Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001190897
Ethics application status
Approved
Date submitted
27/05/2021
Date registered
6/09/2021
Date last updated
3/06/2022
Date data sharing statement initially provided
6/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Reducing Sleep Apnoea for the Prevention of Dementia
Scientific title
REducing Sleep Apnoea for the PrEvention of Dementia (REShAPED): a multi-site feasibility randomised controlled trial
Secondary ID [1] 304329 0
Nil known
Universal Trial Number (UTN)
Trial acronym
REShAPED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep apnoea 322085 0
Subjective cognitive impairment 322086 0
Mild cognitive impairment 322536 0
Condition category
Condition code
Respiratory 319801 319801 0 0
Sleep apnoea
Neurological 319802 319802 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
CogSleep OSA Treatment: The intervention is to treat hypoxaemia due to obstructive sleep apnoea (OSA) in older adults for two years using a number of proven modalities including continuous positive airway pressure (CPAP), mandibular advancement splints (MAS), positional therapy and oxygen therapy as determined by the medical officers. In most cases CPAP will be first line therapy. The frequency of the different modalities will be different for each individual as will the number and type of modalities used by each individual. Once provided to participants, all modalities are self-administered and individual will be ask to use the treatment nightly.

Description of different modalities available:
- CPAP is a machine that delivers air pressure through a face mask which covers participants nose or is placed over their nose and mouth while sleeping.
- Mandibular advancement splints (MAS): These devices consist of a customized mouth guard used to treat OSA. MAS function by comfortably positioning the patient’s mandibular forward, clearing the obstructed airway and are only worn while the patient is sleeping. A dentist will need to take dental impressions from the patient to create the custom-made device.
- Positional therapy: This device is a compact and is worn across participant’s chest in a soft, adjustable strap. This device delivers gentle vibrations that prompt the participant to shift to his/her side without disturbing his/her sleep.
- Oxygen therapy: The oxygen is delivered through plastic tubing known as nasal cannula, typically at a rate of several liters per minute.

A decision to step down to other modalities will be based on a treatment plan developed by CogSleep investigators in conjunction with the clinical opinion of the medical officer.

Additionally, participants will receive up to 8 behavioural program sessions (30-60 minutes each) over a 6-month period. These sessions will be either face-to-face or telehealth consultations as decided between the trained sleep apnea therapist and the participant. The program will incorporate a collaborative approach using individualised and structured goal-setting in combination with motivational interviewing to further facilitate treatment adherence, engagement and maximal outcomes. The duration of the intervention will be 24 months, with OSA treatment occurring throughout, and the behavioural program for the first 6 months of the study.

Treatment adherence using compliance reports from devices will be assessed through the 6 months program and then at 6 and 24 months. Treatment response will be assessed by hypoxic burden (sleep apnea severity) at 6 and 24 months.

All participants in both arms will receive 8 psycho education emails for the first 6 months. The psychoeducation material was based on information developed in previous studies from our research lab, and updated to reflect more recent advances in evidence/best practice, as well as to better suit delivery via email. The emails will contain simple and practical tips about sleep hygiene (e.g. the impact of sleep on health, creating a sleep-conducive bedroom, sleep and memory, age-related sleep changes) and healthy brain ageing (e.g. importance of keeping the brain active, diet and exercise, brain health, depression and anxiety).
Intervention code [1] 320680 0
Treatment: Devices
Comparator / control treatment
No treatment control group: Participants randomised to this arm of the study will receive 8 psycho education emails for the first 6 months. After completion of the trial at 24 months, the control participants will be invited to be assessed by a sleep clinician and offered treatment options.

There will be no OSA treatment restrictions in this group. Participants will not be barred from seeking independent advice and treatment for sleep apnoea. Any such treatments will be recorded at each visit.
Control group
Active

Outcomes
Primary outcome [1] 327663 0
Acceptability as assessed by proportion of eligible participants who agree to be randomised, measured using audit of study records. Target proportion is 50%.
Timepoint [1] 327663 0
Before randomization of each participant
Primary outcome [2] 327664 0
The 6-month and 24-month measurements of ODI will be averaged (with equal weight) and compared to baseline on the WatchPAT device. The target average reduction must be >=30%.
Timepoint [2] 327664 0
6 and 24 months post-randomisation
Primary outcome [3] 327665 0
Tolerability of the outcome assessment is assessed by percentage of participants from whom we have complete data from either the Paired Associate Learning (PAL) test or the Rey Auditory Verbal Learning Test (RAVLT). Target proportion >=60%.
Timepoint [3] 327665 0
2 years after randomization.
Secondary outcome [1] 396149 0
Number of drop-ins (person who is randomized into the control group who then receives a recognized OSA treatment [no general weight loss]) as determined by interviewing the participant at each follow-up.
Timepoint [1] 396149 0
At the conclusion of study.
Secondary outcome [2] 396150 0
Number of drop-outs (person who is assigned to the active treatment arm but declines to receive further OSA treatment) as determined by interviewing the participant at each follow-up.
Timepoint [2] 396150 0
At the conclusion of study.
Secondary outcome [3] 396151 0
Number of adverse events (e.g. CPAP skin marks or rashes, dryness in the nose or mouth; tenderness of the teeth and jaws due to MAS, assessed by patient self-report)
Timepoint [3] 396151 0
2 years after intervention commencement.
Secondary outcome [4] 396152 0
Type of adverse events self-reported by participants.
Timepoint [4] 396152 0
2 years after intervention commencement
Secondary outcome [5] 396153 0
Exploratory outcome: Visual Memory (mean number of attempts made by a subject needed for them to successfully complete the stage) as assessed by the PAL subset from the CANTAB.
Timepoint [5] 396153 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [6] 396154 0
Visual Learning (number of times the subject chose the incorrect box for a stimulus adjusted for the estimated number of errors on trials not completed) as assessed by the Paired Associate Learning (PAL) subtest from the Cambridge Neuropsychological Test Automatic Battery (CANTAB).
Timepoint [6] 396154 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [7] 396155 0
Exploratory outcome: Cognitive flexibility (number of correct responses across all assessed trials) as assessed by the Multitasking test (MTT) from the CANTAB.
Timepoint [7] 396155 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [8] 396156 0
Cognitive flexibility (number of incorrect responses across all assessed trials) as assessed by the Multitasking test (MTT) from the CANTAB.
Timepoint [8] 396156 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [9] 396157 0
Exploratory outcome: Sustained attention (number of omission errors) as assessed by the Multitasking test (MTT) from the CANTAB.
Timepoint [9] 396157 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [10] 396158 0
Exploratory outcome: Sustained attention (number of commission errors) as assessed by the Multitasking test (MTT) from the CANTAB.
Timepoint [10] 396158 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [11] 396159 0
Processing speed (median response latency in milliseconds) as assessed by the Multitasking test (MTT) from the CANTAB.
Timepoint [11] 396159 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [12] 396160 0
Target detection (A’) as assessed by the Rapid Visual Processing (RVP) test from the CANTAB.
Timepoint [12] 396160 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [13] 396161 0
Exploratory outcome: Target detection (probability of a false alarm) as assessed by the Rapid Visual Processing (RVP) test from the CANTAB.
Timepoint [13] 396161 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [14] 396162 0
Exploratory outcome: Processing speed (Median response latency in milliseconds) as assessed by the Rapid Visual Processing (RVP) test from the CANTAB.
Timepoint [14] 396162 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [15] 396163 0
Verbal learning (number of correct answers on Trials 1-5) as assessed by the Rey Auditory Verbal Learning Test (RAVLT).
Timepoint [15] 396163 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [16] 396164 0
Verbal memory (number of correct answers on Trial 7) as assessed by the Rey Auditory Verbal Learning Test (RAVLT).
Timepoint [16] 396164 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [17] 396165 0
Verbal retention (number of correct answers on Trial 7/5 (percent retention)) as assessed by the Rey Auditory Verbal Learning Test (RAVLT).
Timepoint [17] 396165 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [18] 396166 0
Executive functioning (cognitive flexibility) as assessed by the Trailmaking Test Part B.
Timepoint [18] 396166 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [19] 396167 0
Executive functioning (response inhibition) as assessed by condition 3 of the DKEFS Colour Word Interference Test.
Timepoint [19] 396167 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [20] 396168 0
Exploratory outcome: Processing speed (number correct) as assessed by the Symbol Digit Modalities Test (oral version).
Timepoint [20] 396168 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [21] 396169 0
Exploratory outcome: Overall health status (number of points) as assessed by the EuroQol 5-dimension scale (EQ5D).
Timepoint [21] 396169 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [22] 396170 0
Exploratory outcome: Health related quality of life (number of points) as assessed by the Australian Quality of Life Inventory,
Timepoint [22] 396170 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [23] 396171 0
Exploratory outcome: Brain morphology changes (hippocampal volume, temporal lobe cortical thickness, entorhinal cortex and WML volume) assessed using Magnetic Resonance Imaging in n=90.
Timepoint [23] 396171 0
baseline and 2 years after intervention commencement
Secondary outcome [24] 396173 0
Exploratory outcome: Depressive symptom severity (number of points) using the Patient Health Questionnaire-9 (PHQ-9).
Timepoint [24] 396173 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [25] 396174 0
Exploratory outcome: High-sensitivity C - reactive protein values (mg/L) from blood test.
Timepoint [25] 396174 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [26] 396176 0
Exploratory outcome: Neurofilament light chain (Nfl) values (pg/mL) from blood test. .
Timepoint [26] 396176 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [27] 396177 0
Exploratory outcome: Glial fibrillary acidic protein (GFAP) values ((ng/mL) from blood test.
Timepoint [27] 396177 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [28] 396178 0
Exploratory outcome: p-tau-181 values (ng/µL) from blood test.
Timepoint [28] 396178 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [29] 396179 0
Exploratory outcome: p-tau-217 values (pg/mL) from blood test.
Timepoint [29] 396179 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [30] 396181 0
Exploratory outcome: Apnea/hypopnea index (pAHI) over the whole night as assessed by number of Apnea and Hypopnea events per hour of actual sleep on the WatchPAT device.
Timepoint [30] 396181 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [31] 400562 0
Exploratory outcome: Oxygen saturation mean (%) as assessed by the WatchPat device.
Timepoint [31] 400562 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [32] 400563 0
Exploratory outcome: Total time (minutes) of oxygen saturation below 90% as assessed by the WatchPat device.
Timepoint [32] 400563 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.
Secondary outcome [33] 410371 0
Percentage of referred participants who screen positive to sleep apnoea (ODI>=10) at screening using the WristOx device.
Timepoint [33] 410371 0
Prior to randomisation
Secondary outcome [34] 410372 0
Executive Functioning (response inhibition with set shifting) as assessed by Condition 4 of the DKEFS Colour Word Interference Test.
Timepoint [34] 410372 0
2 years after intervention commencement. The model will also include the same test information collected at baseline and 6 months.

Eligibility
Key inclusion criteria
1. Subjective cognitive decline (new onset cognitive decline within the last 5 years)
2. Able to provide informed written consent
3. Fluent English literacy
4. Adults aged between 50-75 years
5. Mild – Severe OSA based on an average ODI equal to or greater to 10 with 3% oxygen desaturation determined by oximetry over two nights.
Minimum age
50 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous or current CPAP or mandibular device or oxygen user or body position device user (within past 3 months)
2. People highly dependent on medical care
3. Previous diagnosis of dementia or MMSE less than 24
4. Previous major head injury or loss of consciousness equal to or greater than 30 minutes
5. Previous or current substance misuse or use of medicinal cannabis
6. Previous or current neurological disorder diagnosis (e.g. Parkinson’s, multiple sclerosis, epilepsy, stroke)
7. Psychiatric or developmental disorders (e.g. Schizophrenia, bipolar disorder, autism)
8. Current major depression diagnosis
9. Major sleep disorders (e.g. narcolepsy, severe restless legs syndrome, severe insomnia disorder unrelated to a sleep-breathing disorder)
10. Shift workers
11. Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
12. Currently participating in or has participated in a research study of an investigational agent or device within 4 weeks of enrolment.
13. Prohibited medications
Ongoing use of Anti-psychotic medication, mood stabilizers, benzodiazepines, wakefulness promoters and stimulants. Stable dosing (30 days prior to enrolment) of anti-depressants for non-major depressive disorder permitted. Melatonin or Circadin to be ceased before randomisation

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 by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation) which will be stratified by sites.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
N/A
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
There are three primary feasibility targets which are listed in the primary outcome section. We will compare our observed raw proportions against these targets. Our go rule is that we meet the criteria of all three primary outcomes. Our protocol modification and adjustment rule is that we are within 10% of meeting one or more of the criteria. However, our stop rule will trigger if one or more of our raw proportions is more than 10% away from meeting the criteria of any of the three listed outcomes.

The criteria will be considered to be met when the raw proportion observed is greater than the target proportion listed below for each of the three criteria (i.e., these outcomes are not subjected to statistical probability testing).

Between groups comparisons will be tested using Fisher’s Exact Test when they are proportions and using independent group t-tests or Mann-Whitney U Test, as appropriate.

Continuous secondary and exploratory outcomes will be analysed using mixed model analyses of variance. Participants and sites will be classed as random effects and treatment and time as fixed effects. The effect size will be calculated inside a treatment-by-time interaction using the least square means procedure. We will allow our mixed model to handle any missing data but will also impute using multiple imputation as a further sensitivity analysis. We will examine effect sizes for subgroups including age (50-64 vs. 65+), SMC vs. MCI, and according to ODI reductions and adherence.

A full statistical analysis plan will be published during data collection.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
27/06/2022
Actual
Date of last participant enrolment
Anticipated
1/10/2023
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
180
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 19558 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment hospital [2] 19561 0
Macquarie University Hospital - Macquarie Park
Recruitment hospital [3] 19562 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 34167 0
2050 - Camperdown
Recruitment postcode(s) [2] 34170 0
2109 - Macquarie Park
Recruitment postcode(s) [3] 34171 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 308702 0
Government body
Name [1] 308702 0
National Health and Medical Research Council (NHMRC)
Country [1] 308702 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney, Camperdown, NSW 2006
Country
Australia
Secondary sponsor category [1] 310118 0
None
Name [1] 310118 0
Address [1] 310118 0
Country [1] 310118 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308625 0
Sydney Local Health District Human Research Ethics Committee (RPAH zone)
Ethics committee address [1] 308625 0
Level 11, KGV Building Missenden Road CAMPERDOWN NSW 2050
Ethics committee country [1] 308625 0
Australia
Date submitted for ethics approval [1] 308625 0
26/05/2020
Approval date [1] 308625 0
03/12/2020
Ethics approval number [1] 308625 0
X20-0230 & 2020/ETH00564

Summary
Brief summary
A major source of sleep disruption in older adults is obstructive sleep apnoea (OSA), a disorder characterised by frequent pauses in breathing due to partial or complete airway closure during sleep. These events result in sleep disturbance and oxygen deprivation, which previous studies have shown to be associated with an increased risk of dementia.

Therefore, there is an imperative to establish definitively whether treatment of sleep apnoea can prevent dementia. This multi-site feasibility randomised-controlled trial aims to determine whether it is feasible to deploy a targeted intervention to treat sleep apnoea in participants with subjective memory complaints and determine the magnitude of effect on memory decline. Participants will be randomised to the intervention or control group for 2 years. Participants in the intervention group will receive treatment for their OSA following an algorithm and incorporating key principles of goal setting and behavioural sleep management. Participants in the control group will have their screening results sent to their referring medical practitioner, with recommendations for further investigation.

Further, 90 participants will undergo a 25 min MRI at the study center during their standard visit at baseline and 24 months. For the MRI scan, participants will be selected based on participant choice and willingness to participate, as well as, if they pass the MRI safety questionnaire and consent.

The primary outcome is the feasibility of the trial. The stop-go criteria to determine feasibility will depend on meeting the acceptability, hypoxic burden, and tolerability criteria. The secondary outcomes listed are primary being collected for the propose of showing feasibility of collection rather than serious intension of showing efficacy.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes
N/A

Contacts
Principal investigator
Name 111362 0
Prof Sharon Naismith
Address 111362 0
Level 2 Building G, Brain & Mind Centre 100 Mallet Street, Camperdown NSW 2050 Australia
Country 111362 0
Australia
Phone 111362 0
+61 02 9351 0781
Fax 111362 0
Email 111362 0
sharon.naismith@sydney.edu.au
Contact person for public queries
Name 111363 0
Dr Camilla Hoyos
Address 111363 0
Level 2, Building D17, Charles Perkins Centre
Johns Hopkins Drive, Camperdown NSW 2050
Country 111363 0
Australia
Phone 111363 0
+61 02 9114 0409
Fax 111363 0
Email 111363 0
camilla.hoyos@sydney.edu.au
Contact person for scientific queries
Name 111364 0
Prof Sharon Naismith
Address 111364 0
Level 2 Building G, Brain & Mind Centre 100 Mallet Street, Camperdown NSW 2050 Australia
Country 111364 0
Australia
Phone 111364 0
+61 02 9351 0781
Fax 111364 0
Email 111364 0
sharon.naismith@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
Available after main trial publication with no end date determined
Available to whom?
Only researchers who provide a methodologically sound proposal
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Requirement to sign data access agreement. Using Scientific contact information in ANZCTR:
Dr Camilla Hoyos
Phone: +61 2 9114 0409
Email: camilla.hoyos@sydney.edu.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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