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
ACTRN12619000549123
Ethics application status
Approved
Date submitted
21/03/2019
Date registered
8/04/2019
Date last updated
28/01/2020
Date data sharing statement initially provided
8/04/2019
Type of registration
Retrospectively 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. All participants enrolled in the study will undergo 4 continuous night’s of supervised auto-titrating CPAP (4–20 cmH20) in the sleep laboratory, followed by a two-week wash-out period, followed by 4 nights using a placebo (sham) therapy in a randomized crossover design. Participants will be given an 8-hour sleep opportunity on each night of the attended and supervised sleep laboratory visits. The CPAP device will be used for the duration of sleep opportunity with a dedicated and trained overnight sleep technologist providing support to maximise adherence to the intervention each night. Prior to starting the intervention CPAP/placebo, participants will also have a face-to-face consultation with a qualified CPAP therapist that includes CPAP education and mask fitting.

Phillips Respironics' Continuous Auto Positive Airway Pressure (APAP 37234) used in the treatment of Sleep Disordered Breathing. ARTG Number: 133792. The CPAP device is designed for the treatment of Obstructive Sleep Apnea only in spontaneously breathing patients. When set in Auto-CPAP therapy mode, the system will monitor breathing as you sleep and automatically adjust the pressure to meet the participants' requisite needs.
Intervention code [1] 301026 0
Treatment: Devices
Comparator / control treatment
Sham CPAP therapy is delivered using an identical looking device and mask to active CPAP but involves the delivery of subtherapeutic positive pressure. The Sham CPAP is a placebo control for studies employing CPAP devices. The Sham CPAP has internal modifications which limit the amount of positive airway pressure delivered to the participant, while still recording participant breathing patterns (for compliance / usage monitoring). The device also contains a modification to the bias flow port of the mask elbow. This bias flow modification allows greater than normal amounts of air to escape the system further reducing the delivered pressure. The Sham CPAP is designed to deliver similar ‘human factors’ challenges as a conventional CPAP device, while blinding the patient to the modifications. The actual delivered pressures are typically below 1 cmH2O and do not prevent sleep disordered breathing.
Control group
Placebo

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 therapeutic and sham CPAP.
Timepoint [1] 305680 0
24-hour period encompassing night 4 (N-4) of the active CPAP arm, N-4 of the sham CPAP arm. Resting wake EEG recording blocks at T3 block (7pm) - baseline block (10am) on Day 4.
Primary outcome [2] 307827 0
Mean steering deviation from the median lane position during the simulated drives, compared between therapeutic and sham CPAP.
Timepoint [2] 307827 0
24-hour period encompassing night 4 (N-4) of the active CPAP arm, N-4 of the sham CPAP arm. The three x 3-hourly, 90-minute sessions of driving on Day 4 after three nights of supervised active/sham CPAP.
Drive 1 (Day 4, 11am), Drive 2 (Day 4, 2pm), Drive 3 (Day 4, 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 therapeutic and sham CPAP.
Timepoint [1] 346155 0
N-4 of active and sham CPAP arms and 6 month long-term follow-up. Baseline (Day 4, 10am), Test block T1 (Day 4, 12.30pm), T2 (Day 4, 3:30pm), T3 (Day 4, 6.30pm), T4 (Day 9.30pm), T5 (Day 5, 8am).
Secondary outcome [2] 367680 0
Daytime vigilance on the Karolinska Drowsiness Test (KDT)
Timepoint [2] 367680 0
N-4 of active and sham CPAP arms and 6 month long-term follow-up.
Baseline (Day 4, 10am), Test block T1 (Day 4, 12.30pm), T2 (Day 4, 3:30pm), T3 (Day 4, 6.30pm), T4 (Day 9.30pm), T5 (Day 5, 8am).
Secondary outcome [3] 367681 0
Sustained attention on the psychomotor vigilance task (PVT)
Timepoint [3] 367681 0
N-4 of active and sham CPAP arms and 6 month long-term follow-up.
Baseline (Day 4, 10am), Test block T1 (Day 4, 12.30pm), T2 (Day 4, 3:30pm), T3 (Day 4, 6.30pm), T4 (Day 9.30pm), T5 (Day 5, 8am).
Secondary outcome [4] 367682 0
Subjective sleepiness on the Karolinska Sleepiness Scale (KSS)
Timepoint [4] 367682 0
N-4 of active and sham CPAP arms and 6 month long-term follow-up.
Baseline (Day 4, 10am), Test block T1 (Day 4, 12.30pm), T2 (Day 4, 3:30pm), T3 (Day 4, 6.30pm), T4 (Day 9.30pm), T5 (Day 5, 8am).
Secondary outcome [5] 367683 0
Sleep EEG profiles including slow wave activity during polysomnography (power spectral analysis)
Timepoint [5] 367683 0
Night 3 (N-3) of the active and sham CPAP arm, N-3 of the sham CPAP arm,
Secondary outcome [6] 367684 0
Brain arousal markers (K complex/slow oscillation detection and arousal intensity) during polysomnography.
Timepoint [6] 367684 0
N-3 of the active CPAP arm, N-3 of the sham CPAP arm,
Secondary outcome [7] 367686 0
High-density EEG profiles during overnight polysomnography
Timepoint [7] 367686 0
N-4 of the active and sham CPAP arms and 6 month long-term follow-up
Secondary outcome [8] 367687 0
Simulated driving performance (AusEd task)
Timepoint [8] 367687 0
N-4 of the active and sham CPAP arms and 6 month long-term follow-up
Drive 1 (Day 4, 11am), Drive 2 (Day 4, 2pm), Drive 3 (Day 4, 5pm).

Eligibility
Key inclusion criteria
Males and females;
Community-dwelling aged 35-65 years;
Polysomnography confirmed moderate to severe OSA based on the apnea-hypopnea index (AHI) =15/hr;
Able to give informed consent;
Fluent in English;
CPAP or mandibular device naïve;
Ability to perform neurobehavioural tests and driving simulator task.
Current driver’s license
Performance impairment during a 90-minute driving simulation and/or answering positive to questions reporting driving accidents or impairment and/or physician opinion.
Willingness to use CPAP
Minimum age
35 Years
Maximum age
65 Years
Gender
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.
A need for immediate prescription of CPAP treatment

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)
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) that is not available to staff who enrol participants. 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.

We will attempt to blind outcomes assessors by limiting knowledge of treatment allocation to three people; one CPAP therapist, one investigator and one trial physician. The trial physician will be unblinded only if required to withdraw a participant. The CPAP therapist will deliver CPAP education, fitting of the CPAP device, configuring and monitoring compliance with all CPAP devices. The CPAP therapist is not involved in data collection, processing analysis/assessment and will be advised to follow the blinding protocol set out by the investigators.

We will attempt to blind participants by informing them that we’re testing two CPAP machines that deliver pressurised air in a different way/at two different settings. During a post-study debriefing interview participants were informed that the low-pressure machine was a placebo.

If unintentional un-blinding occurs with individuals charged with collecting and processing data and those assessing outcomes, they will no longer be permitted to have contact with the participant for the remainder of the trial.
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
Blinded (masking 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 therapeutic CPAP and sham CPAP 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 minus sham differences in local sleep intrusion in wake (theta power as calculated above, theta wave density) to CPAP minus sham 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. Outcomes will also be compared before and after 6 months CPAP by paired t-test. 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).

41 patients completing this crossover study will provide 80% power (two-tailed alpha = 0.025) to detect a moderate effect size of 0.5 standard deviations in the two primary outcomes

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
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
Address [1] 299342 0
National Health and Medical Research Council
GPO Box 1421
Canberra City ACT 2601
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
Level 11 KGV Building Missenden Rd. CAMPERDOWN. NSW 2050
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
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 using CPAP therapy, at two different settings, 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, and compare the effect of using different CPAP device settings.
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
Dr 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
Dr 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 other documents available
Summary results
No Results