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Trial registered on ANZCTR


Registration number
ACTRN12621000144819
Ethics application status
Approved
Date submitted
29/10/2020
Date registered
12/02/2021
Date last updated
12/02/2021
Date data sharing statement initially provided
12/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The 'Train Smart' Study: Investigating the role of exercise training 'dose' on brain blood flow, brain volume, and cognitive function in middle-aged adults
Scientific title
A randomised controlled study investigating the effects of three different 12-week aerobic exercise training interventions on brain blood flow, brain volume, and cognitive function in middle-aged adults
Secondary ID [1] 302565 0
MRF1200852
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitive decline and dementia 319447 0
Vascular health 319448 0
Physical inactivity 319449 0
Condition category
Condition code
Neurological 317416 317416 0 0
Studies of the normal brain and nervous system
Cardiovascular 317417 317417 0 0
Normal development and function of the cardiovascular system
Mental Health 317418 317418 0 0
Studies of normal psychology, cognitive function and behaviour
Public Health 317419 317419 0 0
Health promotion/education
Neurological 317973 317973 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 1: Moderate-intensity interval training
Participants will perform 12 weeks of supervised (exercise physiologist/scientist), work-matched cycling training, performed three times per week on a cycle ergometer in a laboratory. Training sessions will consist of 6 x 4-min exercise intervals at an intensity of ~60% peak aerobic power, with each interval interspersed with 3 min of passive recovery. Each session will take ~45-50 min (with warm-up and cool down). Individualised exercise intensity will be determined during a number of incremental exercise tests, which will be performed every 2 weeks during the intervention to ensure training progression (i.e., intensity from each individual incremental exercise test will determine the workload for the succeeding 2 weeks of training, which is expected to gradually increase at each 2-week training block). Training will be administered in groups of up to 4 participants per trainer, depending on participant availability. Adherence to the intervention (i.e., session attendance) will be monitored and documented by the principal investigator.

Group 2: High-intensity interval training
Participants will perform 12 weeks of supervised (exercise physiologist/scientist), work-matched cycling training, performed three times per week on a cycle ergometer in a laboratory. Training sessions will consist of 4 x 4-min exercise intervals at an intensity of ~90% peak aerobic power, with each interval interspersed with 3 min of passive recovery. Each session will take ~35-40 min (with warm-up and cool down). Individualised exercise intensity will be determined during a number of incremental exercise tests, which will be performed every 2 weeks during the intervention to ensure training progression (i.e., intensity from each individual incremental exercise test will determine the workload for the succeeding 2 weeks of training, which is expected to gradually increase at each 2-week training block). Training will be administered in groups of up to 4 participants per trainer, depending on participant availability. Adherence to the intervention (i.e., session attendance) will be monitored and documented by the principal investigator.
Intervention code [1] 318857 0
Prevention
Intervention code [2] 318858 0
Lifestyle
Comparator / control treatment
Group 3: Moderate-intensity continuous training
Participants will perform 12 weeks of supervised (exercise physiologist/scientist), work-matched cycling training, performed three times per week on a cycle ergometer in a laboratory. Training sessions will consist of 24 min of exercise at ~60% peak aerobic power, Each session will take ~30-35 min (with warm-up and cool down). Individualised exercise intensity will be determined during a number of incremental exercise tests, which will be performed every 2 weeks during the intervention to ensure training progression (i.e., intensity from each individual incremental exercise test will determine the workload for the succeeding 2 weeks of training, which is expected to gradually increase at each 2-week training block). Training will be administered in groups of up to 4 participants per trainer, depending on participant availability. Adherence to the control treatment (i.e., session attendance) will be monitored and documented by the principal investigator.
Control group
Active

Outcomes
Primary outcome [1] 325448 0
Brain volume:
This will be assessed using 7Tesla (7T) Ultra-High Field magnetic resonance imaging (MRI) scanner and a MP2RAGE sequence.
Timepoint [1] 325448 0
Baseline, half-way point in the training intervention (6 weeks), at the end of training (12 weeks; primary endpoint), and 12-weeks after the end of training.
Primary outcome [2] 325449 0
Global brain blood flow (7T MRI):
Global (whole brain) blood flow will be measured using an arterial-spin labelling sequence.
Timepoint [2] 325449 0
Baseline, half-way point in the training intervention (6 weeks), at the end of training (12 weeks; primary endpoint), and 12-weeks after the end of training.
Secondary outcome [1] 387985 0
Cognitive function (composite secondary outcome).
To assess cognitive function, a study-specific battery of neuropsychological tests will be performed. Briefly, the study-specific test battery is designed to assess general cognition, processing speed, attention, working memory, memory, executive function, language, visuospatial ability.
Timepoint [1] 387985 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [2] 387986 0
Regional brain blood flow (7T MRI):
Regional (e.g., anterior cingulate or dorsolateral prefrontal cortex) blood flow will be measured using an arterial-spin labelling sequence.
Timepoint [2] 387986 0
Baseline, half-way point in the training intervention (6 weeks), at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [3] 387987 0
Brain blood vessel health (7T MRI):
A magnetic resonance angiogram sequence will be used to measure narrowing (stenosis) and stiffness (pulse-wave velocities) of brain arteries.
Timepoint [3] 387987 0
Baseline, half-way point in the training intervention (6 weeks), at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [4] 387988 0
Brain white matter microstructure integrity (7T MRI):
The microstructure integrity of the brain’s white matter, important for communication between different parts of the brain, will be assessed using ‘Diffusion weighted imaging’ and ‘FLAIR’ sequences.
Timepoint [4] 387988 0
Baseline, half-way point in the training intervention (6 weeks), at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [5] 387989 0
Brain metabolism (7T MRI):
Resting state brain metabolism will be assessed using an echo-planar imaging, blood oxygen level dependent’ (EPI* BOLD), sequence.
Timepoint [5] 387989 0
Baseline, half-way point in the training intervention (6 weeks), at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [6] 388242 0
Blood biomarkers of neurodegeneration (e.g., neurofilament light chain)
Timepoint [6] 388242 0
Baseline (pre and post first training session) and post-training (pre and post last training session)
Secondary outcome [7] 388243 0
Blood biomarkers of neurogenesis (e.g., BDNF, Irisin, Cathepsin-B, GPLD1)
Timepoint [7] 388243 0
Baseline (pre and post first training session) and post-training (pre and post last training session)
Secondary outcome [8] 388244 0
Blood biomarkers of metabolism (e.g., lactate, glucose, insulin, IGF-1, HbA1c, Vitamin E)
Timepoint [8] 388244 0
Baseline (pre and post first training session) and post-training (pre and post last training session)
Secondary outcome [9] 388245 0
Blood biomarkers of inflammation (e.g., IL-1, IL-6, IL-10, TNF-alpha, IFN-alpha, IFN-gamma, CRP)
Timepoint [9] 388245 0
Baseline (pre and post first training session) and post-training (pre and post last training session)
Secondary outcome [10] 388246 0
Blood lipid profile
Blood will be analysed for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and free-fatty acids.
Timepoint [10] 388246 0
Baseline (pre and post first training session) and post-training (pre and post last training session)
Secondary outcome [11] 388247 0
Blood biomarkers of vascular health (e.g., VEGF, eNOS, FSTL-1, Homocysteine)
Timepoint [11] 388247 0
Baseline (pre and post first training session) and post-training (pre and post last training session)
Secondary outcome [12] 389720 0
APOE e4 Genotyping:
The APOE e4 genotype of our study population will be assessed via a venous blood sample.
Timepoint [12] 389720 0
Baseline
Secondary outcome [13] 389721 0
Muscle biomarkers associated with neuroprotection
A muscle biopsy (voluntary) will be analysed for proteins associated with neuroprotection (e.g., FNDC5/irisin pathway, kynurenine aminotransferase, PGC-1a) using Western blot, RT-PCR, and proteomic analyses.
Timepoint [13] 389721 0
Baseline and at the end of training (12 weeks)
Secondary outcome [14] 389722 0
Muscle mitochondrial respiratory function
A muscle biopsy (voluntary) will be analysed for mitochondrial respiratory function using an Oroboros high-resolution mitochondrial respirometer
Timepoint [14] 389722 0
Baseline and at the end of training (12 weeks)
Secondary outcome [15] 390622 0
Cerebral blood flow velocity (composite secondary outcome):
Using transcranial Doppler ultrasound, blood flow velocity in the middle cerebral artery (MCAv) will be measured at rest and in response to:
- Cognitive stimulation via voluntary eye movement and a reading task (Neurovascular coupling)
- Changes in blood pressure via repeated sit-to-stand maneuvers (Dynamic cerebral autoregulation)
- Changes in blood carbon dioxide via by rebreathing of different carbon dioxide concentrations (Cerebrovascular reactivity to hypercapnia)
Timepoint [15] 390622 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [16] 390624 0
Peripheral Vascular Function:
Peripheral vascular function will be assessed via brachial artery flow-mediated dilation.
Timepoint [16] 390624 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [17] 390625 0
Body Composition:
Composite measures of participant height (stadiometer) and weight (standard scale) will be measured for the calculation of BMI, and waist/hip measurements (steel tape) will be measured for the calculation of waist-to-hip ratio.
Timepoint [17] 390625 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [18] 390626 0
Mood (composite secondary outcome):
Participants will be asked to complete The Generalised Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire (PHQ-9) to assess general mood.
Timepoint [18] 390626 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [19] 390627 0
Fatigue:
Participants will be asked to complete the Fatigue Assessment Scale (FAS) questionnaire.
Timepoint [19] 390627 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [20] 390628 0
Quality of Life:
Participants will be asked to complete the Assessment Quality of Life (AQoL) questionnaire.
Timepoint [20] 390628 0
Baseline, at the end of training (12 weeks), and 12-weeks after the end of training.
Secondary outcome [21] 390630 0
Physical activity levels (min/week) will be assessed using a wrist accelerometer (Actigraph) over a 7-day period.
Timepoint [21] 390630 0
Baseline and 12-weeks after the end of training.

Eligibility
Key inclusion criteria
- Aged 45-65
- Able to participate in 36 exercise sessions over 12 weeks
- Normal cognition on screening
- Healthy or overweight (BMI 18-30)
- Sign off from doctor to participate in the study
Minimum age
45 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Involved in regular exercise training in the previous 6 months
- Significant medical co-morbidities precluding participation in an exercise intervention (e.g., severe cardiac disease)
- Contraindications to have MRI
- Mild cognitive impairment on screening
- Recent diagnosis (14 days), close contact, or symptomatic of COVID-19
- Underweight or obese (BMI < 18 or > 30)
- History of any serious traumatic brain injury (e.g., ICU stay, rehab required, and/or a prolonged period of unconsciousness).
- High blood pressure (over 160/100 mmHg)
- Current or ex-smoker (last 12 months)
- Any blood disorders or brain tumours
- Taking hormone replacement therapy

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)
Allocation will be concealed by using sealed opaque envelopes, which will be drawn by a person independent to the study at Victoria University.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated to three groups (MICT, MIIT, or HIIT) using computerised sequence generation with blocks of varying size and randomized order. Randomisation will be stratified by sex (male or female).
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)
Efficacy
Statistical methods / analysis
A priori calculations (G*Power 3.1.9.4) were performed based on previously reported changes in regional cerebral blood flow (as measured by arterial spin labelling) following 8 weeks of moderate-intensity continuous training in healthy older males (aged 60-70 years; n = 17), as compared with a passive control . We calculate that 75 (n=25 per group) participants are required to detect a meaningful and significant increase (d = 0.82) in regional cerebral blood flow (a = 0.05, 80% power, mean difference between groups of 4.4 ± 1.9 mL/100 g/min). Considering moderate-intensity interval exercise induced larger increases in middle cerebral artery velocity as compared with moderate-intensity continuous exercise, we believe a sample size of n = 25 based on changes following 8 weeks of moderate-intensity continuous training is a conservative estimate for the current study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 31705 0
3011 - Footscray

Funding & Sponsors
Funding source category [1] 306998 0
Government body
Name [1] 306998 0
National Health and Medical Research Council - Medical Research Future Fund (MRFF)
Address [1] 306998 0
16 Marcus Clarke St,
Canberra ACT 2601
Country [1] 306998 0
Australia
Primary sponsor type
University
Name
Victoria University
Address
Ballarat Road
Footscray, Victoria, 3011
Country
Australia
Secondary sponsor category [1] 307564 0
University
Name [1] 307564 0
University of Melbourne
Address [1] 307564 0
Parkville VIC 3010
Country [1] 307564 0
Australia
Secondary sponsor category [2] 307569 0
Other
Name [2] 307569 0
The Florey Institute of Neuroscience and Mental Health
Address [2] 307569 0
30 Royal Parade, Parkville VIC 3052
Country [2] 307569 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307130 0
Victoria University Human Research Ethics Committee
Ethics committee address [1] 307130 0
Ballarat Road
Footscray, Victoria, 3011
Ethics committee country [1] 307130 0
Australia
Date submitted for ethics approval [1] 307130 0
23/09/2020
Approval date [1] 307130 0
18/11/2020
Ethics approval number [1] 307130 0
HRE20-178

Summary
Brief summary
AIM:
The aim of this clinical trial is to investigate how different doses of aerobic exercise training affect brain blood flow, brain volume, and cognitive function in middle-aged (45-65 y) adults, and to translate this new knowledge into more individualised exercise prescriptions to better prevent the development of dementia.

HYPOTHESES:
1. Moderate-intensity interval training will improve resting brain blood flow, brain volume, and cognitive function to a greater extent than moderate-intensity continuous training.
2. These responses will be augmented as the intensity of interval aerobic exercise training increases (i.e., with high-intensity interval training as compared with moderate-intensity interval training).

METHODS:
In a single-blind, randomised-controlled trial, the study will follow a three-group parallel design. Groups will be matched on total brain volume (MRI), and participants will be assigned to one of three 12-week, work-matched, aerobic exercise interventions: 1) moderate-intensity continuous training (MICT; n =25), 2) moderate-intensity interval training (MIIT; n = 25), or 3) high-intensity interval training (HIIT; n = 25). These exercise modes were chosen as a means to investigate the most effective ‘dose’ of aerobic exercise training to improve brain blood flow, brain volume, and cognitive function. Briefly, the experimental protocol will consist of 1) screening, familiarisation, and baseline testing, 2) a 12-week aerobic exercise intervention with testing at the 6-week mark, 3) post-training testing, and 4) 12-week follow up testing.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106138 0
Dr James Broatch
Address 106138 0
Victoria University
Institute for Health and Sport (IHES)
Ballarat Road
Footscray, 3011
Victoria
Country 106138 0
Australia
Phone 106138 0
+61 3 99196283
Fax 106138 0
Email 106138 0
james.broatch@vu.edu.au
Contact person for public queries
Name 106139 0
Dr James Broatch
Address 106139 0
Victoria University
Institute for Health and Sport (IHES)
Ballarat Road
Footscray, 3011
Victoria
Country 106139 0
Australia
Phone 106139 0
+61 3 99196283
Fax 106139 0
Email 106139 0
james.broatch@vu.edu.au
Contact person for scientific queries
Name 106140 0
Dr James Broatch
Address 106140 0
Victoria University
Institute for Health and Sport (IHES)
Ballarat Road
Footscray, 3011
Victoria
Country 106140 0
Australia
Phone 106140 0
+61 3 99196283
Fax 106140 0
Email 106140 0
james.broatch@vu.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans to share individual participant data
What supporting documents are/will be available?
No other documents available
Summary results
No Results