Trial Review

The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12621001760864
Ethics application status
Approved
Date submitted
27/08/2021
Date registered
23/12/2021
Date last updated
4/04/2024
Date data sharing statement initially provided
23/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The AUstralian multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention study (AU-ARROW)
Scientific title
The effectiveness of an AUstralian multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention study; a 2-year, single-blind, multi-site, randomised study
Secondary ID [1] 305116 0
AA2020 (protocol number)
Universal Trial Number (UTN)
Trial acronym
AU-ARROW
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer's disease 323338 0
Dementia 323339 0
Condition category
Condition code
Neurological 320909 320909 0 0
Alzheimer's disease
Neurological 320910 320910 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
MULTIDOMAIN LIFESTYLE (ML) INTERVENTION:
There are 4 intervention domains, to be introduced sequentially at group meetings over the first 4 months: the physical activity domain in weeks 1-4, diet education in weeks 5-8, cognitive training in weeks 8-12, and health education & medical monitoring in weeks 13-16. Once participants have received education concerning an intervention domain, they are asked to adopt lifestyle changes advised for that domain for the remainder of the 24-month study.
The physical activity will require time commitment of at least 3 hours/week, brain training 2 hours/week, dietary intervention may involve longer meal preparation time, as well as time to record food intake (15-20 minutes daily, for 1 week/month) in a diet app. Health monitoring will require a maximum of one hour/week. The 42 ML group meetings over the 24 months will last 60-90 minutes each. There are also 27 telehealth dietary counselling calls over the 24 months (15-20 minutes/call). Please note that computer access, home internet and mobile phone usage are inclusion criteria for enrolment.

INDIVIDUAL ML INTERVENTIONS:

Physical activity intervention: 30-minute aerobic exercise for 4 days/week at 70-80% heart rate reserve and at 6-8 rate of perceived exertion (RPE), 20-minutes of resistance training for 2 days/week at 4-6 RPE, and 15-minutes of stretching exercises for 2 days/week at 2-3 RPE, to be carried out at study-designated gyms. Personalised regimes will be provided following physical assessments by accredited exercise physiologists. Exercise regimes will be updated 6 times over the 24 months, as participant fitness improves. Exercise regimes can be carried out by participants in the gyms at a time of their choosing, and participants will also be encouraged to engage in exercise physiologist-approved group classes. Such classes will be run by qualified staff, typically in groups of 10-20/class. The study-associated gyms will have exercise physiology and first aid qualified staff on site at all times, to ensure correct equipment use, and to encourage adherence. All participants will be provided with Fitbits, to be worn all waking hours, preferably also at night, for the full 24 months.
Gym program example:
Resistance training: 2 times/week: Upright Bike 5 minutes, level 1-2; Seated leg press, 2 sets, 8-12 repeats (reps), 30 kg; Lat Pulldown, 2 sets, 8-12 reps, 10 kg; Seated row, 2 sets, 8-12 reps, 10 kg; Seated bench press, 2 sets, 8-12 reps, 10 kg; Seated shoulder press, 2 sets, 8-12 reps, 5 kg.
Cardio training: 4 times/week: Upright bike 5 minutes, speed 1-2, 45% of maximum heart rate (max HR); Upright bike - 10 minutes, speed 3, 65% of max HR; Treadmill, 10 minutes, 6 km/mild incline, 65% max HR; Elliptical trainer, 10 minutes, speed 3, 65% max HR; Cool down, - upright bike 5 minutes, speed 2, 45% max HR.
Balance and Flexibility: 2 times/week: Single leg stance 30 seconds (sec), 3 x each leg; Tandem stance, 30 sec, 2 each way; Calf stretch, 30 sec, 1 each leg; Seated hamstring stretch, 30 sec, 1 each side; Seated gluteal stretch, 30 sec, 1 each side; Seated quadriceps stretch, 30 sec, 1 each side; Seated spine twist, 30 sec, 1 each side; Chest stretch, 30 sec, once; Upper back stretch, 30 sec, once; Triceps stretch, 30 sec, 1 each arm.

Diet Education: Dietary counselling via group education and individual synchronous telehealth, by the study’s accredited dietitians, to support adopting the MIND diet (Mediterranean-DASH intervention for neurodegenerative delay). Dietary advice will be presented in the context of the NHMRC Australian Dietary Guidelines. Following weeks 5-8 diet education sessions, participants will receive monthly telehealth dietary counselling up to month 24, complimented by use of the Easy Diet Diary app.

Cognitive training: Participants will be asked to complete 30-minute sessions of online BrainHQ computerised cognitive training (CCT), 4 times/week, on a home computer or laptop. Trial staff with BrainHQ intervention trial experience will explain use of the program at the initial CCT meetings; and at later CCT-related monthly group meetings, will provide support for increased cognitive and social engagement, and address training and adherence problems.

Medical Monitoring component: Participants will receive Australian medical guideline-based health education to promote self-management of cardiometabolic risk factors through regular blood pathology tests, weight monitoring, blood pressure measurement, and healthy lifestyle goal-setting. Medical Monitoring group meetings will be facilitated by study dietitians, exercise physiologists or other trained study staff.

INITIAL 16 WEEKLY GROUP MEETINGS:
These will all be presented using PowerPoint slides. Group discussion will be encouraged. Groups of approximately 15 participants will be determined at the start of the intervention, and participants will remain in these groups for the 24 months. Each intervention domain will be introduced by specialists for that domain, as mentioned above. ALL group meetings for ML participants will last a maximum of 90 minutes.

Weeks 1-4: Physical activity
In these first 4 group meetings, participants will be introduced to a variety of physical training activities by study exercise physiologists (aerobic, resistance, balance and stretching exercises), and they will be educated on the links between regular physical activity and cardiac health, associated reduction in type 2 diabetes and hypertension, and improved balance. They will be given strategies to promote adherence. Individualised exercise regimes will be explained, as well as how to determine rate of perceived exertion. During these 4 weeks, ML participants will start their gym membership, and they will have equipment use explained by study exercise physiologists and exercise physiology students, during a group visit to the gym.

Weeks 5-8: Diet education
In these 4 meetings, an accredited dietitian will provide nutrition education and teach nutrition literacy skills, to increase the capability, opportunity and motivation of participants to adopt the MIND diet and change their dietary behaviours. Use of the Easy Diet Diary app will be explained. The dietitians will explain MIND diet components, foods to increase intake of and those to limit; NHMRC Australian Dietary Guidelines, healthy serving sizes, recipes, meal timing, snack ideas, and nutrition information label reading.

Weeks 9-12: Cognitive training
At these 4 group meetings, the online BrainHQ CCT program will be explained to participants, who will then be asked to complete 30-minute BrainHQ CCT exercises for 4 days/week at home on a computer or laptop, through month 24. The importance of cognitive and social activity will be explained, and appropriate activities suggested. Meetings will include material to help participants relate CCT activities to real life challenges, and will be facilitated by trial staff with BrainHQ intervention experience.

Weeks 13-16: General health education and medical monitoring
These group meetings will be facilitated by a study dietitian, exercise physiologist, or other trained trial staff member. The meetings will include education focused on cardiovascular and metabolic health, and will include information concerning the links between cardiovascular disease, diabetes type II, hypertension, as well as metabolic and lipid dysregulation and the increased risk of cognitive decline. It will be emphasized that the risk of such conditions can be reduced with regular exercise and diets such as the MIND diet. Participants will be encouraged to have their blood pressure, blood glucose and lipid levels monitored regularly, to facilitate timely treatment and clinical advice for any emerging health conditions.

MONTHLY MEETINGS FROM MONTHS 5 TO 24:
Following the first 16 weeks, there will be monthly facilitated group meetings, with 5 meetings dedicated to each of the four domains above. Topics (domains) will rotate every month, and meetings will be conducted by study exercise physiologists, dietitians, research officers, or other trained study staff. The meetings may involve PowerPoint presentations, and will reinforce each intervention’s purpose, discuss problems, and will encourage adherence. Blood pressure will be measured by a trained research assistant at each meeting.
CLINICAL CONSULTATIONS:
Clinician consultations occur every 6 months (in person at 0, 12 & 24 months, and via “Telehealth” at 6 & 18 months), to discuss 6-monthly blood test results (fasting glucose, lipids, Haemoglobin A1c), vital signs, medication changes and adverse events. The clinician will also provide Australian guideline-based medical advice to support the adoption of a healthier lifestyle. In-person consultations will last 30-45 minutes; Telehealth consultations will last 20-30 minutes.
ADHERENCE CRITERIA:
Participants may be withdrawn from the study if unable to attend one or more of the 6-monthly reviews, if their adherence to the exercise regimen or the CCT drops below 70% for over a month (without good reason, such as unexpected injury, or holiday). Adherence reviews will occur on a 4-6 weekly basis. Physical activity monitoring will be through gym attendance data, downloadable Fitbit data (for example, heart rate and daily steps), also the 3-monthly logs of all activities in the Physical and Mental Activities survey, and the 1-week/month physical activity log. Participant BrainHQ log-in times will be monitored to check program adherence. The 3-monthly MIND diet surveys, the 6-monthly Cancer Council of Victoria food frequency questionnaire, and the diet diary app will provide data on participant dietary changes; however, no minimum adherence level has been set for the diet intervention. Monthly group meetings and dietitian Telehealth, BrainHQ support, gym staff support, exercise physiologists’ reviews and 6-monthly clinician advice will all encourage intervention adherence.
Intervention code [1] 321512 0
Prevention
Intervention code [2] 321513 0
Lifestyle
Comparator / control treatment
The main intervention above will be compared to a "control" group, equal in number, these participants will undergo the following much lower level of intervention:
• Lifestyle Education: Five group meetings over 24 months (whereas main intervention has weekly meetings for 16 weeks, followed by monthly meetings for rest of intervention) facilitated by the trial exercise physiologists, dietitians, or other staff members, in groups of approximately 15 participants. These meetings of 1.5-2 hours will provide education on physical activity, healthy eating patterns (such as the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet), the NHMRC Australian Dietary Guidelines), brain-stimulating activities and health monitoring, and will encourage healthy lifestyle practices. Attendance at these group meetings will be recorded, and participant blood pressure measurements will also be carried out at each of these meetings, either by the facilitator, or another qualified staff member who will also be present for some of the meeting. The group meetings will occur at the clinic sites, and each meeting will include both pre-prepared education presentations (PowerPoint) as well as informal discussion time.
• Australian Guideline-based health monitoring and clinical advice: Annual 30-45 minute consultation with a clinician to discuss 6-monthly blood test results (fasting glucose, lipids, Haemoglobin A1c), blood pressure, body weight measurement, medication changes, any adverse events, and to reinforce the health advantages of adopting a healthier lifestyle. Although part of the intervention, these consultations will occur at the required yearly clinic visits, at which participants also undergo neuropsychological and physical assessments.
• The control participants will also be provided with Fitbits, to be worn all waking hours and preferably also at night, for the study to be able to collect data on participant physical activity.
• The online 3-monthly modified CHAMPS (physical and cognitive activities survey), MIND diet questionnaire and Brief Medical Review survey will provide further monitoring of participant lifestyle changes, as well as health-related monitoring. These regular surveys also serve as a reminder of lifestyle changes that could be adopted by the “control” group. Please note that computer access, home internet and mobile phone usage are all inclusion criteria for enrolment in the study, for allocation to either group.

Control group
Dose comparison

Outcomes
Primary outcome [1] 328696 0
The Primary Outcome is a Global Cognitive composite Score.
The global composite score will include scores from the Free and Cued Selective Reminding Test, Immediate and Delayed Visual Paired Associates, Number Span forward, backward and sequencing, Verbal Fluency by letters (F,A,S) and by Category (animals, vegetables, fruits), Digit Symbol Substitution Test, Immediate and Delayed Story Recall, and Trail making tests A and B.
Timepoint [1] 328696 0
24 months after start of intervention, compared to baseline measurement (0 months).
Secondary outcome [1] 399981 0
Global Cognitive Composite Score (at time points other than for Primary Outcome)
The global composite score will include scores from the Free and Cued Selective Reminding Test, Immediate and Delayed Visual Paired Associates, Number Span forward, backward and sequencing, Verbal Fluency by letters (F,A,S) and by Category (animals, vegetables, fruits), Digit Symbol Substitution Test, Immediate and Delayed Story Recall, and Trail making test A and B.
Timepoint [1] 399981 0
Other time points for the Global Composite Score are at 6, 12 and 18 months after start of intervention.
Secondary outcome [2] 399982 0
Executive Function Composite.
Composite score from tests: Verbal Fluency by Letter (F,A,S) Verbal Fluency by Category (animals, vegetables, fruits), Number span, Digit Symbol Substitution Test (DSST), Trail Making test B.
Experimental measures include Cogstate One Back, and the Clock drawing Test.
Timepoint [2] 399982 0
All above tests are administered at Baseline (0 months) as well as 6, 12, 18 and 24 months after start of intervention, (Cogstate One Back is administered at Baseline, as well as 12 and 24 months after the start of intervention)
Secondary outcome [3] 399991 0
Processing Speed Composite.

Composite score from tests: the Digit Symbol Substitution Test (DSST), Trail Making test A.

Experimental measures include Cogstate Detection and Identification and the Clock drawing test.
Timepoint [3] 399991 0
All above tests administered at Baseline (0 months) as well as 6, 12, 18 and 24 months after start of intervention, (Cogstate Detection and Identification is administered at Baseline as well as 12 and 24 months after intervention start)
Secondary outcome [4] 399995 0
Episodic Memory Composite
Composite score from tests: Free and Cued Selective Reminding Test, Delayed Visual Paired Associates, Delayed Story Recall.
Experimental measures include Cogstate One-Card Learning, Face Name Associative Memory Exam, Behavioral Pattern Separation of Objects
Timepoint [4] 399995 0
All above tests are administered at Baseline (0 months) as well as 6, 12, 18 and 24 months after start of intervention, (Cogstate One-Card Learning, Face Name Associative Memory Exam, Behavioral Pattern Separation of Objects are administered at Baseline, as well as 12 and 24 months after intervention start)
Secondary outcome [5] 402213 0
Clinical Dementia Rating:
Clinical Dementia Rating Sum Of Boxes Score.
Timepoint [5] 402213 0
Administered at Baseline, as well as 12 and 24 months after start of intervention.
Secondary outcome [6] 402214 0
Risk of Type 2 Diabetes/metabolic syndrome
Assessed by Blood Pathology tests - Fasting Blood glucose and Haemoglobin A1c tests
Timepoint [6] 402214 0
Data from fasting blood samples collected at Baseline as well as 6, 12, 18 and 24 months after start of intervention
Secondary outcome [7] 402215 0
Hypertension
Blood pressure measured using a blood pressure monitor
(Sphygmomanometer)
Timepoint [7] 402215 0
Measures taken at Baseline then monthly up to 24 months following the start of the intervention for the Multidomain intervention group (ML participants). Blood pressure measured at Baseline then 3-monthly for the Health Education and coaching group (HC participants)
Secondary outcome [8] 402216 0
Risk of Cardiovascular disease
Tests include:
Blood Pathology from fasting blood samples : Lipid profile including LDL-cholesterol, HDL-cholesterol, Total Cholesterol, triglycerides.
Timepoint [8] 402216 0
Blood pathology tests are carried out at Baseline and then at 6, 12, 18 and 24 months after the start of the intervention.
Secondary outcome [9] 402217 0
Mindfulness, as measured using the Five-Facet Mindfulness Questionnaire.
Timepoint [9] 402217 0
Questionnaire completed by participants at Baseline, then 12 and 24 months after start of intervention
Secondary outcome [10] 402219 0
Loneliness
Measured using the De Jong Gierveld Loneliness Scale
Timepoint [10] 402219 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [11] 402220 0
Social Isolation, as measured using the Lubben Social Network Scale
Timepoint [11] 402220 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [12] 402221 0
Psychological Wellbeing, as assessed using the Depression, Anxiety, and Stress Scale (DASS)
Timepoint [12] 402221 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [13] 402223 0
Overall dietary changes, as measured using the Cancer Council of Victoria Food Frequency Questionnaire (CCV-FFQ)
Timepoint [13] 402223 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [14] 402224 0
MIND diet adherence, as measured using the Cancer Council of Victoria Food Frequency Questionnaire (CCV-FFQ)
Timepoint [14] 402224 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [15] 402225 0
Physical Function composite, as assessed using the Short Physical Performance Battery, 400 m walk test and Grip Strength Test (using a hand dynamometer)
Timepoint [15] 402225 0
These assessments are carried out on all participants at Baseline, and at 6, 12, 18 and 24 months following the start of the intervention.
Secondary outcome [16] 402226 0
Quality of Life, as measured using the Euroqol-5D test.
Timepoint [16] 402226 0
This questionnaire is administered at Baseline, and at 12 and 24 months after the start of the intervention
Secondary outcome [17] 402227 0
General Health Status, as measured using the Short Form Health Survey (SF-36)
Timepoint [17] 402227 0
This survey is completed by all participants at Baseline and at 12 and 24 months following the start of the intervention.
Secondary outcome [18] 402229 0
Subjective cognitive Impairment, as determined by the McCusker Subjective Cognitive Impairment Inventory (McSCI) and Everyday cognition (ECog) tests
Timepoint [18] 402229 0
Questionnaires are completed at Baseline and at 12 and 24 months following the start of the intervention.
Secondary outcome [19] 402230 0
Everyday Functional Status, as assessed by the Instrumental Activities of Daily Living (IADL) Scale (partner form)
Timepoint [19] 402230 0
This questionnaire is completed by the participant's study partner at Baseline, and at 12 and 24 months following the start of the intervention.
Secondary outcome [20] 402231 0
Sleep quality, as assessed by the "Pittsburgh Sleep Quality Index" (PSQI)
Timepoint [20] 402231 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [21] 402232 0
Cognition, as assessed by the BrainHQ tests
Timepoint [21] 402232 0
BrainHQ assessment is completed by all participants at clinic visits, at Baseline, then 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [22] 402233 0
Safety, as assessed by the Brief Medical Review Survey, and data from adverse event report forms.
Timepoint [22] 402233 0
The Brief Medical Review Survey is administered every 3 months up to 24 months following the start of the intervention. Adverse Event (AE) report forms will be completed as necessary, from recruitment up until the last clinic visit.
Secondary outcome [23] 402234 0
Brain amyloid-beta deposition levels, provided as a Centiloid measure.
Measured by Brain Positron Emission Tomography (PET), completed using one of the following Alzheimer's disease beta-amyloid-specific tracers: 18F-labelled Florbetaben, or 18F-NAV4694 (also known as flutafuranol F 18)
Timepoint [23] 402234 0
PET scans are completed at Baseline and at 24 months following the start of the intervention.
Secondary outcome [24] 402241 0
Hyperspectral retinal imaging investigations.
Retinal imaging completed with a hyperspectral eye camera
Timepoint [24] 402241 0
Retinal scans to be completed at Baseline and at 24 months following start of intervention.
Secondary outcome [25] 402242 0
Sleep Apnoea markers,
measured using WatchPAT (TM) devices worn for 2 consecutive nights.
Timepoint [25] 402242 0
WatchPAT (TM) devices will be worn for 2 consecutive nights at Baseline, and at 12 and 24 months following start of intervention
Secondary outcome [26] 402243 0
Alzheimer's Disease preclinical blood biomarker investigations
Assay systems include Single Molecular Array (SIMOA), and/or immunoprecipitation followed by mass-spectrometry. Biomarkers to be investigated include Plasma Alzheimer's disease amyloid-beta peptide isoforms, plasma tau (total and phosphorylated isoforms), glial fibrillary acidic protein, and neurofilament light.
Timepoint [26] 402243 0
Fasted blood samples collected at Baseline, and 12 and 24 months following start of intervention.
Secondary outcome [27] 402284 0
Feasibility,
The data for this outcome includes adherence data from gym attendance, BrainHQ login frequency, the Cancer Council of Victoria Food Frequency Questionnaire, group meeting attendance, Fitbit data, assessment completion (self-report and objective measures), and the Participant End of Study Feedback Survey.
Timepoint [27] 402284 0
The data for this outcome comes from multiple sources as listed above, which will be collected throughout the study, and will be evaluated following the conclusion of the study.
Secondary outcome [28] 402403 0
Urine analysis for potential early Alzheimer's disease biomarkers
Samples will be investigated using liquid-chromatography mass spectrometry (LCMS), immunoassay, and/or nuclear magnetic resonance spectroscopy. The measurements may include, but are not limited to, inflammatory markers, biogenic amines, short chain fatty acids, cytokines, and small molecules such as organic acids, sugars and phenolics
Timepoint [28] 402403 0
Urine samples will be collected at Baseline, and at 6, 12, and 24 months following start of intervention.
Secondary outcome [29] 403314 0
Changes in physical activities, as measured using the Physical and Mental Activities Questionnaire, (Modified "Community Healthy Activities Model Program for Seniors" CHAMPS questionnaire)
Timepoint [29] 403314 0
The Modified CHAMPS questionnaire is completed by all participants at Baseline and every 3 months up to 24 months, after the start of the intervention.
Secondary outcome [30] 403315 0
Changes to cognitive activities, as measured using the supplementary questions included in our modified Physical and Mental Activities Questionnaire, (Modified "Community Healthy Activities Model Program for Seniors" CHAMPS questionnaire),
Timepoint [30] 403315 0
The Modified CHAMPS questionnaire is completed by all participants at Baseline and every 3 months up to 24 months, after the start of the intervention.
Secondary outcome [31] 403316 0
Pain severity, as measured using the Brief Pain Inventory
Timepoint [31] 403316 0
This questionnaire is administered to all participants at Baseline, and at 6, 12, 18 and 24 months following the start of the intervention.
Secondary outcome [32] 403317 0
Impact of pain on daily function, as measured using the Brief Pain Inventory
Timepoint [32] 403317 0
This questionnaire is administered to all participants at Baseline, and at 6, 12, 18 and 24 months following the start of the intervention.
Secondary outcome [33] 403318 0
Brain MRI measures, obtained following analysis of Brain MRI data. There are several different MRI measures, and due to space constraints, these outcomes have been listed in the attached supporting (pdf) document.
Timepoint [33] 403318 0
Participant brain MRI scans are to be completed at Baseline and at 24 months following the start of the intervention.
Secondary outcome [34] 403319 0
Motivation to change Lifestyle, as assessed by the Motivation to Change Lifestyle and Health Behaviours for Dementia Risk Reduction (MCLHB-DRR) questionnaire.
Timepoint [34] 403319 0
Questionnaire completed by all participants at Baseline and 24 months after start of intervention.
Secondary outcome [35] 403320 0
Dietary change monitoring, assessed from Easy Diet Diary app data and diet history information (ML participants only), and the 3-monthly MIND diet survey (all participants).
Timepoint [35] 403320 0
Easy Diet Diary app data is collected for 1 week/month from months 2 to 24 of the intervention (ML participants only), dietitian telehealth consultations will occur at least monthly from months 2 to 24 of the intervention (ML participants only). The MIND Diet Survey is completed online by all participants, during initial screening, then 3-monthly up to 24 months from the start of the intervention.
Secondary outcome [36] 403323 0
Changes in physical activity, using data obtained from Fitbit activity trackers
Timepoint [36] 403323 0
All participants are provided with Fitbits at Baseline visits, and data will be collected continuously for 24 months from the start of the intervention.
Secondary outcome [37] 403324 0
Changes in the use of medical resources, as assessed in the 6-monthly (ML participants) or yearly (HC participants) clinician consultation reports, in combination with information from the online Brief Medical Review surveys. (composite outcome)
Timepoint [37] 403324 0
Clinician consultation occurs every 12 months for HC participants and 6-monthly for the ML participants. The Brief Medical Review survey is completed online every 3 months by all participants.
Secondary outcome [38] 403325 0
Hearing, as assessed by the Speech, Spatial, and Qualities of Hearing Scale-short form (SSQ-12)
Timepoint [38] 403325 0
This questionnaire is administered to all participants at Baseline, and at 6, 12, 18 and 24 months following the start of the intervention.
Secondary outcome [39] 403326 0
Insomnia, as assessed by the Insomnia Severity Index (ISI)
Timepoint [39] 403326 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.
Secondary outcome [40] 403327 0
Risk of Obstructive Sleep Apnoea, as assessed by the STOP Bang Questionnaire
Timepoint [40] 403327 0
This questionnaire is completed by all participants at Baseline, then at 6, 12, 18 and 24 months after start of intervention.

Eligibility
Key inclusion criteria
• Age 55 – 79 years
• Sedentary lifestyle
• Lives independently
• Not allergic to seafood
• Must have internet access, mobile phone, and computer or iPad at home
• Lives in a region where the interventions will be delivered
• Participants must be willing to complete all study-related activities for the 24 months of the trial
• Participants must be able to provide written consent in English.
• Participants must not have any physical disabilities that would preclude them being able to complete any of the lifestyle intervention domains.
• Does not plan to travel outside of the home geographic area (to the extent that attending group meetings, assessment visits, or gym sessions (if in the ML group) are not feasible), for more than 1 month at a time, or for more than 3 months over the course of the study
• Poor diet
• Current absence of significant cognitive impairment according to Clinical Dementia Rating (CDR) scale (less than or equal to 0.5), or CDR-sum of boxes (less than or equal to 1), also passing a validated telephone administered cognitive battery (telephone MoCA score greater than or equal to 18)
• Needs to satisfy at least 1/4 of the following 4 criteria:
1- Increased vascular and /or metabolic risk factors, as indicated by systolic blood pressure greater than or equal to 125 mm Hg at screening, or on treatment for hypertension, LDL cholesterol at greater than or equal to 3.0 mmol/L at screening, TG/HDL ratio greater than 1.0 at screening, or on treatment for dyslipidaemia, or glycated haemoglobin at 6% (42 mmol/L) or higher at screening, or on treatment for diabetes (except insulin)
2- Aged 70 or over
3- First or second degree family history of significant cognitive decline/memory problems/dementia (including parents, siblings, aunts/uncles, grandparents and/or half-siblings)
4- Body Mass Index (BMI) 30-39.9
Minimum age
55 Years
Maximum age
79 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Body Mass Index (BMI) greater than or equal to 40
• Regular use of prescribed or over the counter medication with cognitive adverse effects, including opiates/opioids, anticholinergics, antiepileptics, or benzodiazepines; also use of mood-stabilising psychotropics, psychostimulants, or antipsychotics within the last 3 months
• On anti-depressants, unless on stable dose for 4 weeks prior to screening
• Regular use of systemic corticosteroids
• Any significant neurologic disease, including any form of dementia, mild cognitive impairment, Parkinson's disease, Huntington's disease, normal pressure hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder, subdural haematoma, multiple sclerosis, or history of significant head trauma with persistent neurologic sequelae or known structural brain abnormalities
• Current or past use of medications for memory impairment or AD (e.g., cholinesterase inhibitors, memantine)
• Any history of bipolar disorder or schizophrenia as per DSM V (Diagnostic and statistical manual of Mental Disorders V) criteria
• History of major depression in last 6 months
• History of alcohol or substance abuse or dependence within the past 2 years, as per DSM V criteria, or pattern of alcohol use over the last 3 months averaging in excess of 21 standard drinks per week or 4 standard drinks in any given day
• Significant cardiovascular disease (including NYHA Class III or IV congestive heart failure, clinically significant aortic stenosis, history of cardiac arrest, or uncontrolled angina)
• Serious conduction disorder (e.g. 3rd degree heart block), uncontrolled arrhythmia, or new Q waves or ST-segment depressions (>3 mm) on ECG (treated atrial fibrillation for more than 1 year or occasional premature ventricular contractions on ECG are not exclusions)
• Myocardial infarction, major heart surgery (i.e. valve replacement, bypass surgery, stent placement, angioplasty), deep vein thrombosis, or pulmonary embolus in the past 6 months
• Large vessel stroke in the past 2 years
• History of Transient Ischaemic Attack (TIA) or small vessel stroke in the last 6 months; TIA occurring more than 6 months ago with residual effects
• Lung disease requiring oral corticosteroids or oxygen
• Clinically significant abnormalities in laboratory blood test results as per site study clinician
• Renal disease (eGFR needs to be over 30 mL/min)
• Past or current use of insulin to treat type 2 diabetes
• Current or past history of gall bladder stones (cholecystectomy accepted)
• History within the last 2 years of treatment for primary or recurrent malignant disease, excluding non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen post-treatment
• History of hip fracture, joint replacement, or spinal surgery within last 6 months
• Currently receiving physical therapy or cardiopulmonary rehabilitation
• Currently receiving dietitian advice
• History of a malabsorptive bariatric procedure (gastric bypass, biliopancreatic diversion); or other bariatric procedures involving restriction (i.e., sleeve, band)
• Site PI/Study Clinician discretion regarding medical status, appropriateness of participation or concern about intervention adherence
• Enrolment in another clinical trial, either currently, or in the 30 days prior to randomisation

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)
Randomisation will be done by computer, This will only occur after all screening has been completed, eligibility has been determined, and participants have been informed of their eligibility to be in the study, Group allocation (randomisation) will then be performed by an experienced trial assistant independent from the AU-ARROW study team, and participants will be informed by phone and sealed letter of their group allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be carried out in REDCap, through the REDCap randomisation module. REDCap is the main data storage system we are using for the study.
In this randomised, controlled, single-blind study design, eligible participants will be randomised to either ML or HC study arms on a 1:1 basis. The ‘allocationTable’ function within the ‘redcapAPI’ R library will be used to generate an allocation table which will be uploaded for use via the REDCap Randomisation Module. Randomisations in the allocation table will be stratified using the REDCap entries for by sex (male or female), age group at screening (less than 70, or greater than or equal to 70), and study site (Perth or Sydney). Allocations will also be based on blocked randomisation, with block sizes known only to the study statistician and data manager. To ensure that no strata’s allocations are exhausted throughout the course of the study due to high drop-out rates or increased recruitment, the ‘replicates’ parameter passed to ‘allocationTable’ for each stratum will be set to 600 (i.e., the total sample size across strata).
Misrandomisations will be documented but reallocation will not occur and the original randomisation assignment will be maintained. In the event of a REDCap outage, randomisation will be delayed until the service resumes, and no manual randomisations will be performed.
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
This is a Single-blind clinical trial - Study staff conducting neuropsychological assessments and physical assessments are blinded to group allocation. The participants, dietitians, one exercise physiologist at each site, clinicians and the trial coordinators are aware of group allocation.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Analysis plan:
Together with the US-POINTER trial, AU-ARROW is part of the collaborative WW-FINGERS initiative. A comprehensive statistical analysis plan (SAP), is being finalised in close collaboration with the US-POINTER statistical team. The SAP will be finalised and approved by the Steering committee prior to formal data lock and unblinding of study data for interim analyses (3-month preliminary analysis and 12-month progress analysis). A final analysis will also be completed at the conclusion of the study.
The analyses will incorporate the intention-to-treat (ITT) principle, in which data from all participants will be analysed according to their original intervention assignment and full follow-up will be attempted regardless of intervention adherence. All results will be reported as point estimates (mean differences across groups) and interval estimates (95% confidence intervals). All tests of significance for the primary outcomes will be two-sided (will test simultaneously for relative differences in either direction between intervention groups) with adjustments made for multiple comparisons. All tests of significance for the secondary outcomes will be one-sided with no adjustments made for multiple comparisons. A p-value of 0.05 will be considered statistically significant. Differences between the two treatment arms post-intervention will be assessed using a MMRM analysis approach for all outcomes. Cross-sectional evaluation at the end of the study between the two study arms will be evaluated using Student’s t-tests for normally distributed data, X2 testing for categorical data and Kruskal-Wallis testing for non- normally distributed data.

Sample size calculations:
Sample size calculations were derived from the US-POINTER study (sister study, which we are trying to replicate protocol, in an Australian setting), which has a sample size of 2000 participants. The US-POINTER sample size was chosen to provide a minimum of 85% power at the (two-sided) 0.05 significance level to detect a mean difference 0.03SD/year in the primary outcome – a composite score of global cognition that is comparable across cohorts. The AU-ARROW target sample size of 600 participants was chosen to obtain 80% power to detect a 0.05 SD/year change in the primary outcome variable. As AU-ARROW is being conducted in the context of several other similar trials, it is not a stand-alone assessment and will also contribute to the power of the overarching international initiative. Under the supervision of study statistician, and site clinical trial coordinators, all the WA site data will be merged into the NSW site database at regular intervals.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/01/2022
Actual
23/05/2022
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
600
Accrual to date
161
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA

Funding & Sponsors
Funding source category [1] 309504 0
Government body
Name [1] 309504 0
National Health and Medical Research Council Medical Research Future Fund (NH&MRC MRFF)
Country [1] 309504 0
Australia
Funding source category [2] 310046 0
Charities/Societies/Foundations
Name [2] 310046 0
US Alzheimer's Association
Country [2] 310046 0
United States of America
Primary sponsor type
University
Name
Macquarie University
Address
Balaclava Road, North Ryde, NSW 2109
Country
Australia
Secondary sponsor category [1] 311094 0
University
Name [1] 311094 0
Edith Cowan University
Address [1] 311094 0
270 Joondalup Drive, Joondalup WA 6027
Country [1] 311094 0
Australia
Secondary sponsor category [2] 311095 0
Charities/Societies/Foundations
Name [2] 311095 0
Australian Alzheimer's Research Foundation
Address [2] 311095 0
8 Verdun Street, Nedlands, 6009, WA
Country [2] 311095 0
Australia
Secondary sponsor category [3] 318416 0
Charities/Societies/Foundations
Name [3] 318416 0
Australian Lions Foundation
Address [3] 318416 0
31-33 Denison St, Newcastle West NSW 2302
Country [3] 318416 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309290 0
Macquarie University Human Research Ethics Committee (Medical Sciences Committee)
Ethics committee address [1] 309290 0
Ethics committee country [1] 309290 0
Australia
Date submitted for ethics approval [1] 309290 0
22/10/2020
Approval date [1] 309290 0
03/12/2020
Ethics approval number [1] 309290 0
Reference No:52020921222545

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

Contacts
Principal investigator
Name 113646 0
Prof Ralph Martins
Address 113646 0
Department of Biomedical Sciences,
Faculty of Medicine, Health and Human Sciences,
Macquarie University,
75 Talavera Road,
North Ryde, 2109 NSW
Country 113646 0
Australia
Phone 113646 0
+61 2 9850 4573
Fax 113646 0
Email 113646 0
[email protected]
Contact person for public queries
Name 113647 0
Stephanie Fuller
Address 113647 0
Department of Biomedical Sciences,
Faculty of Medicine, Health and Human Sciences,
Macquarie University,
75 Talavera Road,
North Ryde, 2109 NSW
Country 113647 0
Australia
Phone 113647 0
+61 2 9850 2774
Fax 113647 0
Email 113647 0
[email protected]
Contact person for scientific queries
Name 113648 0
Ralph Martins
Address 113648 0
Department of Biomedical Sciences,
Faculty of Medicine, Health and Human Sciences,
Macquarie University,
75 Talavera Road,
North Ryde, 2109 NSW
Country 113648 0
Australia
Phone 113648 0
+61 2 9850 4573
Fax 113648 0
Email 113648 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
participant confidentiality


What supporting documents are/will be available?




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.