
3333 University Way
Kelowna, BC V1V 1V7
Canada
Country [1] 277732 0
Canada

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290312 0
University Of Western Australia Human Research Ethics
Ethics committee address [1] 290312 0
Ethics committee country [1] 290312 0
Australia
Date submitted for ethics approval [1] 290312 0
22/04/2013
Approval date [1] 290312 0
23/05/2013
Ethics approval number [1] 290312 0
RA/4/1/6136

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 44850 0
Prof Daniel Green
Address 44850 0
University of Western Australia
School of Sport Science Exercise and Health
35 Stirling Hwy.
Crawley 6009.
Western Australia
Country 44850 0
Australia
Phone 44850 0
+61 8 64885609
Fax 44850 0
+61 8 64881039
Email 44850 0
[email protected]
Contact person for public queries
Name 44851 0
Kay Cox
Address 44851 0
University of Western Australia
School of Sport Science Exercise and Health
35 Stirling Hwy.
Crawley 6009.
Western Australia
Country 44851 0
Australia
Phone 44851 0
+61 8 64882379
Fax 44851 0
+61 8 64881039
Email 44851 0
[email protected]
Contact person for scientific queries
Name 44852 0
Daniel Green
Address 44852 0
University of Western Australia
School of Sport Science Exercise and Health
35 Stirling Hwy.
Crawley 6009.
Western Australia
Country 44852 0
Australia
Phone 44852 0
+61 8 64885609
Fax 44852 0
+61 8 64881039
Email 44852 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
At this stage there are no plans for data sharing.


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 Land versus Water Walking Interventions on Vascular Function in Older Adults.2021https://dx.doi.org/10.1249/MSS.0000000000002439
EmbaseThe Impact of 6-Month Land versus Water Walking on Cerebrovascular Function in the Aging Brain.2021https://dx.doi.org/10.1249/MSS.0000000000002685
N.B. These documents automatically identified may not have been verified by the study sponsor.