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Trial registered on ANZCTR


Registration number
ACTRN12618000629235
Ethics application status
Approved
Date submitted
18/04/2018
Date registered
20/04/2018
Date last updated
24/09/2019
Date data sharing statement initially provided
24/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of methamphetamine and alcohol on cognition and driving performance.
Scientific title
Characterising the effect of methamphetamine and alcohol on driving behaviour and performance in healthy volunteers
Secondary ID [1] 294647 0
Nil
Universal Trial Number (UTN)
Trial acronym
MeAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Drugged drivers 307152 0
Condition category
Condition code
Public Health 306274 306274 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Over the four-week experimental period, participation will receive all of the experimental doses.

One dose combination will be taken at each session (i.e. active methamphetamine + active alcohol, active methamphetamine + placebo alcohol, placebo methamphetamine + active alcohol and placebo methamphetamine + placebo alcohol) and the order of dosing will be randomised.

The active treatments are:
1. 0.42mg/kg d-methamphetamine in capsule, mixed with microcellulose crystalline in
size #0 gelatine capsule. Administered using a combination of no more than three
capsules to reach required dose, rounded to the nearest five (i.e. required dose of
33.1mg would be 35mg) (capsules will be 5mg, 10mg and 20mg).

2. Drink of weighted dose of vodka mixed with orange juice to obtain 0.04% blood alcohol
content (BAC)

The placebo treatments are:

1. Microcellulose crystalline only in size #0 capsule (identical in taste, texture, weight and
smell)

2. Drink of orange juice only, with rim of glass wiped with 5ml vodka to ensure double-
blind condition.

Each dose is weight related.
The doses of d-methamphetamine (and placebo) and the alcohol drink (and placebo) will be orally administered. The methamphetamine (and placebo) to be delivered in identical gelatine size #0 capsules. No more than three combined capsules will be provided at one time in order to reach the required dose. The dose of alcohol will be administered within a single 300mL cup of orange juice. The placebo drink will contain orange juice only. Adherence to the treatment protocol will be confirmed by assessing that the patient has consumed the treatment (both capsule and drink).
The treatment combination administered (i.e. active methamphetamine + active alcohol, active methamphetamine + placebo alcohol, placebo methamphetamine + active alcohol and placebo methamphetamine + placebo alcohol) will be randomised and will be provided once to participants at baseline at each of the four testing sessions. A one-week washout period will occur between testing sessions.
Prior to dosing at each testing visit (each at V1, V2, V3 and V4), participants will provide one saliva sample to screen for evidence of recent use of drugs [amphetamine/d-methamphetamine, 3,4- methylenedioxymethamphetamine (MDMA), cocaine, cannabis (del ta-9-tetrahydrocannabinol), opiates and ketamine] using the Securetec DrugWipe 6s device. This screening assessment requires an absorbent pad to be placed over the tongue for approximately 20 seconds. 1ml of saliva will be taken per sample, therefore approximately 4ml in total over each of the four experimental sessions. A sample volume of less than 10 micro litres is sufficient for analysis. The device is wiped on the tongue, when the colour has changed from pink to yellow there is the required amount of saliva to obtain the results.
For the purpose of determining salivary d-methamphetamine concentrations, oral fluid samples will be collected at two time points during each testing session using the Quantisal™ Oral Fluid Collection Device (each at V1, V2, V3 and V4). Oral fluid samples will be collected by a registered nurse, and will occur: Prior to the first cognitive assessment (approximately 25 mins post-dosing), and prior to leaving the testing site (approximately 2 hours post-dosing). At each sample collection time-point, 1ml of oral fluid will be collected. A total of 8ml will be collected per participant over the four experimental sessions.
Prior to dosing at each testing visit (each at V1, V2, V3 and V4), participants will also provide one baseline breathyser analysis to assess for the presence of alcohol. The breathalyser will then be used on four occasions over the course of the experimental session to ensure the desired BAC peak (0.04% BAC) is reached for testing, and record descending BAC post-peak. Specifically, breathalyser readings will be taken to ensure 0.0% BAC at the beginning of the testing session; confirm 0.04% BAC prior to cardiac and cognitive tasks; obtain BAC prior to the driving simulator task; obtain descending % BAC following the driving simulator task, prior to the second set of cognitive tasks; and obtain % BAC at the end of testing. All participants will be given a new, sterile mouth piece to use on each testing session. These will be deposited into biohazard bins after use.
A registered research nurse trained in venepuncture or a qualified venepuncture technician will collect blood samples at three time-points at each testing session (each at V1, V2, V3 and V4): prior to cognitive and driving tests and at ~ 2 hours post-driving test. This will be done via cannulation.
Heart rate, blood pressure readings will be measured using a blood pressure monitor. QT intervals will be assessed using the 12-lead Holter standard Electrocardiogram (ECG). Measurements will be taken to investigate participants’ cardiac effect of the treatments, individually and combined. Assessment will occur approximately 1 hour post ingestion of the treatment, and post driving-task (approximately 3 hours post dosing).
The CogTrack™ System 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: Digit vigilance, Spatial working memory, Numeric working memory. Participants will be assessed at 1 hour post-dosing and at 3 hours post dosing.
Driving performance will be assessed using the Forum 8 driving simulator, and driving performance will be assessed once per study session, for a 1 hour duration. The simulator consists of a car unit with adjustable car seats and a dashboard and includes a steering wheel, turn sign indicators, gear lever, brake and accelerator pedals for vehicle control. The system generates realistic roadway scenery which is presented on three integrated TV screens 1.90 meters in front of the centre of the steering wheel. The speed and gear number are displayed on the dashboard and screen. Auditory feedback is provided by speakers and included the sound of the engine, braking, speeding in curves, and driving off-road. Driving assessment will take place at 2 hours post dosing.
Intervention code [1] 300713 0
Treatment: Drugs
Comparator / control treatment
The placebo treatments are:
1. Microcellulose crystalline only in size #0 capsule (identical in taste, texture, weight and
smell)

2. Drink of orange juice only, with rim of glass wiped with 5ml vodka to ensure double-
blind condition.
Control group
Placebo

Outcomes
Primary outcome [1] 305281 0
Associations between d-methamphetamine and alcohol combinations produce upon cognitive performance
Timepoint [1] 305281 0
After administration of treatment combination. Specifically, this will occur at 1 hour post-dosing and at 3 hours post dosing. This will be assessed using the CANTAB cognitive battery; where and vigilance indices: digit vigilance; spatial working memory; and numeric working memory will be assessed.
Primary outcome [2] 305282 0
Associations between combined d-methamphetamine and legal levels of alcohol upon driving performance indices
Timepoint [2] 305282 0
After administration of treatment combination. Specifically, this will occur at 2 hours post dosing. This will be assessed using the Forum 8 driving simulator. Weaving of the car, expressed as standard deviation of the lateral position (SDLP), standard deviation of speed (SDS, km/h) and lapses will be assessed.
Primary outcome [3] 305283 0
Evaluate the efficacy of co-monitoring eye closure and saccadic activity to identify driving impairment caused by co-consumption of d-methamphetamine and alcohol
Timepoint [3] 305283 0
After administration of treatment combination. Specifically, this will occur at 2 hours post dosing in conjunction with the driving simulator. This will be assessed using the • Sensometrics cap-mounted eye tracking system and OptalertTM, and will measure saccade, fixation, and blink parameters (amplitude, velocity, duration)..
Secondary outcome [1] 344702 0
To identify the effect of d-methamphetamine and alcohol combinations on cardiac indices: heart rate and blood pressure.
Timepoint [1] 344702 0
After dosing, heart rate, blood pressure readings will be measured using a blood pressure monitor. QT intervals will be assessed using the 12-lead Holter standard Electrocardiogram (ECG). Assessment will occur approximately 1 hour post ingestion of the treatment, and approximately 3 hours post dosing.
Secondary outcome [2] 344703 0
Identify the effect of d-methamphetamine and alcohol combinations on sleep; objective (sleep time, awakenings) and subjective (difficulties with sleep).
Timepoint [2] 344703 0
Assessed during the one-week wash-out period between experimetnal sessions (V1, V2, V3 and V4). This will be completed using an Actigraphy sleep monitoring watch and a sleep diary.
Secondary outcome [3] 344704 0
Identify associations between whole blood concentrations of d-methamphetamine on cognitive, driving, cardiac and sleep outcomes
Timepoint [3] 344704 0
After administration of treatment using cannula. Specifically, this will occur at baseline (pre-treatment), approximately 30 minutes post dosing, 1. 5 hours post-dosing and at 2 hours post dosing.
Secondary outcome [4] 345730 0
Identify associations between salivary concentrations of d-methamphetamine on cognitive, driving, cardiac and sleep outcomes.
Timepoint [4] 345730 0
After administration of treatment using oral fluid collection pot. Specifically, this will occur at approximately 30 minutes post dosing and at 2 hours post dosing.

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;
• Non-smoker;
• Social drinker, who is experienced with consuming two alcoholic drinks on a single occasion, typically in a social setting;
• Experience with amphetamine-type substances;
• Is a regular driver (> 4,000 km/year) with three years of driving with a full driver’s licence;
• Less than 100kg in weight (due to weight related doses of d-methamphetamine and 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 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 illicit substance use for one week prior to, and for the duration of the trial.
o No driving or riding a bicycle or motorbike from the testing site;
o No driving, riding, operating heavy machinery for 24 hours after leaving the site
o No alcohol, drugs, or medication (unless consulted with 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.

The study treatment 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 d-methamphetamine 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] 299047 0
Charities/Societies/Foundations
Name [1] 299047 0
The Jack Brockhoff and Edwin Flack Foundation
Address [1] 299047 0
Suite 501,
685 Burke Rd,
Camberwell
VIC 3124
Country [1] 299047 0
Australia
Primary sponsor type
University
Name
Swinburne University of Technology
Address
PO Box 218
Hawthorn, Victoria, 3122
Country
Australia
Secondary sponsor category [1] 298516 0
None
Name [1] 298516 0
N/A
Address [1] 298516 0
N/A
Country [1] 298516 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299981 0
Swinburne University Human Research Ethics
Ethics committee address [1] 299981 0
Research Ethics Officer,
Swinburne Research (H68),
Swinburne University of Technology,
P O Box 218,
Hawthorn, Victoria, 3122.
Ethics committee country [1] 299981 0
Australia
Date submitted for ethics approval [1] 299981 0
27/03/2018
Approval date [1] 299981 0
23/07/2018
Ethics approval number [1] 299981 0

Summary
Brief summary
Amphetamine-type substances, especially d-methamphetamine, are second only to alcohol for incurred personal, economic and societal burden. Both alcohol and methamphetamine produce impairments in many areas of cognitive/neurobehavioural functioning which are also observed under complex driving conditions, and these two drugs are detected in as many as one-third of drivers injured and killed in road traffic accidents. No controlled experimental research is available which assesses performance on these tasks when alcohol and methamphetamine are used in combination, and importantly, how these deficits may translate into increased crash risk.

This trial aims to assess the direct effect of combined usage of low (legal) doses of alcohol combined with d-methamphetamine in measures of higher-order cognitive and neurobehavioural functioning, driving performance and ocular activity. This will be achieved through a within-subjects, double-blind, placebo-controlled design comprising four experimental sessions [alcohol (placebo: 0.00% BAC; active: 0.04% BAC) and d-methamphetamine (0.42mg/kg, placebo; active).

This project will provide vital information of how several behavioural, cognitive, neurobehavioural and physiological indices are affected following combined
alcohol and methamphetamine use, and will show the effect of these combined drugs on driving performance and accident risk.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82154 0
Dr Amie Hayley
Address 82154 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 82154 0
Australia
Phone 82154 0
+61 3 92145585
Fax 82154 0
Email 82154 0
ahayley@swin.edu.au
Contact person for public queries
Name 82155 0
Dr Amie Hayley
Address 82155 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 82155 0
Australia
Phone 82155 0
+61 3 92145585
Fax 82155 0
Email 82155 0
ahayley@swin.edu.au
Contact person for scientific queries
Name 82156 0
Dr Amie Hayley
Address 82156 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 82156 0
Australia
Phone 82156 0
+61 3 92145585
Fax 82156 0
Email 82156 0
ahayley@swin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
It is expected that the results of this trial will be disseminated via peer-reviewed publications and at academic conferences. For these purposes the data will be collated and analysed as group data. If required by the publishing journal, de-identified raw data will be uploaded to an appropriate repository. Otherwise, the trial data will not be made available.
What supporting documents are/will be available?
No other documents available
Summary results
No Results