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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?
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Scientific title
"Local Sleep” in the Awake Brain: An Underlying Cause of Neurobehavioural Deficits in Obstructive Sleep Apnea?
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Secondary ID [1]
294734
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Nil
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Universal Trial Number (UTN)
U1111-1213-6672
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnoea
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Condition category
Condition code
Respiratory
306673
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0
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Sleep apnoea
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
301026
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Treatment: Devices
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
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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.
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Assessment method [1]
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Timepoint [1]
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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.
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Primary outcome [2]
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Mean steering deviation from the median lane position during the simulated drives, compared between the CPAP on and CPAP off (withdrawal) conditions.
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Assessment method [2]
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Timepoint [2]
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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).
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Secondary outcome [1]
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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.
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Assessment method [1]
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Timepoint [1]
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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)
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Secondary outcome [2]
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Daytime vigilance on the Karolinska Drowsiness Test (KDT)
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Assessment method [2]
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Timepoint [2]
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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).
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Secondary outcome [3]
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Sustained attention on the psychomotor vigilance task (PVT)
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Assessment method [3]
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Timepoint [3]
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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)
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Secondary outcome [4]
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Subjective sleepiness on the Karolinska Sleepiness Scale (KSS)
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Assessment method [4]
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Timepoint [4]
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Night 2 (N-2) of therapeutic CPAP, N-2 of CPAP withdrawal. No long-term follow-up experimental visit conducted following new protocol.
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Secondary outcome [5]
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Sleep EEG profiles including slow wave activity during polysomnography (power spectral analysis)
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Assessment method [5]
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Timepoint [5]
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N-1 of therapeutic CPAP, N-1 of CPAP withdrawal.
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Secondary outcome [6]
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Brain arousal markers (K complex/slow oscillation detection and arousal intensity) during polysomnography.
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Assessment method [6]
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Timepoint [6]
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N-1 of therapeutic CPAP. N-1 of CPAP withdrawal.
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Secondary outcome [7]
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High-density EEG profiles during overnight polysomnography
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Assessment method [7]
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Timepoint [7]
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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.
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Secondary outcome [8]
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Simulated driving performance (AusEd task)
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Assessment method [8]
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Timepoint [8]
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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.
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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.
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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.
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Minimum age
35
Years
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Maximum age
65
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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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.
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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)
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Masking / blinding
Open (masking not used)
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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
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Intervention assignment
Crossover
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
Efficacy
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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.
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Recruitment
Recruitment status
Recruiting
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Date of first participant enrolment
Anticipated
26/08/2019
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Actual
27/11/2019
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Date of last participant enrolment
Anticipated
9/03/2023
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Actual
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Date of last data collection
Anticipated
31/03/2023
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Actual
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Sample size
Target
32
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Accrual to date
22
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Final
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Woolcock Institute of Medical Research - Glebe
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Recruitment postcode(s) [1]
22539
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2037 - Glebe
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Funding & Sponsors
Funding source category [1]
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Government body
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Name [1]
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NHMRC
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Address [1]
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National Health and Medical Research Council
GPO Box 1421
Canberra City ACT 2601
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Country [1]
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Australia
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Primary sponsor type
Charities/Societies/Foundations
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Name
Woolcock Institute of Medical Research
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Address
431 Glebe Point Road,
Glebe NSW 2037
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
298612
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Country [1]
298612
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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Sydney Local Health District Ethics Review Committee (RPAH Zone)
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Ethics committee address [1]
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Level 11 KGV Building Missenden Rd. CAMPERDOWN. NSW 2050
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Ethics committee country [1]
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Australia
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Date submitted for ethics approval [1]
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16/04/2018
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Approval date [1]
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18/06/2018
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Ethics approval number [1]
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X18-0122 HREC/18/RPAH167
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Summary
Brief summary
Obstructive sleep apnea (OSA) is a common sleep disorder, and is linked with excessive and inappropriate sleepiness, impaired cognition, increased risk of motor vehicle crashes and workplace accidents. However, not all patients with OSA display daytime impairments and it is still not completely known how OSA affects the brain.
A key to understanding this is by investigating the brain activity of patients with OSA, and how this may change following CPAP therapy, the gold standard clinical treatment for OSA. This can be easily done through non-invasive EEG recordings from electrodes placed on the scalp that are a routine part of sleep studies when screening for OSA. This study uses advanced high-density electroencephalography (hdEEG) to investigate whether areas of ‘tired’ neurons that fall asleep in the awake brain underlie daytime impairments in OSA.
The purpose of this study is to examine the effect of regular CPAP use versus short-term CPAP withdrawal on daytime function and brain wave activity recorded in patients diagnosed with moderate to severe OSA. We will investigate brain activity during sleep and during awake daytime performance testing.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Ronald Grunstein
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Address
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Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe NSW 2037 Australia
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Country
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Australia
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Phone
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+61 (02) 9114 0000
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
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Dr Angela D'Rozario
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Address
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Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe NSW 2037 Australia
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Country
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Australia
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Phone
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+61 (02) 9114 0000
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Name
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Dr Angela D'Rozario
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Address
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Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe NSW 2037 Australia
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Country
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Australia
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Phone
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+61 (02) 9114 0000
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Fax
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Email
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Individual participant data underlying published results only
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When will data be available (start and end dates)?
Data will be made available upon request, after publication, with no end date determined
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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.
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Available for what types of analyses?
Any purpose.
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How or where can data be obtained?
Secure data transfer and signed data access agreement.
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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.
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