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Trial registered on ANZCTR


Registration number
ACTRN12618000727246
Ethics application status
Approved
Date submitted
26/03/2018
Date registered
2/05/2018
Date last updated
23/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Benzodiazepines, alcohol and driving performance
Scientific title
The effect of psychoactive prescription benzodiazepines (alprazolam, temazepam and diazepam) and concomitant alcohol consumption upon performance and ocular activity whilst driving in adults.
Secondary ID [1] 294447 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Drugged driving 307197 0
Condition category
Condition code
Injuries and Accidents 306305 306305 0 0
Other injuries and accidents
Mental Health 306306 306306 0 0
Studies of normal psychology, cognitive function and behaviour
Public Health 306307 306307 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Three separate, double-blind, placebo-controlled cross-over trials will assess the direct effect of combined usage of legal doses of alcohol combined with three commonly used benzodiazepines (Alprazolam, Temazepam and Diazepam).
Each trial will involve four experimental conditions: alcohol (placebo: 0.00% BAC; active: 0.04% BAC) and benzodiazepine drug (placebo; active). The order of the four experimental conditions will be randomised for each participant (placebo-placebo, alcohol active-placebo, alcohol active-drug active, placebo-drug active). There will be a washout period of at least one week between each experimental condition.
Participants will be randomised into one of the three benzodiazepine trials (Trial 1: Alprazolam [1mg], Trial 2: Temazepam [10mg], Trial 3: Diazepam [5mg]).
At each visit, participants will be provided a beverage of orange juice and vodka (alcohol active, 0.04% BAC) or orange juice only (placebo) to consume, and a capsule containing a benzodiazepine (drug active) or inactive placebo. Vodka will be administered 0.38g alcohol/kg body weight, the estimated amount of alcohol required to reach a maximum BAC of 0.04%.
Adherence to consuming the intervention will be confirmed through direct observation of taking the benzodiazepine capsule and drinking the beverage, as well as the return of an empty beverage cup.

Following the treatment, participants will provide blood samples and complete cognitive tasks (CogTrak) at two time-points (30min post-intervention, 2hours post-intervention), a driving test on a driving simulator with simultaneous eye monitoring (50min post-intervention), as well as completing a number of questionnaire relating to subjective state and driving performance.
Intervention code [1] 300735 0
Treatment: Drugs
Comparator / control treatment
The alcohol and benzodiazepine placebo conditions will act as control conditions. Of the four testing sessions:
Placebo-drug will control for the additional effects of the alcohol on drug effects on performance;
Alcohol-placebo will control for the additional effects of the benzodiazepine on alcohol effects on performance;
Placebo-placebo will control for the overall effects of benzodiazepine and alcohol on performance.
Control group
Placebo

Outcomes
Primary outcome [1] 305316 0
Effect of combined use of benzodiazepines and alcohol on driving ability – weaving of the car, expressed as standard deviation of lane position (SDLP), and standard deviation of speed (SDS, km/h) and lapses (change in mean lateral position of the car greater than 100cm, lasting for at least 8sec).

Driving performance will be assessed using the Forum 8 driving simulator, which consists of a car unit with adjustable car seats, a dashboard, a steering wheel, turn sign indicators, gear lever, brake and accelerator pedals. The system generates realistic roadway scenery which is presented on three integrated TV screens (55x97cm) 1.90m in front of the centre of the steering wheel. Auditory feedback is provided by speakers and includes the sound of the engine, braking, speeding in curves, and driving off-road. A 105-km highway driving test scenario was developed by Forum 8, tailored to Australian traffic situations (e.g., common traffic signs, vehicles, buildings, and scenery). Participants will be instructed to drive with a steady lateral position in the left traffic lane while maintaining a steady speed of 100km/h. Overtaking manoeuvres are allowed whenever the car approaches a slower-moving car.

This composite primary outcome will be assessed through analysis of the data taken directly from the driving simulator.
Timepoint [1] 305316 0
After administration of treatment (alcohol and benzodiazepine administration). Specifically, at 1 hour post-alcohol consumption. As absorption of the benzodiazepines used in this study vary, and the study aims to measure effects at the drug peak, the outcome will be assessed 1 hour post-Alprazolam, 2 hours post-Temazepam, and 3 hours post-Diazepam administration.
Primary outcome [2] 305317 0
Effect of combined use of benzodiazepines and alcohol on ocular activity while driving – saccade, fixation, and blink parameters (amplitude, velocity, duration).

The SensoMetrics cap-mounted eye tracking system (SensoMotoric Instruments [SMI], Teltow, Germany) and the OptalertTM (Sleep Diagnostics Pty Ltd., Australia) will be used to record ocular activity. The SMI equipment is a video based mobile eye tracking system with eye and scene cameras. The OptalertTM objectively monitors eye and eyelid movements via infrared light emitters and sensors. Head mounted systems are designed to accurately track pupil size, eye movement and eye point-of-regard data from subjects while allowing complete freedom of head movement. .

This composite primary outcome will be assessed through analysis of the data taken directly from the SMI and OptalertTM.
Timepoint [2] 305317 0
After administration of treatment (alcohol and benzodiazepine administration). Specifically, at 1 hour post-alcohol consumption. As absorption of the benzodiazepines used in this study vary, and the study aims to measure effects at the drug peak, the outcome will be assessed 1 hour post-Alprazolam, 2 hours post-Temazepam, and 3 hours post-Diazepam administration.
Secondary outcome [1] 344829 0
Effect of combined use of benzodiazepines and alcohol on cognition – digit vigilance, spatial working memory, and numeric working memory.

The CogTrack System (http://www.wesnes.com/available-tests) will be used to assess the cognitive effects of the intervention. Three tasks will be used in this study to assess visual processing, processing speed and reaction/decision speed, specifically: 1) Digit vigilance, 2) Spatial working memory, and 3) Numeric working memory. The CogTrack System will be administered on computers in a quiet room with only the investigator present.

This composite secondary outcome will be assessed through analysis of the data taken directly from the CogTrack System.
Timepoint [1] 344829 0
After administration of treatment (alcohol and benzodiazepine administration). Specifically, at 40 minutes and 2.5 hours post-treatment administration.
Secondary outcome [2] 344830 0
Effect of combined use of benzodiazepines and alcohol on a composite of cardiac measures – blood pressure and heart rate.

This composite secondary outcome will be measured using a blood pressure monitor.
Timepoint [2] 344830 0
After administration of treatment (alcohol and benzodiazepine administration). Specifically, at 30 minutes post-treatment administration.

Eligibility
Key inclusion criteria
Male or female, aged 21 to 40 years;
Willing and able to provide written informed consent;
Understands and is willing and able to comply with all study procedures;
Fluent in written and spoken English;
Must have normal or corrected-to-normal vision;
In good general health as judged by the investigator and research nurse;
Non-smoker;
Social drinker, who is experienced with consuming two alcoholic drinks on a single occasion, typically in a social setting;
Experience with benzodiazepines;
Is a regular driver (> 4,000 km/year) with three years of driving with a full driver’s licence;
Less than 95kg in weight (due to the weight related dosing of alcohol);
Willing to abstain from the following prior to their scheduled visit:
o No food or drinks (except water) within 2 hours prior to testing
o No caffeine-containing products within 12 hours prior to testing
o No alcohol within 24 hours prior to testing
o No drugs/medication for at least 1 week prior to testing (except for prophylactic antibiotics, contraceptive pill or other routine medications to treat benign conditions, such as antibiotics to treat acne).
o No driving or riding a bicycle or motorbike from the site
o No driving, riding, operating heavy machinery for 24 hours after leaving the site
o No alcohol, drugs, or medication (unless you have consulted with your doctor) for 24 hours after leaving the site
Minimum age
21 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Unable to understand or comply with testing procedures;
Inability to speak or read English;
History of drug or substance abuse or current illicit drug abuse;
History of neurological conditions or previous or current history of psychiatric, cardiac, endocrine, gastrointestinal, or bleeding disorders;
Pregnant, potentially pregnant or lactating;
Taking any form of ongoing medication (except for prophylactic antibiotics, contraceptive pill or other routine medications to treat benign conditions, such as antibiotics to treat acne);
Unable to participate in scheduled visit, treatment plan, tests and other study procedures according to the protocol;
Current participation in any other studies involving investigational or marketed products within 30 days prior to the screening visit;
Have previously participated in this study.

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)
Blinding will be achieved by enlisting a disinterested third-party to code the treatments, and maintain the key to this code until data collection is completed.

For each of the three benzodiazepines, the capsules will be delivered to the Principal Investigator in a sealed white plastic bottle, labelled with the name of the drug in capital letters and either the letter “A” or “B” to signify the blinded drug randomisation group
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation of the order of treatment visits will be determined by random allocation by a disinterested third party. All consenting participants will be assigned a participant number. The randomisation order that has been placed next to the participants’ number will be the allocated treatment order for that individual using publicly available randomisation software (Research Randomiser Software Version 4.0).

Randomisation codes will be kept in a sealed envelope in a locked filing cabinet. Although study investigators will know the location of, and have access to, the sealed envelope, they will not access it during data collection and data screening procedures. Access will only occur in the case of an emergency when the participant’s allocated treatment needs to be known. If this occurs, the ethics committee will be informed.
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
Phase 2
Type of endpoint(s)
Pharmacodynamics
Statistical methods / analysis
Demographic data will be presented with summary statistics (number of participants, mean, standard deviation, median and range for variables) for each study. A mixed model ANOVA will be used to assess differences in neurocognitive and driving performance variables between the alcohol dose group (placebo, active) and benzodiazepine group (placebo, active) for each condition. Post hoc comparisons will be undertaken where significant condition or interaction effects are observed to determine the significance of differences between groups as a function of treatment group.

Correlations between cognitive outcome scores and the driving simulator across time points as function of treatment group will be conducted using Pearson product moment coefficient r. The predictive ability of performance on cognitive outcome to performance on the driving simulator task will be assessed using linear regression models. All statistical analyses will be conducted with the use of SPSS 24.0 (SPSS Inc., USA), and tests are two-tailed with a conventional level of significance of p< 0.05.

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)
VIC

Funding & Sponsors
Funding source category [1] 299074 0
Government body
Name [1] 299074 0
National Health and Medical Research Council (NHMRC)
Address [1] 299074 0
National Health and Medical Research Council
GPO Box 1421
Canberra, ACT, 2601
Country [1] 299074 0
Australia
Primary sponsor type
University
Name
Swinburne University of Technology
Address
PO Box 218
Hawthorn, Victoria, 3122
Country
Australia
Secondary sponsor category [1] 298313 0
None
Name [1] 298313 0
Address [1] 298313 0
Country [1] 298313 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300008 0
Swinburne University Human Research Ethics
Ethics committee address [1] 300008 0
Research Ethics Officer,
Swinburne Research (H68),
Swinburne University of Technology,
P O Box 218,
Hawthorn, Victoria, 3122.
Ethics committee country [1] 300008 0
Australia
Date submitted for ethics approval [1] 300008 0
23/02/2018
Approval date [1] 300008 0
19/04/2018
Ethics approval number [1] 300008 0
SRH Project 2018/061

Summary
Brief summary
Benzodiazepines are common psychoactive medications, used treat to conditions such as anxiety and insomnia, whose therapeutic effects can be accompanied by side effects such as drowsiness and impaired judgment. Observational research suggests an increased risk of road trauma for benzodiazepine and alcohol-affected drivers; however, it is currently legal to drive after consuming legal levels of alcohol and prescribed benzodiazepines, despite the potential risk to road users.

This project aims to evaluate the effect of three common benzodiazepines (Alprazolam, Temazepam and Diazepam), in combination with alcohol, on:
1. driving performance, to assess road risk; and
2. eye movements during driving, to identify objective markers of drowsiness and driving impairment.

This project will provide vital information regarding the effect of combined benzodiazepine and alcohol use on several physical, cognitive and neurobehavioural indices. This will be achieved through three separate double-blind, placebo-controlled, cross-over trials assessing the direct effect of combined usage of legal levels of alcohol (placebo; 0.04% BAC) and ONE of the three benzodiazepines (placebo; Alprazolam [1mg] OR Temazepam [10mg] OR Diazepam [5mg]). There will be 4 experimental sessions (alcohol + benzodiazepine, alcohol + placebo, placebo + benzodiazepine, and placebo + placebo) involving questionnaires, biological sampling (saliva, blood), cognitive tests, and a driving test on a driving simulator with simultaneous eye monitoring.
It is hypothesised that alcohol and benzodiazepines alone and in combination will have an adverse effect on driving performance, and will be marked by specific eye movement patterns.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82246 0
A/Prof Luke Downey
Address 82246 0
Swinburne University of Technology,
Faculty of Health, Arts and Design
School of Health Sciences
Centre for Human Psychopharmacology
Mail H24
PO Box 218
Hawthorn, Victoria, 3122
Country 82246 0
Australia
Phone 82246 0
+61 3 92145781
Fax 82246 0
Email 82246 0
ldowney@swin.edu.au
Contact person for public queries
Name 82247 0
A/Prof Luke Downey
Address 82247 0
Swinburne University of Technology,
Faculty of Health, Arts and Design
School of Health Sciences
Centre for Human Psychopharmacology
Mail H24
PO Box 218
Country 82247 0
Australia
Phone 82247 0
+61 3 92145781
Fax 82247 0
Email 82247 0
ldowney@swin.edu.au
Contact person for scientific queries
Name 82248 0
A/Prof Luke Downey
Address 82248 0
Swinburne University of Technology,
Faculty of Health, Arts and Design
School of Health Sciences
Centre for Human Psychopharmacology
Mail H24
PO Box 218
Country 82248 0
Australia
Phone 82248 0
+61 3 92145781
Fax 82248 0
Email 82248 0
ldowney@swin.edu.au

No data has been provided for results reporting
Summary results
Not applicable