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Trial registered on ANZCTR


Registration number
ACTRN12615001224516
Ethics application status
Approved
Date submitted
22/09/2015
Date registered
9/11/2015
Date last updated
19/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Novel brain biomarkers of performance impairment in good sleepers
Scientific title
Novel brain biomarkers of driving and vigilance performance in those with good sleep during extended wakefulness
Secondary ID [1] 287485 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Normal brain and nervous system functioning 296368 0
Condition category
Condition code
Neurological 296565 296565 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
50 healthy individuals 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
- Letter Cancellation Task
- Emotion Perception Task
- Thermal sensation scale
- 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] 292916 0
Behaviour
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296181 0
Driving simulator (AusED) steering deviations
Timepoint [1] 296181 0
-Time 1 (baseline - 3.5 hours awake) Midday
-Time 2 (20.5 hours awake)
-Time 3 (26.5 hours awake)
Primary outcome [2] 296324 0
10 minute Psychomotor Vigilance Task - Reaction time
Timepoint [2] 296324 0
-Time 1 (baseline - 3.5 hours awake) Midday
-Time 2 (20.5 hours awake)
-Time 3 (26.5 hours awake)
Secondary outcome [1] 317727 0
Absolute and relative EEG power (0.5-32Hz)
Timepoint [1] 317727 0
-Throughout the whole sleep period and during the cognitive tests occurring at Time 1 midday (baseline - 3.5 hours awake), Time 2 (20.5 hours awake) and Time 3 (26.5 hours awake)
Secondary outcome [2] 318152 0
Magnetic Resonance Spectroscopy/Diffusion Tensor Imaging

Brain metabolites (including creatine, glutamate, glutamine, aspartate, glutathione and n-acetyl aspartate) will be assessed as a composite outcome using Magnetic Resonance Spectroscopy
Timepoint [2] 318152 0
At baseline, 1 week prior to laboratory stay
Secondary outcome [3] 318153 0
Tumor Necrosis Factor- a (TNF)

The TNF-a outcomes are assessed from blood samples.

The TNF-a outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [3] 318153 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [4] 318154 0
IL-6

The IL-6 outcomes are assessed from blood samples.

The IL-6 outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [4] 318154 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [5] 318155 0
IL-1beta

The IL-1beta outcomes are assessed from blood samples.

The IL-1beta outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [5] 318155 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [6] 318156 0
C-reactive protein (CRP)

The CRP outcomes are assessed from blood samples.

The CRP outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [6] 318156 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [7] 318157 0
sE-selectin

The sE-selectin outcomes are assessed from blood samples.

The sE-selectin outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [7] 318157 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [8] 318158 0
IL-1ra

The IL-1ra outcomes are assessed from blood samples.

The IL-1ra outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [8] 318158 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [9] 318159 0
hs-TNT

The hs-TNT outcomes are assessed from blood samples.

The hs-TNT outcomes examined will be absolute levels at baseline and following extended wakefulness as well as the delta change in levels from baseline to extended wakefulness. These outcomes will be assessed as correlates with primary performance outcomes.
Timepoint [9] 318159 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [10] 318160 0
Four choice reaction time task - reaction time
Timepoint [10] 318160 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [11] 318161 0
Visuomotor skills - Symbol-Digit Substitution Task (mean correct responses)
Timepoint [11] 318161 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [12] 318162 0
State anxiety taken from the State-Trait Anxiety Questionnaire
Timepoint [12] 318162 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [13] 318163 0
Karolinksa Sleepiness Scale - mean sleepiness rating
Timepoint [13] 318163 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [14] 318164 0
Karolinska Drowsiness Test - Absolute and relative EEG power (0.5-32Hz)
Timepoint [14] 318164 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [15] 318165 0
Posture/Balance control - centre of pressure when standing

Posture/balance control will be assessed with using posturography board.
Timepoint [15] 318165 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [16] 318166 0
Peripheral Blood Pressure

Peripheral blood pressure will be assessed using an automated blood pressure monitor
Timepoint [16] 318166 0
Every two hours, beginning at midday until the end of the protocol (24 hours continued wakefulness)
Secondary outcome [17] 318167 0
mRNA expression profiles

Whole blood transcriptome will be analysed using microarray analysis to examine full mRNA expression profiles at baseline and extended wakefulness as well as the change in expression from baseline to extended wakefulness. This exploratory analysis is to identify any specific expression profiles and is not specifically targeted.
Timepoint [17] 318167 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [18] 318168 0
Working memory (n-back 1,2,3) correct responses
Timepoint [18] 318168 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [19] 318169 0
Letter cancellation task (correct responses) will assess attention.
Timepoint [19] 318169 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [20] 318170 0
Central Blood Pressure and Pulse Wave Analysis (PWA)

This outcome will be assessed using a sphygmomanometer
Timepoint [20] 318170 0
Every 2 hours beginning at midday and continuing until the end of the protocol.
Secondary outcome [21] 318171 0
Actigraphy variables will provide an objective measure of activity and inform rest/wake periods during the 24hour day
Timepoint [21] 318171 0
At baseline for one week prior to laboratory stay
Secondary outcome [22] 318172 0
Genetic polymorphisms will be assessed via genetic analysis from blood sample
Timepoint [22] 318172 0
samples collected at 6.15am upon awakening and 6.15am the following morning after 24hours of wakefulness
Secondary outcome [23] 318174 0
Brief Smell Identification Test (B-SIT)

The B-SIT is believed to be a measure of the functional integrity of the orbitofrontal cortex and has been linked with vigilance performance (Killgore WD, McBride SA, Killgore DB, Balkin TJ, Kamimori GH. Baseline odor identification ability predicts degradation of psychomotor vigilance during 77 hours of sleep deprivation. The International journal of neuroscience. 2008;118(9):1207-25).
Timepoint [23] 318174 0
At baseline taken at 7.30pm prior to baseline sleep study
Secondary outcome [24] 318680 0
Magnetic Resonance Spectroscopy/Diffusion Tensor Imaging

Grey matter regions (including hippocampi, amygdala, and thalami) will be assessed as a composite outcome using Magnetic Resonance Spectroscopy.
Timepoint [24] 318680 0
At baseline, 1 week prior to laboratory stay

Eligibility
Key inclusion criteria
Age 25-65 years
Weight <150kg
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?
Yes
Key exclusion criteria
PSG confirmed sleep disorders (e.g. OSA)
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 necessary sample to achieve an accurate estimate of the normal cut-offs for driving simulator performance is based on our previous study (Vakulin et al, J Clin Sleep Med 2014;10(6):647-655) where participants underwent the driving simulator task using the same length drive (but different time of day). Data from 20 participants gave a mean+/-SD of lateral steering deviation of 36.5+/-9.2 cm. Thus, the upper limit of normal (mean+2SD) was 54.6 cm with a 99% confidence interval around the 2SD limit of 49–61 cm. Assuming a similar mean+/- SD in the proposed project, a sample size of 50 will provide approximately half the 99% confidence interval around the 2SD limit to 51–58 cm. Doubling of sample to 100, for example, provides little further improvement in 99% confidence interval to 52-57 cm, thus we believe that 50 individuals will provide robust normative data for driving simulator performance in this study.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
2/09/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 292093 0
Other Collaborative groups
Name [1] 292093 0
Cooperative Research Centre (CRC) for Alertness, Safety and Productivity
Country [1] 292093 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Cooperative Research Centre (CRC) for Alertness, Safety and Productivity
Address
Alertness CRC Ltd
Monash University
Ground Floor BASE Facility
264 Ferntree Gully Road
Notting Hill, VIC, 3468
Country
Australia
Secondary sponsor category [1] 290772 0
None
Name [1] 290772 0
Address [1] 290772 0
Country [1] 290772 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293579 0
Sydney Local Health District (RPAH Zone)
Ethics committee address [1] 293579 0
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 293579 0
Australia
Date submitted for ethics approval [1] 293579 0
Approval date [1] 293579 0
14/08/2015
Ethics approval number [1] 293579 0

Summary
Brief summary
This neurobehavioural dysfunction, such as impaired driving ability, has a critical impact on health and society. Many individuals underestimate their impairment and there is wide inter-individual variability in how individuals are affected by sleepiness and its consequences. For example, some may report few symptoms while others with apparent mild disease exhibit severe sleepiness. Unravelling this problem of interindividual variability demands better assessment tools as conventional metrics such as sleep studies are uninformative. 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. Performance under these conditions will be used to assess individual risk of vigilance failure such as impaired driving, and aid in the development of practically deployable biomarkers for predicting vulnerability to vigilance failure.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60406 0
Prof Ronald Grunstein
Address 60406 0
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 60406 0
Australia
Phone 60406 0
+61 2 91140007
Fax 60406 0
Email 60406 0
[email protected]
Contact person for public queries
Name 60407 0
Andrew Vakulin
Address 60407 0
Adelaide Institute for Sleep Medicine: A Flinders Centre of Research Excellence
School of Medicine, Faculty of Medicine, Nursing and Health Sciences, Flinders University.
Sleep and Respiratory Medicine, Repatriation General Hospital, Southern Adelaide Local Health Network
201-216 Daws Road,
Daw Park, SA 5041
Country 60407 0
Australia
Phone 60407 0
+61 8 8275 2847
Fax 60407 0
Email 60407 0
[email protected]
Contact person for scientific queries
Name 60408 0
Andrew Vakulin
Address 60408 0
Adelaide Institute for Sleep Medicine: A Flinders Centre of Research Excellence
School of Medicine, Faculty of Medicine, Nursing and Health Sciences, Flinders University.
Sleep and Respiratory Medicine, Repatriation General Hospital, Southern Adelaide Local Health Network
201-216 Daws Road,
Daw Park, SA 5041
Country 60408 0
Australia
Phone 60408 0
+61 8 8275 2847
Fax 60408 0
Email 60408 0
[email protected]

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