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Trial registered on ANZCTR


Registration number
ACTRN12617001440314
Ethics application status
Approved
Date submitted
7/10/2017
Date registered
11/10/2017
Date last updated
20/09/2022
Date data sharing statement initially provided
17/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
BRAIN Training Trial: Balance, Resistance, or INterval Training Trial: A Randomised
Controlled Trial of Three Exercise Modalities in Mild Cognitive Impairment
Scientific title
BRAIN Training Trial: A randomised controlled trial of Balance, Resistance, or INterval Training on cognitive function in older adults with Mild Cognitive Impairment.
Secondary ID [1] 293069 0
National Health and Medical Research Council (NHMRC) Project Grant: APP1121409
Universal Trial Number (UTN)
U1111-1203-2255
Trial acronym
BRAIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mild Cognitive Impairment 305001 0
Condition category
Condition code
Neurological 304323 304323 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1. Study Sites:
This multi-site randomised control trial will take place across 3 study sites: University of Sydney (Australia), University of Queensland (Australia), and University of British Columbia (Canada).

2. Intervention Arms and Training Location:
Eligible and consenting participants at each study site will be randomly allocated to one of three study arms; progressive-resistance training (PRT), high-intensity interval training (HIIT) or a balance, toning & mobility (SHAM) sham-control group.
Participants will train supervised 2-3 days per week (depending on study arm), for 52 weeks. Trainers will have a background in exercise and sports science, exercise physiology, kinesiology or physiotherapy.

The location of the exercise sessions will vary according to the study site as follows:
- University of Sydney and University of British Columbia: PRT and HIIT training sessions will be performed in university-based gymnasiums; BTM sessions will be performed in separate rooms to the PRT and HIIT training groups.
- University of Queensland: PRT training sessions will be performed in a gymnasium based in a retirement village; HIIT and BAT will be performed in separate rooms within the same retirement village. Resident of the retirement village and members of the community will have access to the training areas.

2.1. Intervention Arm 1: Progressive Resistance Training (PRT)
The PRT intervention will be performed 2 session per week for 52 weeks and consist of 7 exercises performed using pneumatic resistance machines for 3 sets of 8 repetitions at 80% of 1 repetition maximum (1RM). Participants will be instructed to contract concentrically ‘as fast as possible’ and then take 3-4 seconds through the eccentric phase. Rest between repetitions will be 10-15 seconds, and 1 to 2 minutes between sets.
Exercises will be performed in the following order: bilateral leg press, bilateral chest press, unilateral knee extension, bilateral seated row, bilateral knee flexion, bilateral triceps pushdown, unilateral hip abduction. Total session time will be approximately 60 minutes, with a ratio of 1 trainer to 4 participants.

Weeks 1 and 2 of the intervention will include familiarisation (session 1), assessment of 1RM (session 2) and gradual increase in target intensity from 50% (session 3), 60% (session 4), 70% (session 5) until 80% of 1RM is reached in session 6. Thereafter training intensity will be set at 80% 1RM and progressed by a projected gain in strength of 3% 1RM each session, used in conjunction with daily ratings of perceived exertion (15-18/20 on the Borg Scale). At the start of every 7th session, 1RM will be re-tested and target weight at 80% 1RM will be recalculated based on the new 1RM.

Muscle visualisation and mental imagery:
Prior to each set, and during the rest intervals, participants will be shown a poster depicting the exercise being performed and the muscles targeted. The instructor will show participants where these muscles are located and encourage participants to feel the area. During the contraction phase of each repetition, participants will be asked to visualise and focus on the contracting muscles as they perform the movement 'as fast as they can'.

2.2. Intervention Arm 2: High Intensity Interval Training (HIIT)
The HIIT intervention will be performed 3 sessions per week for 52 weeks and the heart rate (HR) target used during the intervention will be set based on the peak HRpeak achieved on the stress test at baseline.
The HIIT intervention will be performed on a treadmill, recumbent cross trainer or bike, depending on feasibility, preference, and co-morbidities such as osteoarthritis or balance impairment.
Each session will consist of an 8-minute warm up at 60% peak HR; one 4-minute interval with a progressive increase in intensity so as to achieve 85% peak HR by the end of minute 2, and maintain 85% to 95% peak HR during minutes 3 and 4 of the interval; and a 3-minute cool down at 60% peak HR.

Heart rate will be monitored continuously during all sessions using a heart rate monitor to adjust the workload used (speed or slope of treadmill; resistance or revolutions per minute on cross trainer or bike) so as to keep the HR during the last 2 minutes of the interval at 85-95% of peak, and at 60% during warm-up and cool-down.

Sessions 1 to 4 of the intervention will include familiarisation and gradual increase of the time spent at 85-95% peak HR during the interval from 30, 60, 90 to 120 seconds in each successive session.

Individuals with atrial fibrillation or on beta-blockers will be included, but we will use the Borg Scale of Perceived Exertion (rating 16-17/20) to adjust the workload in addition to HR. Total session time will be 15 minutes, with a ratio of 1 trainer for 4 participants.
Intervention code [1] 299315 0
Treatment: Other
Intervention code [2] 299317 0
Prevention
Comparator / control treatment
Sham Exercise Control Group: Balance, Toning & Mobility (SHAM)

This 30 minute session will be performed 2 days per week for 52 weeks and include breathing exercises, stretching, calisthenics and simple balance exercises designed so as not to notably increase HR or aerobic capacity or enhance strength due to the emphasis on low intensity and minimally progressive exercises. Only very light elastic bands, cones and small implements will be used during the exercises. This regimen allows for maintenance of blinding to our hypothesis, as it is similar to what many older adults anticipate in group exercise classes. This group serves to control for confounding variables such as attention, social interaction, and changes in lifestyle secondary to study participation. Training will be performed with a ratio of 1 trainer to 8-10 participants.
Control group
Placebo

Outcomes
Primary outcome [1] 303596 0
Change in overall executive domain of cognitive function score (composite measure) calculated based on the scores attained in the following tess: - Neurotrax Stroop Interference Test - Neurotrax Go-No Go Test - Neurotrax Catch Game - Trails A and B Test (Trails B minus Trails A score) - Category Fluency Test - WAIS-IV Matrix Reasoning Test
Timepoint [1] 303596 0
At 26 weeks and 52 weeks (primary timepoint) after randomisation. Also during the 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation as a secondary outcome measure.
Secondary outcome [1] 339534 0
Change in composite measures of secondary domains of cognitive function (memory, attention/working memory, visual-spatial, language, information processing speed, motor skills) as assessed by the following tests: - NeuroTrax Verbal (paired associates) and Non-Verbal (visual-spatial) Memory tests - Hopkins Verbal Learning Test Revised (HVLT-R) (Total learning and delayed recall) - Benton Visual Retention Test (BVRT) - NeuroTrax Information Processing Speed Test - WAIS-IV Digit Span forwards and backwards tests - NeuroTrax Visual Spatial Processing test - NeuroTrax Verbal Rhyming test - WAIS-IV Coding - Trails Making Test form A (TMT-A)
Timepoint [1] 339534 0
At 26 weeks and 52 weeks after randomisation and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [2] 339535 0
Change in Clinical Cognitive Status as assessed using Clinical Dementia Rating Scale (CDR)
Timepoint [2] 339535 0
At 26 weeks and 52 weeks after randomisation and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [3] 339536 0
Change in scores for subjective cognitive complaint as assessed using the following instruments: (1) Cognitive change Index (CCI) and (2) Set of subjective cognitive complaint questions (non-validated questionnaire): 1. Have you noticed difficulties with your memory? (YES/NO) 2. Have you been concerned about your memory? (YES/NO) 3. Have you mentioned any concerns about memory to anyone? (YES/NO) 4. Have others commented on your memory? (YES/NO) 5. Have you seen a GP, specialist or other health professional about your memory? (YES/NO)
Timepoint [3] 339536 0
At 26 weeks and 52 weeks after randomisation and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [4] 339537 0
Change in score of functional impairment due to cognition as assessed using Amsterdam independent activity of daily living (IADL) Questionnaire
Timepoint [4] 339537 0
At 26 weeks and 52 weeks after randomisation and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [5] 339548 0
Change in functional mobility as assessed using the Short Physical Performance Battery, 6-minute Walk Test, Five Times Sit to Stand Test, and 4-metre usual and maximal gait speed tests.
Timepoint [5] 339548 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [6] 339549 0
Change in performance on gait under usual and dual task conditions with a seated letter fluency task administered either prior or after the three gait trials (determined at random). Gait trials (order determined at random): 1) Gait at usual speed without cognitive task; 2) gait at usual speed with a subtraction task; 3) gait at usual speed with a verbal fluency task.
Timepoint [6] 339549 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [7] 339550 0
Change in balance as assessed using static and dynamic balance tests:
- Static balance: Timed stand feet hip width, feet together, feet near tandem, feet tandem, 1 leg, feet tandem eyes closed, one leg eyes closed.
- Dynamic balance: Timed 3mt walk with feet in tandem.
Timepoint [7] 339550 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [8] 339551 0
Change in structural, metabolic or functional brain changes as assessed using MRI Morphology and Cerebral Perfusion: Structural changes using 3D T1-weighted, FLAIR, DTI; Metabolic changes using ASL; Functional changes using rs-fMRI; microbleeds using SWI)

Areas of interest: Posterior Cingulate Cortex (PCC) and Hippocampus volumes, perfusion and connectivity; White Matter Hyperintensity volume and distribution, total Grey and White Matter volume, mean Cerebral Blood Flow (rCBF) and Cerebral Blood Volume (rCBV), Hippocampal rCBF and rCBV, structural connectivity in the default mode network (DMN) and frontal-subcortical network, and functional connectivity in DMN and Fronto-executive network.
Timepoint [8] 339551 0
Only University of Sydney study site at 52 weeks after randomisation.
Secondary outcome [9] 339552 0
Change in whole body and regional lean and adipose tissue assessed using Dual-energy X-ray absorptiometry (DXA)
Timepoint [9] 339552 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [10] 339553 0
Change in bone density in the lumbar spine and hip assessed using the following techniques:
- Dual-energy X-ray absorptiometry (DXA)
- Peripheral quantitative computed tomography (pQCT)(*)
(*)Only at University of Queensland
Timepoint [10] 339553 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [11] 339554 0
Waist Circumference using the International Diabetes Federation protocol
Timepoint [11] 339554 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [12] 339555 0
Changes in ambulatory blood pressure for 24 hours assessed using Oscar 2 with Sphygmocor Inside.
Timepoint [12] 339555 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [13] 339556 0
Changes in blood pressure assessed assessed using the following:
- Resting brachial systolic and diastolic pressures and central aortic systolic blood pressure: SphygmoCor XCEL PWA (pulse wave analysis).
- Orthostatic blood pressure: SunTech automatic blood pressure monitor.
Timepoint [13] 339556 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [14] 339557 0
Changes in individual measures of arterial stiffness including:
Carotid-femoral pulse wave velocity (PWV), pulse wave analysis (PWA) , central aortic systolic blood pressure, central pulse pressure, augmentation index (AIx): assessed using Sphygmacor Xcel
Timepoint [14] 339557 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [15] 339558 0
Changes in Heart Rate Variability (HRV) assessed using SphygmoCor CvMS
Timepoint [15] 339558 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [16] 339559 0
Changes in individual vascular measures:
- Skin blood flow assessed using Laser Doppler perfusion monitor
- Cerebral blood flow assessed using Transcranial Doppler
- Flow Mediated Dilation assessed using reactivity of the brachial artery
Timepoint [16] 339559 0
At 52 weeks after randomisation. Only at University of Queensland study site.
Secondary outcome [17] 339560 0
Changes in biomarkers of brain pathology and cognitive function:
BDNF, IGF-1, IGF-1 Binding protein 3, HOMA (insulin and glucose), APOE, Serum Cortisol, Epigenetic analysis, GWAS, Nitric Oxide, Vitamin D, Vitamin B12
Timepoint [17] 339560 0
At 52 weeks after randomisation(*). (*) Only at University of Sydney and University of Queensland study sites.
Secondary outcome [18] 339561 0
Change in scores of fear of falling as assessed using the Tinetti Falls-efficacy scale.
Timepoint [18] 339561 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [19] 339562 0
Change in scores of exercise related self-efficacy assessed using the Ewart's Self-efficacy scale.
Timepoint [19] 339562 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [20] 339563 0
Change in self-reported attitude to ageing assessed using the Attitudes to Ageing Questionnaire (AAQ)
Timepoint [20] 339563 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [21] 339564 0
Changes in individual measures of frailty as assessed using:
- FRAIL Scale
- Fried phenotype index
Timepoint [21] 339564 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [22] 339565 0
Change in empathy assessed using the Toronto Empathy Questionnaire
Timepoint [22] 339565 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [23] 339566 0
Change in happiness assessed using the Oxford Happiness Questionnaire
Timepoint [23] 339566 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [24] 339568 0
Change in self-reported measure of depression assessed using the Geriatric Depression Scale (GDS-30 item)
Timepoint [24] 339568 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [25] 339569 0
Change in self-reported size and satisfaction of social support assessed using the Duke Social Support Index.
Timepoint [25] 339569 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [26] 339570 0
Change in self-reported quality of liife score as assessed using the Short Form 36 Health Survey Questionnaire (SF-36)
Timepoint [26] 339570 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [27] 339571 0
Change in individual measures of functional status as assessed using the following instruments:
- KATZ Index of Independence in Activities of Daily Living Assessment (ADL)
- Life Space Assessment Scale
- Use of assistive devices questionnaire
- Use of Community & Health Services questionnaire
Timepoint [27] 339571 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [28] 339572 0
Change in objective sleep quality measurement assessed over 7 days using using a Motion Watch 8 actigraphy system (MW8; camntech) together with a 7-day Consensus Sleep Diary (CSD) 
Timepoint [28] 339572 0
At 52 weeks after randomisation(*). (*) Only in University of British Columbia study site.
Secondary outcome [29] 339573 0
Change in subjective measure of sleep quality assessed using the Pittsburgh Sleep Quality Index (PSQI)
Timepoint [29] 339573 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [30] 339574 0
Change in objective measure of physical activity participation as assessed over 7-days using an Axivity MEMS 3-axis accelerometer and diary.
Timepoint [30] 339574 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [31] 339575 0
Change in individual subjective measures of physical activity participation as assessed using:
- Paffenbarger Physical Activity Questionnaire
- Physical Activity Scale for the Elderly
Timepoint [31] 339575 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [32] 339576 0
Change in individual measures of nutritional status as assessed using:
- Mini Nutritional Assessment (MNA)
- MediCul Index
Timepoint [32] 339576 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [33] 339577 0
Change in alcohol intake assessed using the CAGE Alcohol questionnaire
Timepoint [33] 339577 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [34] 339583 0
Attitudes towards the intervention assessed using semi-structured interviews with participants allocated to HIIT and PRT intervention groups.
Timepoint [34] 339583 0
At 52 weeks after randomisation.
Secondary outcome [35] 339584 0
Adherence to the training protocol assessed using daily exercise attendance logs with record of exercise dose and intensity (HIIT: %HRpeak and PRT %1RM) per session.
Timepoint [35] 339584 0
All exercise sessions during the 52 week intervention period.
Secondary outcome [36] 339594 0
All adverse events related and not related to the intervention. Gathered using weekly health status check and reporting of events throughout the study period.
Timepoint [36] 339594 0
All exercise sessions during the 52 week intervention period.
Secondary outcome [37] 339975 0
Change in Aerobic Capacity measured by indirect calorimetry during a maximal walking treadmill exercise test to fatigue.
Timepoint [37] 339975 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [38] 339976 0
Change in individual measures of muscle strength and power as assessed using:

- Maximal dynamic muscle strength assessed using 1 repetition maximum (1RM) on pneumatic resistance machines: Bilateral leg press, unilateral knee extension, bilateral chest press, bilateral triceps extension.

- Maximal muscle power assessed using pneumatic resistance machines: bilateral leg press, unilateral knee extension, bilateral chest press, bilateral triceps extension.

- Maximal isometric muscle strength assessed using stand-held dynamometer: unilateral hip abduction, unilateral knee extension, unilateral triceps extension, unilateral ankle dorsiflexion. Maximal grip strength using hand-held dynamometer.
Timepoint [38] 339976 0
At 52 weeks after randomisation in all study sites and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.
Secondary outcome [39] 403234 0
Change in global cognition defined as the z-score of the average of all cognitive domains (executive, memory, attention/ working memory, visual spatial, verbal function, information processing and motor skills).
Timepoint [39] 403234 0
At 26 weeks and 52 weeks after randomisation and 5-yearly follow-up (24, 36, 48, 60, 72 months) after randomisation.

Eligibility
Key inclusion criteria
1. Mild Cognitive Impairment (MCI) defined as the presence of all four generally accepted criteria (*)
1.1. Absence of dementia: Clinical Dementia Rating scale (CDR) score below 1.
1.2. No or minimal functional impairment due to cognition: Amsterdam IADL
Questionnaire score equal or greater than 40, rated by informant or participant if no
informant available.
1.3. Subjective memory/cognitive complaint:
a) Cognitive Change Index (CCI) scale:
Participant or informant responds to 3 or more statements with a rating of 3, 4 or 5
(‘mild to severe problem’); OR
b) Subjective memory complaint questionnaire: Participant or informant responds ‘yes’
to question (1): ‘Have you noticed difficulties with your memory?’ and ‘yes’ to questions
2 OR 3: (2)‘Have you been concerned about your memory?, (3)Have you mentioned
any concerns about memory to anyone? respectively, as per recommendations for
the assessment of subjective memory complaint.
1.4. Objective cognitive impairment: Score between 19 and 25 on the Montreal
Cognitive Assessment (MoCA).

2. Age 60 or above

3. Ambulatory without the assistance of a person

4. If from non-English speaking background, must have completed some education in English.

5. Residing in the community, including retirement villages and other senior housing or activity sites (independent level of care)

6. Willing to participate in a study which involves attending supervised exercise sessions 3 days per week for 12 months

There will be 3-stage screening, which includes: Telephone screen by research assistant of participant and informant (if available) for willingness to participate, sedentary status, no exclusionary medical history, no current mayor depression (PHQ-9 score of 9 or below), no planned move, no planned vacation for more than 4 consecutive weeks during the 12 month stuy period. This will be followed by In-person screen to assess criteria for mild cognitive impairment, and later on by In-person screen by physician to perform medical screen and stress testing (to ascertain unstable or unsuitable medical conditions).

(*) Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240-6.
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Diagnosis of dementia
2. High level residential care
3. Non-ambulatory or requiring person to assist when walking
4. 1 stroke in the past 12 months or 2 or more strokes in a lifetime
5. Cardiovascular event/surgery in the past 6 months
6. Progressive neurological disease
7. Inability to read and identify objects on a computer screen and draw on a piece of paper due to vision impairment
8. Current major depressive episode (PHQ-9 score above 9)
9. Psychosis or substance abuse according to DSM-IV criteria.
10. Alcohol abuse (Responded ‘Yes’ to questions 3 and 4 of the CAGE, and reported risky drinking behaviour using NHMRC standard criteria)
11. From a non-English speaking background (NESB) without any education in English
12. Already practicing =150 min moderate intensity exercise, PRT or HIIT regularly
13. Medical contraindications to the planned exercise due to chronic or unstable or terminal diseases
14. Planned move, or planning to be away for 4 or more consecutive weeks during the study period
15. Traumatic brain injury or >2 seizures in the past 12 months

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)
Central randomisation will be performed using WebCRT system, a secure web-based randomisation program hosted by the Norwegian University of Science and Technology (NTNUS).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomly permuted block randomization (block size = 6-8) will be established with stratification for site, gender and age (60-74; 75+). Randomisation will occur at the completion of the baseline assessment. Subjects who dropout prior to completion of baseline testing will not be randomised.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
1.1. The study is powered for our primary hypothesis that both PRT and HIIT will improve Executive Function Domain relative to the control. We will recruit 70 participants per group for a total sample size of 210 across the three sites. This sample size will allow to demonstrate a relative ES of 0.48 (PRT vs. Control or HIIT vs. Control) assuming alpha less than 0.05 and beta of 0.2. Sample size has not been inflated for loss to follow-up, as we will utilise linear repeated measures mixed models and/or General Linear Models in intention-to-treat analyses including all randomised participants irrespective of dropout or adherence. We do not intend to compare PRT to HIIT as we hypothesise both to be effective, therefore the comparisons are for intervention vs. control only.

Justification for sample size:
There are only 2 published studies of high intensity PRT (SMART (1)) or vigorous intensity aerobic exercise (Baker (2)) reporting executive function changes in older adults. Relative ES for Executive Function in SMART for PRT at 6 months was +0.3 and relative ES for Executive Function in Baker for vigorous intensity aerobic exercise at 6 months was +0.68 (average = 0.49 relative ES for these comparisons).

We believe this is conservative for several reasons: a) BRAIN study intervention period is twice as long (12 months versus 6 months), b) BRAIN intervention uses power training with mindful focusing which is potentially more effective than slow velocity PRT (used in SMART), c) BRAIN HIIT intensity at 85-95% peak heart rate is more intense than vigorous intensive aerobic exercise at 75-85% peak heart rate (used in Baker's study), d) The control group in BRAIN (2 days per week of low intensity non-progressive training) is less stimulating than the SMART control group (2-3 days per week calisthenics plus ‘sham cognitive’ training). We anticipate less of an improvement or even a decline in the BRAIN control group at 12 months compared to the SMART control group.

1. Fiatarone Singh MA, Gates N, Saigal N, et al. The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double-blind, double-sham controlled trial. J Am Med Dir Assoc 2014;15:873-80.

2. Baker LD, Frank LL, Foster-Schubert K, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol 2010;67:71-9.

1.2. Statistical Analysis Plan:
An intention-to-treat analytic strategy has been designed with statistician consultation, inclusive of all participants randomised, regardless of dropout. We will analyse all outcomes via repeated measures linear mixed models or GLM of baseline, 6- and 12-month time points, adjusted for baseline values and all covariates selected a priori (age, sex, education, study site) as well as any additional potential confounders associated with the dependent variable of interest identified. Mixed models will be constructed to determine the interaction of GROUP x TIME (i.e., PRT vs. Control and HIIT vs. Control). We will report estimated marginal means (95% CIs), mean differences between groups and Hedges’ bias corrected effect sizes (95% CIs) for all primary and secondary outcomes, and accept significance at the 5% level for the primary outcomes of cognitive function as well as the above pre-specified secondary outcomes. We hypothesise that cognition will improve in both PRT and HIIT relative to Control in these models, and have not powered this as a non-inferiority study. Unspecified secondary outcomes will undergo Bonferroni adjustment for multiple comparisons. Mediation analysis will be conducted to test the hypotheses that cardiovascular and muscular fitness and other central and systemic adaptations differentially mediate the cognitive benefits of PRT and HIIT. Clinical meaningfulness will be assessed in accord with available data on the expected annual rates of change and Minimal Clinically Important Differences (MCIDs) in this cohort for all outcomes where these differences have been defined. Secondary exploratory analyses will include per protocol and complete case analysis based on attendance rate or adherence to the training protocol.


Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Innability to carry out participant assessment and intervention delivery due to COVID-19 restrictions.
Date of first participant enrolment
Anticipated
1/11/2017
Actual
29/01/2018
Date of last participant enrolment
Anticipated
18/12/2020
Actual
2/03/2020
Date of last data collection
Anticipated
2/03/2026
Actual
Sample size
Target
210
Accrual to date
Final
160
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment postcode(s) [1] 17689 0
4072 - University Of Queensland
Recruitment postcode(s) [2] 36015 0
2006 - The University Of Sydney
Recruitment outside Australia
Country [1] 9269 0
Canada
State/province [1] 9269 0
Vancouver

Funding & Sponsors
Funding source category [1] 297690 0
Government body
Name [1] 297690 0
National Health and Medical Research Council (NHMRC)
Country [1] 297690 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Exercise and Sport Science, C42, Faculty of Health Sciences, University of Sydney
75 East Street, Lidcombe, NSW, 2141, Australia
Country
Australia
Secondary sponsor category [1] 296713 0
None
Name [1] 296713 0
Address [1] 296713 0
Country [1] 296713 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298763 0
University of Syndey Human Research Ethics Committee
Ethics committee address [1] 298763 0
Research Integrity & Ethics Administration
Research Portfolio
Level 2, Margaret Telfer Building (K07)
The University of Sydney
NSW 2006 Australia
Ethics committee country [1] 298763 0
Australia
Date submitted for ethics approval [1] 298763 0
28/04/2017
Approval date [1] 298763 0
15/06/2017
Ethics approval number [1] 298763 0
2017/368
Ethics committee name [2] 298780 0
University of Queensland Human Ethics
Ethics committee address [2] 298780 0
Cumbrae-Stewart Building #72
The University of Queensland
St Lucia, QLD 4072
Ethics committee country [2] 298780 0
Australia
Date submitted for ethics approval [2] 298780 0
15/06/2017
Approval date [2] 298780 0
08/08/2017
Ethics approval number [2] 298780 0
2017000853 / 2017 / 368
Ethics committee name [3] 298781 0
The University of British Columbia Clinical Research Ethics Board
Ethics committee address [3] 298781 0
Room 210, 828 West 10th Avenue
Vancouver, BC V5Z 1L8
Ethics committee country [3] 298781 0
Canada
Date submitted for ethics approval [3] 298781 0
07/07/2017
Approval date [3] 298781 0
Ethics approval number [3] 298781 0

Summary
Brief summary
Mild cognitive impairment (MCI) affects at least 10% of older adults globally, and in this cohort the risk of incident dementia is greatly increased from 1-2% per annum to 10-15%. Exercise has been shown to be beneficial for some cognitive outcomes in MCI, although results are heterogeneous, and the optimum exercise dose and modality for preservation or improvement of cognition is not fully defined. Progressive resistance training (PRT) has been shown to have larger effects on cognition than aerobic training in meta-analyses. The limited benefit of some aerobic training studies may be due to insufficient intensities of the intervention, which have produced suboptimal changes in aerobic capacity or other physiological adaptations potentially mechanistic for improved brain function. High intensity interval training (HIIT) results in more beneficial cardiovascular adaptations compared to standard moderate intensity aerobic training. The wealth of data linking aerobic fitness to cognition suggests that HIIT, which approximately doubles the average improvement in aerobic fitness compared to standard training, is of potentially great interest in MCI therefore. However, HIIT has never been tested alone or directly compared to PRT for cognitive benefits in any cohort. We hypothesize that PRT and HIIT will be robust, alternative exercise interventions to improve cognition in MCI. We will conduct a multi-national, randomised controlled trial over 4 years in which we randomise 210 older adults with MCI in Australia and Canada to PRT, HIIT or a sham exercise control group for 12 months. Executive function is the primary cognitive outcome.

Secondary outcomes include other cognitive domains, biomarkers for cognitive decline and distinct mediators of benefit for PRT (e.g., anabolic hormones, lean mass) vs. HIIT (e.g., arterial stiffness, aerobic fitness), functional status, brain structure and connectivity, and psychological wellbeing.

The study is powered for our primary hypothesis that both PRT and HIIT will improve Executive Function Domain relative to the control. We will recruit 70 participants per group for a total sample size of 210 across the three sites. This sample size will allow to demonstrate a relative ES of 0.48 (PRT vs. Control or HIIT vs. Control) assuming alpha less than 0.05 and beta of 0.2. Sample size has not been inflated for loss to follow-up, as we will utilise linear repeated measures mixed models and/or General Linear Models in intention-to-treat analyses including all randomised participants irrespective of dropout or adherence. We do not intend to compare PRT to HIIT as we hypothesise both to be effective, therefore the comparisons are for intervention vs. control only.

BRAIN will be the first trial of HIIT for cognition in any cohort, and the largest and only multi-national study of exercise for Mild Cognitive Impairment ever conducted.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78150 0
Prof Maria Fiatarone Singh
Address 78150 0
Susan Wakil Health Building D18, Western Avenue, The University of Sydney, Camperdown NSW 2006
Country 78150 0
Australia
Phone 78150 0
+61 2 9351 9755
Fax 78150 0
Email 78150 0
[email protected]
Contact person for public queries
Name 78151 0
Trinidad Valenzuela
Address 78151 0
Susan Wakil Health Building D18, Western Avenue, The University of Sydney, Camperdown NSW 2006
Country 78151 0
Australia
Phone 78151 0
+61 2 9351 9669
Fax 78151 0
Email 78151 0
[email protected]
Contact person for scientific queries
Name 78152 0
Maria Fiatarone Singh
Address 78152 0
Susan Wakil Health Building D18, Western Avenue, The University of Sydney, Camperdown NSW 2006
Country 78152 0
Australia
Phone 78152 0
+61 2 9351 9755
Fax 78152 0
Email 78152 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


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
EmbaseStudy protocol for the BRAIN Training Trial: A randomised controlled trial of Balance, Resistance, and INterval training on cognitive function in older adults with mild cognitive impairment.2022https://dx.doi.org/10.1136/bmjopen-2022-062059
N.B. These documents automatically identified may not have been verified by the study sponsor.