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Trial registered on ANZCTR


Registration number
ACTRN12613001171707
Ethics application status
Approved
Date submitted
8/10/2013
Date registered
24/10/2013
Date last updated
7/07/2022
Date data sharing statement initially provided
7/07/2022
Date results information initially provided
7/07/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Novel brain biomarkers of performance impairment in sleep apnea
Scientific title
Novel brain biomarkers of driving and vigilance performance in obstructive sleep apnea during extended wakefulness
Secondary ID [1] 282091 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnea 288594 0
Condition category
Condition code
Respiratory 288924 288924 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
85 patients with moderate-severe obstructive sleep apnea will be recruited to undergo an experimental laboratory protocol following a screening visit and after obtaining informed consent.
One week of actigraphy and sleep-wake diary and indoor-outdoor activity logs, will be performed prior to the test visit to measure sleep hours and activities at home, and participants will be advised to observe regular sleep hours with 8-hours in bed.

The experimental protocol visit consists:
- baseline sleep study followed by 28 hours of extended wakefulness challenge (EWC) with detailed assessment including:

Primary performance outcomes measure
-Three 90 minute computerised AusEd driving simulator tasks measured at Time 1 (9.30am, 3.5 hours awake), Time 2 (2.30am, 20.5 hours awake) and Time 3 (8.30am, 26.5 hours awake)

Secondary performance outcome measure
-10 minute psychomotor vigilance test (PVT) measures every 2 hours throughout the EWC starting from midday.

Primary Predictor Variables
-Baseline sleep study is performed from 10pm-6am (EEG data will be subjected to spectral power analysis as part of data processing/analysis)
-Auditory Event Related potentials (ERP) data will be collected at between 8.30-9.30am (baseline assessment only)
-Resting awake EEG during a 7 minute Karolinska Drowsiness Test measure every 2 hours throughout the EWC startinf at midday
-Magnetic Resonance Spectroscopy/Diffusion Tensor Imaging occurs within 1 week prior to laboratory EWC visit (assessed at baseline only)

Secondary Predictor Variables
-mRNA expression profiles from baseline to end of EWC (blood/mRNA samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
-Posture/Balance control assessments measured every 2 hours throughout the EWC starting at midday
-Peripheral Blood Pressure measures every 2 hours throughout the EWC starting at midday
Computerised performance tests measure every 2 hours through out the EWC starting at midday :
- Working memory (N-back 1,2,3)
- Visuomotor skills (Digit Symbol Substitution Task)
- 4 Choice Reaction Time Task
-Central Blood Pressure and Pulse Wave Analysis (PWA) measures every 2 hours throughout the EWC starting at midday
-Statistical Learning Task measured at baseline (8.30pm prior to baseline sleep study) and at 8.30pm 24 hours later.
-Actigraphy variables (actigraphy data collected 1 week prior to EWC)
-PSG sleep study variables (collected during the baseline sleep study just prior to EWC)
-Genetic polymorphisms (genetic analysis from blood samples collected at start and end of EWC will occur at the completion of the study)
-Inflammatory marker profiles (from blood sample analysis collected at start and end of EWC will occur at the completion of the study)
-Brief Smell Identification Test (B-SIT) is collected at baseline only at 7.30pm prior to baseline sleep study
-State anxiety questionnaire administered every 2 hours throughout the EWC starting at midday
-Karolinska Sleepiness Scale administered every 2 hours throughout the EWC starting at midday
Intervention code [1] 286698 0
Behaviour
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 289051 0
AusEd driving simulator lateral steering deviation
Timepoint [1] 289051 0
Driving simulator assessments occur 3 times during the Extended Wakefulness Protocol:

-Time 1 (baseline - 3.5 hours awake)
-Time 2 (20.5 hours awake)
-Time 3 (26.5 hours awake)
Secondary outcome [1] 301642 0
Psychomotor Vigilance Test (PVT) - a measure of simple reaction time and vigilance
Timepoint [1] 301642 0
assessed every 2 hours during the EWC

Eligibility
Key inclusion criteria
Age 25-65 years
Weight <150kg
PSG confirmed moderate to severe obstructive sleep apnea with an Apnea Hypopnea Index (AHI) of =15 events/hr and an Oxygen Desaturation Index (ODI) of =3% with =10 events/hr
Ability to read and speak English
Ability to perform neurobehavioural tests
Minimum age
25 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Other PSG confirmed sleep disorders
OSA patients with clinically significant uncontrolled co-morbidity such as: cardiac failure, hypertension, hypercapnia, COPD, Type 1 diabetes
History of head injury or psychiatric/neurological disorders: clinical depression, epilepsy, mania or psychosis, stroke
Currently using CNS active medications/drugs such as: anti-depressives, anti-psychotics, opiates, antihistamines

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Cross-Sectional study
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
The key goal for this project will be obtaining predictors for vulnerability to sleep loss. Analysis is by multiple regression with change in AusEd steering deviation (vulnerability to sleep deprivation) as the primary outcome variable, and a range of candidate biomarkers as predictors, including measurements from MR, sleep/wake EEG and genetic polymorphisms. In a multiple regression model with up to 2 tested predictors adjusting for the another 1-2 additional predictors (covariates) with a significance level of 0.05, a sample size of 78 is required with power of 0.8 to detect a moderate multiple partial correlation coefficient of 0.35, between the tested predictors and the primary outcome variable. Variables not meeting assumptions for parametric statistics will be appropriately transformed. Factor analysis will be employed to assist with grouping similar variables, in order to reduce the number of potential predictors submitted for regression analysis. Secondary analyses will examine the change from rested to 8am the following morning (28 hours awake), and also examine the other outcomes of interest (PVT, n-back etc). We plan to recruit a total of 85 participants, to allow for 7 withdrawals.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
6/09/2012
Actual
6/09/2012
Date of last participant enrolment
Anticipated
15/12/2014
Actual
19/11/2014
Date of last data collection
Anticipated
Actual
26/11/2014
Sample size
Target
85
Accrual to date
Final
58
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 730 0
Royal Prince Alfred Hospital - Camperdown

Funding & Sponsors
Funding source category [1] 286867 0
Government body
Name [1] 286867 0
National Health and Medical Research Council
Country [1] 286867 0
Australia
Primary sponsor type
Other
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Road
Glebe
NSW
2037
Country
Australia
Secondary sponsor category [1] 285659 0
None
Name [1] 285659 0
Address [1] 285659 0
Country [1] 285659 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288928 0
Sydney Local Health District (RPAH Zone)
Ethics committee address [1] 288928 0
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 288928 0
Australia
Date submitted for ethics approval [1] 288928 0
Approval date [1] 288928 0
19/03/2012
Ethics approval number [1] 288928 0
HREC/12/RPAH/40

Summary
Brief summary
Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, impaired cognition, and has a 3 -13 times increased risk of motor vehicle crashes and double the rate of work accidents. This neurobehavioural dysfunction has a critical impact on health and society.
One of the major challenges in dealing with this problem is the difficulty in clinically assessing neurobehavioural dysfunction such as impairment in driving ability. Many patients underestimate their impairment and there is wide inter-individual variability in how patients are affected by sleepiness and its consequences. For example, patients with sleep studies showing severe OSA may report few symptoms while others with apparent mild disease exhibit severe sleepiness. Unravelling this problem of inter-individual variability demands better assessment tools as conventional metrics such as sleep studies are uninformative. What is urgently needed are biomarkers, measured at a single or very limited time points that better reflect the individual risk of vigilance failure such as impaired driving.
In this study, simulated driving and other performance tasks will be administered during a load of prolonged wakefulness extending throughout the night to unmask variation in neurobehavoural function in OSA. Performance under these conditions will be related to practically deployable biomarkers (or combination of biomarkers) measured at baseline. We have compelling preliminary data on brain bioenergetics (magnetic resonance imaging), quantitative electroencephalogram (qEEG) and cortical activation (event related potentials) as candidate biomarkers for neurobehavioural impairment in OSA. Such biomarkers would also be potentially valuable as tests to monitor treatment effectiveness or a phenotyping tools in molecular and genetic discovery in OSA.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38378 0
Prof Ronald Grunstein
Address 38378 0
Ron Grunstein
Professor of Sleep Medicine and NHMRC Practitioner Fellow,
NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research,
University of Sydney and Royal Prince Alfred Hospital

PO Box M77
Missenden Road
NSW
2050
Country 38378 0
Australia
Phone 38378 0
+61 2 91140007
Fax 38378 0
Email 38378 0
[email protected]
Contact person for public queries
Name 38379 0
Andrew Vakulin
Address 38379 0
Woolcock Institute of Medical Research
431 Glebe Point Road
Glebe
NSW
2037
Country 38379 0
Australia
Phone 38379 0
+61 2 9114 0443
Fax 38379 0
Email 38379 0
[email protected]
Contact person for scientific queries
Name 38380 0
Andrew Vakulin
Address 38380 0
Woolcock Institute of Medical Research
431 Glebe Point Road
Glebe
NSW
2037
Country 38380 0
Australia
Phone 38380 0
+61 2 9114 0443
Fax 38380 0
Email 38380 0
[email protected]

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 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. Contact: [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes 15 September 2021 https://doi.org/10.1111/jsr.1348... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSleep spindle activity correlates with implicit statistical learning consolidation in untreated obstructive sleep apnea patients.2021https://dx.doi.org/10.1016/j.sleep.2021.01.035
EmbaseBrain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea.2022https://dx.doi.org/10.1111/jsr.13482
EmbaseClinical predictors of working memory performance in obstructive sleep apnea patients before and during extended wakefulness.2022https://dx.doi.org/10.1093/sleep/zsab289
N.B. These documents automatically identified may not have been verified by the study sponsor.