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Trial registered on ANZCTR


Registration number
ACTRN12619000549123
Ethics application status
Approved
Date submitted
21/03/2019
Date registered
8/04/2019
Date last updated
8/03/2023
Date data sharing statement initially provided
8/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Do ‘tired’ neurons that fall asleep in the awake brain underlie daytime impairments in obstructive sleep apnea?
Scientific title
"Local Sleep” in the Awake Brain: An Underlying Cause of Neurobehavioural Deficits in Obstructive Sleep Apnea?
Secondary ID [1] 294734 0
Nil
Universal Trial Number (UTN)
U1111-1213-6672
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnoea 307617 0
Condition category
Condition code
Respiratory 306673 306673 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study intervention, continuous positive airway pressure (CPAP) therapy, is the routine gold standard treatment for obstructive sleep apnea. Its mode of delivery is through a CPAP device and a face and/or nasal mask worn by the patient nightly whilst sleeping. The study consists of a randomised crossover design with overnight use of therapeutic CPAP (ie. the 'CPAP on' condition) or temporary treatment withdrawal (ie. the 'CPAP off' condition, duration of withdrawal: 7-10 days). These conditions will be allocated in random order.

The experimental visit comprises 2 continuous nights: 1 baseline PSG night with standard laboratory PSG setup, and 1 night with a high-density EEG sensor cap). The high-density EEG sensornet cap comprises 256 interconnected scalp EEG electrodes worn on the head. It records brain activity. The cap will be applied in the morning of the 2nd day of the experimental visit, and will be kept on throughout the day and overnight. The sensornet cap will be removed when the final block of neurocognitive assessments is completed on the morning of the 3rd day.

Participants will be given an 8-hour sleep opportunity on each night. During the 'CPAP on' condition, the CPAP device will be used for the entire duration of sleep opportunity, with a dedicated and trained overnight sleep technologist providing support to maximise adherence. Neurocognitive assessments and driving simulators will be administered on the 2nd day of the experimental visit. The total duration of neurocognitive assessments and driving simulators administered on the 2nd day is 7.0 hours. The first and last blocks of the day (ie. Baseline block and block T4, respectively) involve 30 min of neurocognitive assessments each. Blocks T1, T2 and T3 involve a 90 min driving simulator, followed by 30 min of neurocognitive assessments.

There will be a 1-week washout period between experimental visits.
Intervention code [1] 301026 0
Treatment: Devices
Comparator / control treatment
The 'CPAP off' condition will be the control component of the study. All participants would have been established on CPAP therapy for a duration of at least 3 months, maintaining good compliance with the therapy (average usage: 4 hours/night, 5 nights a week)

The 'CPAP off condition' requires participants to withdraw from CPAP therapy for 7 days (10 days maximum) prior to the experimental overnight sleep study visits. The 'CPAP off' condition is a control for studies employing CPAP devices. This condition is designed to help quantify regional changes in EEG, driving performance, and attention when withdrawn from treatment.
Control group
Active

Outcomes
Primary outcome [1] 305680 0
Local sleep during wake measured as the change in task-related EEG-derived occipito-parietal theta power after repeated simulated driving (3 x 90 min drives at 11am, 2pm, 5pm), compared between CPAP on and CPAP off (withdrawal) conditions.
Timepoint [1] 305680 0
24-hour period encompassing night 2 (N-2) of the CPAP on condition, N-2 of the CPAP off condition. Resting wake EEG recording blocks at T3 block (7pm) - baseline block (10am) on Day 2.
Primary outcome [2] 307827 0
Mean steering deviation from the median lane position during the simulated drives, compared between the CPAP on and CPAP off (withdrawal) conditions.
Timepoint [2] 307827 0
24-hour period encompassing night 2 (N-2) of the CPAP on condition, N-2 of the CPAP off condition. The three x 3-hourly, 90-minute sessions of driving on Day 2 after two nights of supervised CPAP/CPAP withdrawal. Drive 1 (Day 2, 11am), Drive 2 (Day 2, 2pm), Drive 3 (Day 2, 5pm).
Secondary outcome [1] 346155 0
Local sleep during wake measured as the change in task-related EEG-derived occipito-parietal theta wave density after repeated simulated driving (3 x 90 min drives at 11am, 2pm, 5pm), compared between the CPAP on and CPAP off conditions.
Timepoint [1] 346155 0
N-2 of therapeutic CPAP or CPAP withdrawal. Baseline (Day 2, 10am), Test block T1 (Day 2, 12:30pm), T2 (Day 2, 3:30pm), T3 (Day 2, 6:30pm), T4 (Day 2, 9:30pm), T5 (Day 3, 8am)
Secondary outcome [2] 367680 0
Daytime vigilance on the Karolinska Drowsiness Test (KDT)
Timepoint [2] 367680 0
N-2 of therapeutic CPAP and CPAP withdrawal. Baseline (Day 2, 10am), Test block T1 (Day 2, 12:30pm), T2 (Day 2, 3:30pm), T3 (Day 2, 6:30pm), T4 (Day 2, 9:30pm), T5 (Day 3, 8am).
Secondary outcome [3] 367681 0
Sustained attention on the psychomotor vigilance task (PVT)
Timepoint [3] 367681 0
N-2 of the therapeutic CPAP and CPAP withdrawal. Baseline (Day 2, 10am), Test block T1 (Day 2, 12:30pm), T2 (Day 2, 3:30pm), T3 (Day 2, 6:30pm), T4 (Day 2, 9:30pm), T5 (Day 3, 8am)
Secondary outcome [4] 367682 0
Subjective sleepiness on the Karolinska Sleepiness Scale (KSS)
Timepoint [4] 367682 0
Night 2 (N-2) of therapeutic CPAP, N-2 of CPAP withdrawal. No long-term follow-up experimental visit conducted following new protocol.
Secondary outcome [5] 367683 0
Sleep EEG profiles including slow wave activity during polysomnography (power spectral analysis)
Timepoint [5] 367683 0
N-1 of therapeutic CPAP, N-1 of CPAP withdrawal.
Secondary outcome [6] 367684 0
Brain arousal markers (K complex/slow oscillation detection and arousal intensity) during polysomnography.
Timepoint [6] 367684 0
N-1 of therapeutic CPAP. N-1 of CPAP withdrawal.
Secondary outcome [7] 367686 0
High-density EEG profiles during overnight polysomnography
Timepoint [7] 367686 0
N-2 of therapeutic CPAP and CPAP withdrawal. Drive 1 (Day 2, 11am), Drive 2 (Day 2, 2pm), Drive 3 (Day 2, 5pm). No long-term follow-up experimental visits following new protocol.
Secondary outcome [8] 367687 0
Simulated driving performance (AusEd task)
Timepoint [8] 367687 0
N-2 of therapeutic CPAP and CPAP withdrawal. Drive 1 (Day 2, 11am), Drive 2 (Day 2, 2pm), Drive 3 (Day 2, 5pm). No long-term follow-up experimental visits following new protocol.

Eligibility
Key inclusion criteria
The participant's apnea-hypopnea index (AHI) must be greater than or equal to 15/hr to be eligible for the study. The symbol has been replaced with text below.

____________________________

Males and females;
Community-dwelling aged 35-65 years;
Polysomnography confirmed moderate to severe OSA based on the apnea-hypopnea index (AHI) greater than or equal to 15/hr;
Able to give informed consent;
Fluent in English;
Established CPAP users for a duration of at least 3 months (on average 4 hours use per night on at least 5 nights per week)
Ability to perform neurobehavioural tests and driving simulator task.
Current driver’s license
Vulnerable to driving impairment without CPAP therapy/upon withdrawal of therapy, Assessed via positive response(s) to questions reporting driving accidents or impairments prior to established CPAP therapy, and/or physician's opinion.
Minimum age
35 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Clinically significant co-morbidity;
Major neurological problems (e.g. stroke, epilepsy, head injury);
Severe mental health disorder (e.g. current major depression, schizophrenia, bipolar disorder);
Regular use of sleep-affecting medication; benzodiazepines, opioids, antidepressants.
Shift worker or have traveled overseas within the last 2 weeks.
Professional drivers.
Sleep physician has advised against CPAP withdrawal

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)
Allocation is not concealed.

Randomisation will take place at baseline after determining patient eligibility, obtaining informed consent and enrolling the patient. Secure randomisation will be achieved through Research Tools. Participants will be enrolled sequentially according to a computer-generated randomisation list using a random block size (2, 4 or 6). A unique participant randomisation number will be assigned sequentially, in ascending order and will comprise a three-digit number prefixed by “R” (e.g. R001, R002 etc.). This randomisation number will be used to internally identify the treatment group the participant is assigned to.

At randomisation, the randomisation module in Research Tools system requires that the trial coordinator enter a screening number and then confirm that the displayed participant name and DOB match the participant they intend to randomise. All previously entered eligibility data are then automatically assessed. If the participant meets all inclusion/exclusion criteria then the trial coordinator is able to commit online to automatically randomising the participant. Once this occurs, the participant is irrevocably allocated the next available randomisation number and previously concealed treatment assignment. Both the randomisation number and allocated treatment are then displayed and permanently recorded against that participant’s online record.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using an online randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The two primary outcomes (local sleep wake theta power ratio between block T3 and baseline block, AusEd steering deviation from the median lane position) will be compared between CPAP on versus CPAP off conditions by paired t-test. To study if local sleep influences individual variability in OSA-related performance impairment, we will use bivariate correlations to relate CPAP on versus CPAP off differences in local sleep intrusion in wake (theta power as calculated above, theta wave density) to CPAP on versus CPAP off differences in performance on the driving task and PVT. We will explore the relationship between local sleep and performance changes due to CPAP and brain arousal markers and brain blood pressure using linear regression models. Variables will be transformed as necessary to satisfy assumptions of the analyses used. Forty-one patients completing a crossover study (aim to recruit 48 to allow for withdrawals and missing data) will provide sufficient power to detect a moderate effect size of 0.5 standard deviations with 80% power and an adjusted two-tailed significance level to 0.025 for two primary outcomes. This sample of 41 patients is powered to show moderately strong correlations (Pearson’s r of 0.46 and above). The target sample was reduced to 32 due to budgetary constraints.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
26/08/2019
Actual
27/11/2019
Date of last participant enrolment
Anticipated
9/03/2023
Actual
Date of last data collection
Anticipated
31/03/2023
Actual
Sample size
Target
32
Accrual to date
22
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 10799 0
Woolcock Institute of Medical Research - Glebe
Recruitment postcode(s) [1] 22539 0
2037 - Glebe

Funding & Sponsors
Funding source category [1] 299342 0
Government body
Name [1] 299342 0
NHMRC
Country [1] 299342 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Road,
Glebe NSW 2037
Country
Australia
Secondary sponsor category [1] 298612 0
None
Name [1] 298612 0
Address [1] 298612 0
Country [1] 298612 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300248 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 300248 0
Ethics committee country [1] 300248 0
Australia
Date submitted for ethics approval [1] 300248 0
16/04/2018
Approval date [1] 300248 0
18/06/2018
Ethics approval number [1] 300248 0
X18-0122 HREC/18/RPAH167

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

Contacts
Principal investigator
Name 83042 0
Prof Ronald Grunstein
Address 83042 0
Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe NSW 2037 Australia
Country 83042 0
Australia
Phone 83042 0
+61 (02) 9114 0000
Fax 83042 0
Email 83042 0
ron.grunstein@sydney.edu.au
Contact person for public queries
Name 83043 0
Angela D'Rozario
Address 83043 0
Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe NSW 2037 Australia
Country 83043 0
Australia
Phone 83043 0
+61 (02) 9114 0000
Fax 83043 0
Email 83043 0
angela.drozario@sydney.edu.au
Contact person for scientific queries
Name 83044 0
Angela D'Rozario
Address 83044 0
Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe NSW 2037 Australia
Country 83044 0
Australia
Phone 83044 0
+61 (02) 9114 0000
Fax 83044 0
Email 83044 0
angela.drozario@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)?
Data will be made available upon request, after publication, with no end date determined
Available to whom?
Data will be made available upon request, after publication and will be determined upon negotiation with researchers who provided a methodologically sound proposal.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Secure data transfer and signed data access agreement.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.