Trial Review

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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
28/01/2024
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 fitness, brain blood flow, brain volume, and cognitive function in middle-aged adults
Scientific title
A randomised controlled study investigating the effects of two different 12-week aerobic exercise training interventions on cardiorespiratory fitness, 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
Intervention Group: 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 between 4 to 7 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 ~35-55 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 4 weeks during the intervention to ensure training progression (i.e., intensity from each individual incremental exercise test will determine the workload for the succeeding 4 weeks of training, which is expected to gradually increase at each 4-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
Control Group: 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 between 36 to 48 min of exercise at ~60% peak aerobic power. Each session will take ~40-55 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 4 weeks during the intervention to ensure training progression (i.e., intensity from each individual incremental exercise test will determine the workload for the succeeding 4 weeks of training, which is expected to gradually increase at each 4-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] 329985 0
Cardiorespiratory fitness:
Peak oxygen consumption (VO2peak) will be assessed by an incremental exercise test on a cycle ergometer. The test will have a desired time limit of 10 min, and will be discontinued at a symptom-limited endpoint (RPE of 17; 'very hard' on the Borg scale).
Timepoint [1] 329985 0
Baseline, 4 weeks into the training intervention, 8 weeks into the training intervention. 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, 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 [2] 387986 0
Brain blood flow (composite secondary outcome): Global (whole brain) and regional (e.g., anterior cingulate or dorsolateral prefrontal cortex) blood flow will be measured using the 7Tesla (7T) Ultra-High Field magnetic resonance imaging (MRI) scanner, and 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), half-way point in the training intervention (6 weeks), post-training (pre and post last training session), and 12-weeks after the end of training.
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), half-way point in the training intervention (6 weeks), post-training (pre and post last training session), and 12-weeks after the end of training.
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), half-way point in the training intervention (6 weeks), post-training (pre and post last training session), and 12-weeks after the end of training.
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), half-way point in the training intervention (6 weeks), post-training (pre and post last training session), and 12-weeks after the end of training.
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), half-way point in the training intervention (6 weeks), post-training (pre and post last training session), and 12-weeks after the end of training.
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), half-way point in the training intervention (6 weeks), post-training (pre and post last training session), and 12-weeks after the end of training.
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, 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 [19] 390627 0
Fatigue:
Participants will be asked to complete the Fatigue Assessment Scale (FAS) questionnaire.
Timepoint [19] 390627 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 [20] 390628 0
Quality of Life:
Participants will be asked to complete the Assessment Quality of Life (AQoL) questionnaire.
Timepoint [20] 390628 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 [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.
Secondary outcome [22] 404524 0
Brain volume: This will be assessed using 7Tesla (7T) Ultra-High Field magnetic resonance imaging (MRI) scanner and a MP2RAGE sequence.
Timepoint [22] 404524 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 [23] 404525 0
Mental Health Questionnaires
Participants will be asked to complete the Depression, Anxiety, and Stress Scale (DASS21) and the Short-Form 36 Questionnaire (SF36) to assess mental health
Timepoint [23] 404525 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

Eligibility
Key inclusion criteria
- Aged 45-65
- Able to participate in 36 exercise sessions over 12 weeks
- Normal cognition on screening
- BMI of 18 to 40
- Sign off from doctor to participate in the study
Minimum age
45 Years
Maximum age
65 Years
Sex
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 morbidly obese (BMI < 18 or > 40)
- History of any serious traumatic brain injury (e.g., ICU stay, rehab required, and/or a prolonged period of unconsciousness).
- High blood pressure at rest (over 160/100 mmHg)
- Current or ex-smoker (last 12 months)
- Any blood disorders or brain tumours
- Started any new medications (e.g., hormone replacement therapy) in the last 3 months

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 an adaptive randomization application located on a secure network drive at the Florey. An unblinded investigator will input participant covariates into this application, following which allocation will be revealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated to two groups (MICT or HIIT) using an adaptive randomization application, using cardiorespiratory fitness (‘above’ or ‘below’ age-matched norms), age, and sex (male or female) as covariates.
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 total sample size of 70 (n = 35) will yield 80% power to detect a difference in VO2peak between groups corresponding to a medium effect size (d = 0.75), assuming two-tailed significance and a = 0.05. In a recent multi-centre comparison of VO2peak trainability between HIIT and MICT, relative VO2peak was increased by 4.50 ± 3.93 mL/kg/min following HIIT, and 1.50 ± 3.36 mL/kg/min following MICT, in middle-aged and elderly individuals (Williams et al, 2018). Using a mean difference between groups of 3.0 ± 4.0 mL/kg/min, this equates to a total sample size of 58 (n = 29). We have increased the sample size by 20% to account for attrition over the 6-month study period and potential non-usable MRI scans.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/11/2021
Actual
7/11/2021
Date of last participant enrolment
Anticipated
5/06/2023
Actual
22/06/2023
Date of last data collection
Anticipated
26/11/2023
Actual
7/12/2023
Sample size
Target
70
Accrual to date
Final
70
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)
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
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
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
[email protected]
Contact person for public queries
Name 106139 0
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
[email protected]
Contact person for scientific queries
Name 106140 0
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
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.