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Trial registered on ANZCTR


Registration number
ACTRN12624001021561
Ethics application status
Approved
Date submitted
31/07/2024
Date registered
22/08/2024
Date last updated
22/08/2024
Date data sharing statement initially provided
22/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Do cannabidiol and diazepam interact? A proof-of-concept clinical trial.
Scientific title
Does cannabidiol alter the pharmacokinetics and pharmacodynamics of diazepam? A proof-of-concept clinical trial in healthy adults.
Secondary ID [1] 312533 0
CT-2024-CTN-03644-1
Universal Trial Number (UTN)
U1111-1310-6933
Trial acronym
CANNAZEPAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 334407 0
Condition category
Condition code
Mental Health 331044 331044 0 0
Anxiety
Injuries and Accidents 331045 331045 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention (‘perpetrator drug’) will be cannabidiol (CBD).

The specific IP will be a soft-gel capsule containing 200 mg CBD in medium chain triglyceride oil.

Participants will consume 400 mg CBD (or placebo) in the morning (i.e., between 6 AM – 12 PM), preferably with food, and 200 mg CBD (or placebo) in the evening (i.e., between 6 PM – 12 AM), preferably with food for seven consecutive days. The second-last dose (i.e., 400 mg CBD or placebo) will be taken with 10 mg diazepam (the 'victim drug') at a Test Session beginning on the morning of Day 7.

Each 7-day Treatment Period will be separated by a washout period of at least 14-days.

Treatment compliance will be measured using a ‘daily diary’ and a ‘pill count’.
Intervention code [1] 329047 0
Treatment: Drugs
Comparator / control treatment
The control will be a matched placebo. The placebo will be identical to the intervention but will not contain any CBD.
Control group
Placebo

Outcomes
Primary outcome [1] 338810 0
The area under the plasma diazepam concentration–time curve (AUC) (diazepam exposure)
Timepoint [1] 338810 0
Post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [1] 437523 0
The terminal half-life of diazepam (t1/2)
Timepoint [1] 437523 0
Post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [2] 437524 0
The maximum plasma diazepam concentration (Cmax)
Timepoint [2] 437524 0
Post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [3] 437525 0
The time to maximum plasma diazepam concentration (Tmax)
Timepoint [3] 437525 0
Post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [4] 437526 0
Driving performance: Standard deviation of lateral position (SDLP)
Timepoint [4] 437526 0
2, 8 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [5] 437527 0
Driving performance: Distance headway
Timepoint [5] 437527 0
2, 8 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [6] 437528 0
Driving performance: Standard deviation of distance headway
Timepoint [6] 437528 0
2, 8 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [7] 437529 0
Driving performance: Speed
Timepoint [7] 437529 0
2, 8 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [8] 437530 0
Driving performance: Standard deviation of speed
Timepoint [8] 437530 0
2, 8 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [9] 437531 0
Cognitive function: Number of correct patterns (correct responses)
Timepoint [9] 437531 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [10] 437532 0
Cognitive function: Number of attempted patterns (attempts)
Timepoint [10] 437532 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [11] 437533 0
Cognitive function: Response accuracy
Timepoint [11] 437533 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [12] 437534 0
Cognitive function: Number of correct matches (hits)
Timepoint [12] 437534 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [13] 437535 0
Cognitive function: Response time
Timepoint [13] 437535 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [14] 437536 0
Cognitive function: Tracking error
Timepoint [14] 437536 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [15] 437537 0
Cognitive function: Number of correct responses (correct responses)
Timepoint [15] 437537 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [16] 437538 0
Cognitive function: Response time
Timepoint [16] 437538 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [17] 437539 0
Balance: Centre-of-pressure
Timepoint [17] 437539 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [18] 437540 0
Balance: Sway
Timepoint [18] 437540 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [19] 437541 0
Balance: Sway velocity
Timepoint [19] 437541 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [20] 437542 0
Balance: Sway area
Timepoint [20] 437542 0
3, 9 and 25 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [21] 437543 0
Subjective feelings: Strength of drug effect
Timepoint [21] 437543 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [22] 437544 0
Subjective feelings: Euphoric
Timepoint [22] 437544 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [23] 437545 0
Subjective feelings: Sedated
Timepoint [23] 437545 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [24] 437546 0
Subjective feelings: Sleepy
Timepoint [24] 437546 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [25] 437547 0
Subjective feelings: Alert
Timepoint [25] 437547 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [26] 437548 0
Subjective feelings: Anxious
Timepoint [26] 437548 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.
Secondary outcome [27] 437549 0
Subjective feelings: Calm
Timepoint [27] 437549 0
Baseline (i.e., pre-diazepam administration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours post-diazepam administration on Day 7 of the Treatment Period.

Eligibility
Key inclusion criteria
a) Between 21–35 years of age.
b) Holds (and has held for at least 1 year) a full (unrestricted) driver’s licence.
c) Proficient in English (i.e., able to provide informed consent).
Minimum age
21 Years
Maximum age
35 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
a) An ‘active’ (i.e., uncontrolled, symptomatic) physical or mental health condition.
b) Self-reported use of cannabinoids or benzodiazepines within the last 3 months or a positive point-of-care urine drug screen for cannabinoids or benzodiazepines.
c) A self-reported history of allergic reaction (e.g., rhinitis, urticaria, contact dermatitis, anaphylaxis) to cannabinoid- or benzodiazepine-containing products.
d) A self-reported history of liver disease, renal disease, respiratory disease (including sleep apnoea), or drug/alcohol dependence (excluding nicotine dependence).
e) A suspected drug/alcohol dependence (excluding nicotine dependence).
f) A self-reported neurological disorder or intellectual disability.
g) Self-reported or suspected suicidal ideation.
h) A body weight <50 kg or body mass index >30 kg/m2.
i) Regular (i.e., weekly, or more often) use of medications or herbal remedies that induce or inhibit the cytochrome P450 (CYP) enzyme system or are metabolised by CYP enzymes that are inhibited by CBD (e.g., CYP2C19, CYP3A4).
j) Carrying one or more non-functional CYP2C19 alleles (i.e., *2 or *3).
k) Frequent (i.e., more than thrice weekly) use of psychoactive substances (excluding caffeine).
l) Unwilling or unable to adhere to trial procedures.
m) Pregnant, lactating or trying to conceive a child.

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)
Allocation will be concealed using numbered containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software.
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
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
‘Single-point’ continuous variables will be analysed using random-intercept linear mixed-effects models that include Treatment (categorical: Placebo, CBD) as a fixed effect and Participant as a random effect. Sex (categorical: Male, Female) will also be included as fixed effect if it reduces the Akaike Information Criterion (AIC) of the model. If the residuals are non-normally distributed (Shapiro-Wilk test, p<0.05) and/or heteroscedastic (Levene test, p<0.05), the dependent variable will be transformed and re-analysed. If transformation is not curative, a generalised linear mixed-effects model will be substituted. If an appropriate model cannot be generated, the ‘best’ of those described above (i.e., simplest model violating the fewest assumptions) will be utilised.

‘Serial’ continuous variables will be analysed using the same approach, except that the models will: (1) have random-intercepts and slopes; and (2) include Time (categorical) and the Treatment × Time interaction as fixed effects.

Count data will be analysed using generalized linear mixed-effects models that have random-intercepts and slopes and include the relevant fixed effects (as above).

Significant main and interaction effects will be investigated using two-sided, Dunn–Šidák- corrected post-hoc comparisons.

A priori planned pairwise comparisons of each of the pharmacodynamic parameters on CBD verses placebo at the ~24-hour post-diazepam administration timepoint will also be performed.

Statistical significance will be accepted as p<0.05.

Note: The primary analyses will be ‘intention-to-treat’; however, ‘per-protocol’ analyses (i.e., including only those participants who consumed =80% of the intervention) will also be performed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/09/2024
Actual
Date of last participant enrolment
Anticipated
31/05/2025
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 316956 0
Other
Name [1] 316956 0
Lambert Initiative for Cannabinoid Therapeutics
Country [1] 316956 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Country
Australia
Secondary sponsor category [1] 319203 0
None
Name [1] 319203 0
Address [1] 319203 0
Country [1] 319203 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315712 0
The University of Sydney Human Research Ethics Committee
Ethics committee address [1] 315712 0
https://www.sydney.edu.au/research/research-integrity-and-ethics.html
Ethics committee country [1] 315712 0
Australia
Date submitted for ethics approval [1] 315712 0
15/03/2024
Approval date [1] 315712 0
11/04/2024
Ethics approval number [1] 315712 0
2024/HE000214

Summary
Brief summary
Concomitant use of the anxiolytic drugs diazepam and cannabidiol (CBD) is expected to increase in the community. However, findings from a recent investigation by Lambert Initiative scientists suggest that CBD, via inhibition of the CYP2C19 and CYP3A4 enzymes, could reduce the rate at which diazepam is metabolised. Higher plasma diazepam concentrations (or concentrations that remain elevated for an extended period of time) have the potential to increase the risk of unwanted side effects and to exacerbate or prolong diazepam-induced sedation and impairment. This could have significant implications for individuals performing safety sensitive tasks such as driving. Thus, the overall objective of this study is to determine whether CBD alters the pharmacokinetics and pharmacodynamics of diazepam. Participants will complete two 7-day treatment periods: one involving the administration of a placebo, and the other, CBD (600 mg per day). Individuals will receive a single dose of diazepam (10 mg) along with their existing treatment at a test session on the morning of Day 7. Blood will be drawn, and simulated driving and cognitive performance measured, at regular intervals over the following 24 hours. We hypothesise that CBD will: (1) increase diazepam exposure; that is, the area under the plasma diazepam concentration–time curve; and (2) exacerbate diazepam-induced sedation and impairment.
Trial website
https://redcap.sydney.edu.au/surveys/?s=3LL9P39RAAPFRN34
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 135570 0
Dr Danielle McCartney
Address 135570 0
The University of Sydney, Brain and Mind Centre, 94 Mallett Street, Camperdown NSW 2050
Country 135570 0
Australia
Phone 135570 0
+61 404656000
Fax 135570 0
Email 135570 0
[email protected]
Contact person for public queries
Name 135571 0
Danielle McCartney
Address 135571 0
The University of Sydney, Brain and Mind Centre, 94 Mallett Street, Camperdown NSW 2050
Country 135571 0
Australia
Phone 135571 0
+61 404656000
Fax 135571 0
Email 135571 0
[email protected]
Contact person for scientific queries
Name 135572 0
Danielle McCartney
Address 135572 0
The University of Sydney, Brain and Mind Centre, 94 Mallett Street, Camperdown NSW 2050
Country 135572 0
Australia
Phone 135572 0
+61 404656000
Fax 135572 0
Email 135572 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?
All of the individual participant data collected during the trial (in non-identifiable form).
When will data be available (start and end dates)?
Start: Immediately following publication; End: 15 years from the day the study is completed.
Available to whom?
Researchers (upon reasonable request).
Available for what types of analyses?
Meta-analyses.
How or where can data be obtained?
The Principal Investigator ([email protected]).


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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