Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000075583
Ethics application status
Approved
Date submitted
23/12/2014
Date registered
28/01/2015
Date last updated
22/01/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Vulnerability to alertness failure in response to sleep deprivation in people with obstructive sleep apnoea
Scientific title
Measurement of vulnerability to alertness failure of people with obstructive sleep apnoea in response to an extended wakefulness challenge
Secondary ID [1] 285778 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
CRC VAFOSA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnoea 293715 0
Condition category
Condition code
Respiratory 294017 294017 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A series of measurements relating to vulnerability to altertness failure will be undertaken at two laboratory visits, one week apart:
(1) baseline visit, with measurements undertaken in the evening of the visit, throughout the night and in the morning of the baseline visit
(2) an extended wakefulness (sleep loss challenge) visit
Details of the extended wakefulness intervention:
Each participant's wakefulness will be extended by 3 hours based on their habitual sleep onset time (which will be determined using actigraphy and sleep diary sent to the participants one week prior to their baseline visit).

Measurements will be undertaken in the evening of the visit, throughout the night and in the morning.
Intervention code [1] 290833 0
Diagnosis / Prognosis
Comparator / control treatment
Participants: The control group will consist of 50 healthy age and gender matched control participants.

Measurements: The control participants will undergo identical experimental conditions during baseline and extended wakefulness visits.

Rationale: In order to effectively phenotype people with obstructive sleep apnoea [OSA] as vulnerable or resistant to alterness failure, and develop clinically useful tests that discriminate betwen these phenotypes, it is critical to establish a normal range of neurobehavioural function and neurophysiological alertness biomarkers. This group's data will therefore be used as normative data with which to compare the data from participants with OSA.
Control group
Active

Outcomes
Primary outcome [1] 293852 0
Vulnerabilty to alertness failure, defined as meeting both of the following criteria:
(a) Mean steering deviation and/or number of crashes > 2 standard deviations [SD] above the healthy control participants using the AusEd driving simulator
(b) Mean number of psychomotor vigilance task [PVT] lapses > 2 SD above healthy control participants under the same conditions
Timepoint [1] 293852 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Primary outcome [2] 293854 0
AusEd driving simulator performance (specifically steering deviation and number of crashes).

This outcome is one of several tests that form a "test battery."
Timepoint [2] 293854 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Primary outcome [3] 293855 0
Psychomotor vigilance task [PVT] (number of attention lapses)

This outcome is one of several tests that form a "test battery."
Timepoint [3] 293855 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [1] 311994 0
Comprehensive questionnaire developed by the Australasian Sleep Trials Network (ASTN), covering the following participant details:
(a) Demographics
(b) Lifestyle
(c) Medical history
(d) Epworth Sleepiness Scale
(e) Pre-screening for
- sleep apnoea
- insomnia
- restless leg syndrome
- delayed sleep phase disorder
- depression/anxiety
- daily functioning
- fatigue
- disability
(f) Absenteeism
(g) Presenteeism
(h) Accidents (Work and Motor Vehicle)
Timepoint [1] 311994 0
To be administered (online or paper) to all participants prior to their first diagnostic sleep study (prior to the baseline visit of this study).
Secondary outcome [2] 311995 0
Sleep Diary (online) and Activate device measurements (Philips Respironics), specifically
- sleep/wake activity (activate and diary)
- caffeine and other stimulant intake (diary)
- alcohol intake (diary)
- shift work record (diary)
- light exposure (activate)
- heart rate variability (activate)
Timepoint [2] 311995 0
The device and sleep diary will be sent to the participants at least one week prior to their diagnostic (baseline visit) sleep study, with seven nights worth of data to be collected.
Secondary outcome [3] 311996 0
Retrospective Real-Life Outcome data Composite Index, comprised of:
(a) self-reported accidents of the following types in the previous 3 years
- traffic accidents
- near miss traffic accidents
- work place accidents
- near miss work place accidents
(b) objective traffic accident records - police or insurance records (to be confirmed)
(c) Healthcare utilisation costs according to the Australian Medical Benefits Scheme (MBS) and Pharmaceutical Benefits Scheme (PBS) data from the previous 3 years
Timepoint [3] 311996 0
This data will be collected prior to the baseline (diagnostic) visit
Secondary outcome [4] 311997 0
Choice Reaction Time Task (8 minutes)

This is a computer based task, where the participant must respond to 1 of 4 possible stimuli as quickly as possible. Reaction time and decision making is assessed.

This test has 13 outcome measures, assessing correct and incorrect responses, errors of commission and omission (late and early responses), and latency (response speed).

This outcome is one of several tests that form a "test battery."
Timepoint [4] 311997 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [5] 311998 0
Karolinska Drowsiness Test (KDT - 8 minutes)
This test standardises awake EEG recording with defined periods of eyes open and closed. This wake EEG will subsequently be subjected to power spectral analysis.

This outcome is one of several tests that form a "test battery."
Timepoint [5] 311998 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [6] 311999 0
Balance/Posturography Centre of Pressure (COP) measure

(Uses a force platform, 1 minute with eyes open and 1 minute with eyes closed).

This outcome is one of several tests that form a "test battery."
Timepoint [6] 311999 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [7] 312011 0
Electroencephalogram (EEG): quantitative power spectral analysis (PSA) of the EEG based on fast fourier transform (FFT) technique
Timepoint [7] 312011 0
The EEG will be collected during the PSG sleep study and during the "test battery" but the analysis will focus on the four timepoints listed below:
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [8] 312018 0
Polysomnography (PSG, full diagnostic study) with the following measures of alterness failure:
- Quantitative electroencephalogram (EEG), which will be subjected to PSA (power spectral analysis)
- Heart Rate Variability (HRV), to be derived form the electrocardiogram (ECG) signal
- Cardio Pulmonary Coupling (CPC) will be derived from the respiratory and ECG signals
The following additional measurements will also be collected during the PSG:
- Transcutaneous CO2 (TcCO2)
- Peripheral Skin Temperature to determine changes in skin temperature at sleep onset and throughout sleep
Timepoint [8] 312018 0
Baseline visit - with bed time no later than 10pm
The duration of PSG will be from 10pm till 6am.
The entire baseline visit will be from 6pm until 9am.
Secondary outcome [9] 312021 0
Fasting blood sample (~20mL) for measurement of the cytokines:
- Tumor Necrosis Factor-alpha (TNF)
- Interleukin-6 (IL-6)
- Interleukin-1 beta (IL-1 beta)
- C-reactive protein (CRP)
- sE-selectin
- IL-1- receptor antagonist
Timepoint [9] 312021 0
At 6.15am following the baseline visit PSG
Secondary outcome [10] 312022 0
Saliva sample for salivary metabolites relevant to sleep disorders and sleep loss (BioPlatforms Australia):
- Tumor Necrosis Factor-alpha (TNF)
- Iinterleukin-6 (IL-6)
- IL-1 beta
- C-reactive protein (CRP)
- sE-selectin
- IL-1- receptor antagonist
- Salivary alpha-amylase
Timepoint [10] 312022 0
After taking the blood sample, which will be just after 6.15am following the PSG for the baseline visit.
Secondary outcome [11] 312023 0
Dim Light Melatonin Onset (DLMO) will be measured using saliva sampling
Timepoint [11] 312023 0
Once per hour for eight hours, starting from the participant's habitual bed time (estimated from pre laboratory actigraphy and sleep diary).
Secondary outcome [12] 312277 0
Electrocardiogram (ECG) to measure cardiopulmonary coupling (CPC) and heart rate variability (HRV)
Timepoint [12] 312277 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [13] 312278 0
Peripheral skin temperature to determine changes in skin temperature at sleep onset and after sleep.

Peripheral body temperature would be measured continuously throughout the protocol using small skin temperature sensors (iButtons, Thermochron iButton DS1922L; Maxim Dallas Semiconductor Corp, U.S.A.) Ten skin sites will be used; forehead, mid-scapula, mid-clavicular region (chest), upper lateral arm, ventral forearm, thenar prominence (non-dominant hand), mid anterior thigh, mid-calf, palmar surface of index finger (non-dominant), medial metarsal area of plantar foot. These multiple sites will provide a comprehensive examination of skin temperature regions, allowing surface temperature gradients to be calculated.
Timepoint [13] 312278 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [14] 312279 0
Optalert ocular measurements
Timepoint [14] 312279 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [15] 312280 0
Seeing Machines (Drive State Sensor, DSS) - infrared camera based eye movement measure
Timepoint [15] 312280 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [16] 312281 0
- Speech (novel altertness monitoring through voice characteristics, with video recording. The voice recording takes ~45 seconds)
Timepoint [16] 312281 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [17] 312282 0
Near-infrared Spectroscopy (NIRS) to measure brain oxygenation (activity) in right prefrontal cortex during neurocognitive tasks and driving
Timepoint [17] 312282 0
Four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [18] 312283 0
High sensitivity electric potential sensors in non-contact mode (measures disruption in the electric field caused by human body movement) to assess respiration and heart rate during driving.
Timepoint [18] 312283 0
Whilst using the AusEd driving simulator at four timepoints (part of the "test battery"):
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following PSG
(b) During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness (e.g. at 3am for someone with habitual sleep onset time of midnight).
Secondary outcome [19] 320124 0
Karolinska Sleepiness Scale (KSS) - This is a 9-item momentary sleepiness scale designed to assess the individual's state of sleepiness at any given time. 1 corresponds to "Extremely Alert" and 9 corresponds to "very sleepy, fighting sleep, great effort to stay awake".
Timepoint [19] 320124 0
The KSS will be administered 3 times during the cognitive test battery.

The test battery consists of four time-points:
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following overnight PSG
(b)During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness
Secondary outcome [20] 320125 0
Working memory task - N-Back 1,2 and 3: This is a simple working short term memory task that takes about 10 minutes.
Timepoint [20] 320125 0
The test battery consists of four time-points:
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following overnight PSG

(b)During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness
Secondary outcome [21] 320126 0
Digit Symbol Substitution Task - This task requires matching of various symbols with digits 1-9, given a scale where each symbol corresponds to a specific digit. The task lasts 90 seconds and the goal is to obtain as many correct responses in this time period. This is a generic cognition test with memory and speed of processing components, that is used clinically to test for brain injury, age-related cognitive decline, dementia and depression.
Timepoint [21] 320126 0
The test battery consists of four time-points:
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following overnight PSG

(b)During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness
Secondary outcome [22] 320127 0
Post-Test Effort Questionnaires - These are designed to gauge the level of difficulty and effort experienced whilst performing the cognitive test battery.
Timepoint [22] 320127 0
The test battery consists of four time-points:
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following overnight PSG

(b)During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness
Secondary outcome [23] 320128 0
Spielberger State-Trait Anxiety Inventory (State) - This 20-item questionnaire assesses participant state of anxiety and stress during the cognitive test batteries.
Timepoint [23] 320128 0
The test battery consists of four time-points:

(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following overnight PSG

(b)During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness
Secondary outcome [24] 320129 0
Grip Strength - This task requires the participant to squeeze the dynamometer as hard as possible 3x3 seconds on both hands (total 6 squeezes). The grip endurance requires the participant to continually squeeze the dynamometer as hard as possible for as long as possible.
Timepoint [24] 320129 0
The test battery consists of four time-points:
(a) At baseline visit
- evening at 7pm prior to bedtime
- morning at 7am following overnight PSG

(b)During extended wakefulness visit
- evening at 7pm prior to bedtime
- morning after 3 hour extended wakefulness

Eligibility
Key inclusion criteria
(a) Diagnosis of obstructive sleep apnoea
(b) Apnoea-hypopnoea index [AHI] greater than or equal to 10 per hour
(c) Able to provide informed consent
(d) English speaking (to understand instructions for performance tests)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Physician recommended exclusion
(b) Unable to or unwilling to consent
(c) Central sleep apnoea (central apnoea index > 5/hour)
(d) Major co-morbidities (e.g. cardiac or respiratory failure, severe or very severe (GOLD 3/4) chronic obstructive pulmonary disease [COPD], uncontrolled psychiatric illness)
(e) No use of continuous positive airways pressure [CPAP] or mandibular advancement splint [MAS] treatment

Study design
Purpose of the study
Diagnosis
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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/02/2015
Actual
15/09/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
550
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC

Funding & Sponsors
Funding source category [1] 290433 0
Other Collaborative groups
Name [1] 290433 0
Cooperative Research Centre (CRC) for Alertness, Safety and Productivity
Country [1] 290433 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] 289177 0
University
Name [1] 289177 0
Flinders University
Address [1] 289177 0
Research Services Office
Flinders University
GPO Box 2100
Adelaide, SA, 5001
Country [1] 289177 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292144 0
Sydney Local Health District (SLHD) Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 292144 0
Mailing Address:
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 292144 0
Australia
Date submitted for ethics approval [1] 292144 0
25/11/2014
Approval date [1] 292144 0
05/03/2015
Ethics approval number [1] 292144 0
AU/1/31FB18

Summary
Brief summary
The objective of this study is to determine relative vulnerability to alertness failure using a sleep loss (extended wakefulness) challenge in people with obstructive sleep apnoea, and to collect data on related markers of biological function (biomarkers) for comparision. By examining the biomarkers in people who are more vulnerable to alertness failure compared with those who are more resistant, it may be possible to develop new, readily usable measures to predict vulnerability to alertness failure, to allow better tailored care and advice for those individuals.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53234 0
Dr Andrew Vakulin
Address 53234 0
Adelaide Institute for Sleep Health
Repatriation General Hospital
Daws Rd, Daw Park
South Australia 5041
Australia
Country 53234 0
Australia
Phone 53234 0
61 8 8275 1187
Fax 53234 0
61 8 8277 6890
Email 53234 0
[email protected]
Contact person for public queries
Name 53235 0
Dr Andrew Vakulin
Address 53235 0
Adelaide Institute for Sleep Health
Repatriation General Hospital
Daws Rd, Daw Park
South Australia 5041
Australia
Country 53235 0
Australia
Phone 53235 0
61 8 8275 1187
Fax 53235 0
61 8 8277 6890
Email 53235 0
[email protected]
Contact person for scientific queries
Name 53236 0
Dr Andrew Vakulin
Address 53236 0
Adelaide Institute for Sleep Health
Repatriation General Hospital
Daws Rd, Daw Park
South Australia 5041
Australia
Country 53236 0
Australia
Phone 53236 0
61 8 8275 1187
Fax 53236 0
61 8 8277 6890
Email 53236 0
[email protected]

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What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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