Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000526673
Ethics application status
Approved
Date submitted
17/04/2023
Date registered
19/05/2023
Date last updated
13/06/2024
Date data sharing statement initially provided
19/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Controlled Trial of Cannabidiol (CBD) for the treatment of Cannabis Use Disorder (CUD)
Scientific title
A Randomised Controlled Trial of Cannabidiol (CBD) for the treatment of Cannabis Use Disorder (CUD)
Secondary ID [1] 309153 0
None
Universal Trial Number (UTN)
U1111-1289-2424
Trial acronym
CBD-CUD Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cannabis use disorder 329270 0
Drug addiction 329271 0
Condition category
Condition code
Physical Medicine / Rehabilitation 326223 326223 0 0
Other physical medicine / rehabilitation
Mental Health 326906 326906 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1. Cannabidiol:
A parallel experimental group will receive oral Cannabidiol (400mg daily) for a 12-week treatment period.
Cannabidiol is the generic name, Epidyolex is the brand name. Epidyolex is an oral liquid (clear, colourless to yellow solution) containing 100mg per ml, and dispensed in 100 ml containers (bottles). Epidyolex also contains sesame oil, ethanol absolute, sucralose, strawberry flavour.
Participants will be instructed to take their dose of medication at the same time each day. Each medication container has a measuring syringe for participants to accurately administer their dose, and participants will be instructed by the study medical officer on dosing procedures. Participants will be instructed to resume normal dosing regimen in the event they have missed one or more doses. Participants who miss 3 or more consecutive weeks of study medication dosing will be deemed to have withdrawn from the trial intervention. Participants will be requested to bring their medication bottles to their next appointment with the research team or medical officer to review adherence to taking study medication.

2. Cognitive Behavioural Therapy:
All participants will be offered 4 structured 40-50 minute counselling sessions over the 12 week medication phase (Sessions 1-3 during the first 6 weeks; Session 4 in weeks 7-12). The sessions will be based on cognitive behavioural therapy (CBT) and motivation enhancement for relapse prevention, consistent with identified best practice for cannabis cessation interventions and structured (each of the four counselling sessions has a number of target goals) to ensure consistency between counsellors, although there is some flexibility to address issues identified by each participant.
An outline of the sessions are as follows:
Session 1: introduction to the counselling sessions, establishing treatment goals and attitudes to change to tailor the intervention, identify personal triggers, cues and high-risk situations and discuss associated strategies to quit or reduce.
Session 2: manage withdrawal symptoms and cognitive restructuring.
Session 3: review of cognitive strategies and skills enhancement, such as (i) problem-solving skills, (ii) management of insomnia, (iii) relaxation strategies, (iv) stress/anger management and (v) dealing with separation.
Session 4: relapse prevention, lifestyle modification and future goals.

A counselling manual will be developed for the study, and study clinicians (psychologists) will be trained by one of the study's investigators (Dr Steven Childs) to deliver the manualised counselling interventions. The Study Counsellor will keep a log of attendance at counselling sessions (including whether conducted face to face or telehealth, duration, and whether the counselling session was consistent with the intended counselling plan). Participation at counselling will be encouraged for all participants, although is not a mandatory requirement (that is, participants will not be terminated from the study for not participating in counselling).

3. Qualitative Research Interviews
Qualitative research interviews will be conducted with Aboriginal participants in a sub-study examining their perspectives of treatment. Approximately 20% of participants (n=50) will be Aboriginal. All Aboriginal participants will be invited to participate in the qualitative interviews and will sign a separate consent form to the main study. We expect approximately 20-30 Aboriginal participants to agree to take part in the interviews.
Qualitative interviews will be conducted either in person (face to face) or by telephone and estimated to take between 30 to 60 minutes. Interviews will be recorded digitally and transcribed. Interviews will follow a semi-structured format, with a number of ‘lead’ questions regarding key themes to be explored. The Aboriginal qualitative researcher will be skilled in qualitative interview techniques and supervised by an investigator on the study (Dr Michael Doyle).
Intervention code [1] 325604 0
Treatment: Drugs
Intervention code [2] 325868 0
Behaviour
Comparator / control treatment
A parallel control group will receive a placebo for a 12-week treatment period.
The placebo is an oral liquid (clear, colourless to yellow solution) and contains sesame oil, ethanol absolute, sucralose, strawberry flavour to match the active Epidyolex. The placebo will be dispensed in 100ml containers (bottles).
Control group
Placebo

Outcomes
Primary outcome [1] 334098 0
Cannabis-Free Days: assessed using the Time Line Follow-Back approach.
Timepoint [1] 334098 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 (primary endpoint) and week 24 (follow-up) post-commencement of intervention.
Primary outcome [2] 334654 0
Urinary quantitative analysis of THC-COOH (creatinine adjusted)
Timepoint [2] 334654 0
Urine samples are collected at week 1, week 4, week 7, week 10, week 12 (primary endpoint) and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [1] 419331 0
Severity of Cannabis Use Disorder: using the modified MINI DSM5 criteria, assessed by a bounded count, number of DSM-5 Cannabis Use Disorder criteria met out of a possible 11.
Timepoint [1] 419331 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [2] 420707 0
Quantity of Cannabis Use, estimated through self-report data regarding ‘average’ amount of cannabis (in grams) consumed by participants on the days they use cannabis.
Timepoint [2] 420707 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [3] 420708 0
Cravings for cannabis use, assessed using the Marijuana Craving Questionnaire, a 12-item self-report scale.
Timepoint [3] 420708 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [4] 420709 0
Cannabis related problems measured using the Cannabis Problems Questionnaire: self-reported 27 items with a 12-week time frame.
Timepoint [4] 420709 0
Participants will be assessed during research interviews on: Week 1, week 12 and week 24 (follow-up) post-commencement of intervention
Secondary outcome [5] 420710 0
Motivation to change cannabis use: Participant goals regarding their cannabis use, measured using the modified Motivation to Stop Scale: a single item self-reported measure.
Timepoint [5] 420710 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [6] 420711 0
Rates of cannabis abstinence: identified by whether a participant was abstinent vs non-abstinent within the previous 4-week period.
Timepoint [6] 420711 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [7] 420712 0
Safety (adverse events): Adverse events assessed at 3-weekly Study Medical Officer appointments.
Common side effects include: feeling drowsy or sleepy, decreased appetite, diarrhoea, fever, feeling tired or vomiting. Participants will be asked to self-report any side-effects from the study medication and the severity level (mild, moderate, severe).
Timepoint [7] 420712 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [8] 420713 0
Health and quality of life: Participant reported Patient Reported Outcomes Measurement Information System (PROMIS-29). 29 item scale assesses past 7-days, with 7 subscales: Depression, Anxiety, Physical Function, Pain Interference, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities.
All components will be assessed as a composite secondary outcome.
Timepoint [8] 420713 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [9] 420714 0
Mental health: psychosis: Features of psychosis measured using the Psychotomimetic State Inventory (PSIa). 48-item (True / False responses) with following subscales: Delusional Thinking (8 items); Perceptual distortion (10 items); Cognitive Disorganisation (9 items); Anhedonia (7 items); Mania (6 items); Paranoia (8 items).
Timepoint [9] 420714 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [10] 420715 0
Tobacco & Other substance use: Number of days of alcohol, tobacco (and number of cigarettes), e-cigs, and other drug use in past 21 days using modified Australian Treatment Outcomes Profile (ATOP)
Timepoint [10] 420715 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [11] 420716 0
Patient-rated experience: Self-reported measure Treatment Satisfaction Questionnaire for Medication (TSQM) scale, 14-tem questionnaire with four subscales: Effectiveness; Side effects; Convenience; Global satisfaction.

Timepoint [11] 420716 0
Participants will be assessed during research interviews on: Week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [12] 421541 0
Cognitive performance function: A targeted series of computerized tests: Rey Auditory Verbal Learning Test, Flankers Task, Digit Symbol Substitution Task, Reaction Time Index, Rapid Visual Information Processing, Stop Signal Task, N-Back and the Wechsler Test of Adult Reading for premorbid IQ.
All components of the cognitive test will be assessed as a composite secondary outcome.
Timepoint [12] 421541 0
Participants will be assessed during research interviews on: Week 1 and week 12.
Secondary outcome [13] 421542 0
Participant rating of group allocation: Participants will be asked to report which medication they believed they received (CBD or placebo) (testing the blind) (binary forced choice with VAS scale estimate of level of confidence in choice)
Timepoint [13] 421542 0
Participants will be assessed during research interviews on: Week 4, week 7, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [14] 421543 0
Treatment retention: Calculated from treatment records, along with reasons for trial completion (per protocol, drop out, administrative or medical discharge) assigned by SMO.
Timepoint [14] 421543 0
Through clinical records at week 12.
Secondary outcome [15] 421545 0
Qualitative research interviews: questions will have the following themes: (a) how participants perceive their own cannabis use and identify their treatment goals, (b) how participants engage with the study treatment procedures (medication, counselling, the role of Aboriginal Health Workers at study sites), and (c) participants experience of racial discrimination, identification with culture and community, and how their social networks (peers, family and local community) impact on attempts to change their cannabis use.
Timepoint [15] 421545 0
Research interviews will be conducted during weeks 7-12 of treatment intervention.
Secondary outcome [16] 421947 0
Severity of Cannabis Use Disorder: Participants will be assessed using the Cannabis Withdrawal Scale, a 19-item self-report scale.
Timepoint [16] 421947 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [17] 421948 0
Patient-rated experience: Drug Effects Questionnaire-5. Self-reported 5-item questionnaire assessing consumer ratings of drug effects.
Timepoint [17] 421948 0
Participants will be assessed during research interviews on: Week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [18] 421949 0
Tobacco & Other substance use: Fagerstom Test for Nicotine Dependence (FTND).
Timepoint [18] 421949 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.
Secondary outcome [19] 421950 0
Mental Health, PTSD: PTSD Checklist for DSM-5 (PCL-5) – Standard, a 20-question self-report measure
Timepoint [19] 421950 0
Participants will be assessed during research interviews on: Week 1, week 4, week 7, week 10, week 12 and week 24 (follow-up) post-commencement of intervention.

Eligibility
Key inclusion criteria
1. Aged 18 to 65 years.
2. Meeting DSM-5 criteria for moderate or severe Cannabis Use Disorder (more than or equal to 4 out of 11 criteria), with recent frequent cannabis use (more than or equal to 4 days per week in the preceding 4 weeks).
3. Willing and able to provide informed consent to study procedures.
4. Proficient in English at a conversational level sufficient to participate in counselling intervention (assessed by Study Medical Officer (SMO) at medical assessment).
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prescribed medicinal cannabis products (e.g., CBD, THC) for any indication in the previous 4 weeks.
2. Another active (past year) moderate-severe substance use disorder other than tobacco; operationalised on clinical assessment by SMO using DSM5 criteria.
3. Active or severe medical (e.g., pain, epilepsy, cardiovascular disease) or psychiatric conditions (e.g., psychosis, severe affective disorder) as identified by the Study Medical Officer; moderate to severe hepatic disease (transaminase elevations more than 3 times, bilirubin more than 2 times upper normal limits).
4. Pregnant or lactating women (urine beta-hCG).
5. Hypersensitivity to CBD or excipients of Epidyolex.
6.Using medications with known drug-drug hepatic CYP-450 interactions with CBD: 3A4, (e.g., carbamazepine, fluvoxamine, methadone), 2C19 (e.g., rifampin); CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin). The potential range of drug-drug interactions are considerable, and the SMO will make an assessment whether the potential for DDI is clinically significant (e.g., as for medications such as warfarin, HIV or anticonvulsant medications), and the SMO can discuss with PI Lintzeris if uncertain.
7. Not available for follow-up (e.g., travel, impending imprisonment).
8. Court-mandated treatment requiring abstinence from drugs.
9. Current active treatment for cannabis use disorder. People in existing treatment counselling and/or medication-based treatment for their cannabis use disorders (e.g., Alcohol and Other Drug services, private health services) are not eligible for the trial at the time of application. To participate, clients would have to choose to cease their existing treatment (counselling, medication) for a 4-week period prior to being formally assessed for the trial.
10. Received an investigational medicinal product within the last 4 weeks (or 5 half-lives if using long-acting investigational drugs).

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 is concealed for the clinician (person who determined if the participant was eligible for inclusion) to which group the participant will be allocated.
Allocation involved contacting the off-site trial pharmacist who is the holder of the allocation schedule.

The randomisation schedule will be developed by an independent statistician. Eligible participants will be randomised in a 1:1 ratio between groups using variable block randomisation to help maintain blinding, with subjects stratified by study site. The aim is to ensure approximately equal numbers of active / placebo at each site.
Aside from trial pharmacists, no other member of the research team or clinical staff will know the allocation of treatment condition. Participants, clinicians and researchers involved in service delivery, data collection and analysis will remain blinded to study condition (active or placebo medication) by the use of matched placebos manufactured by the pharmaceutical company providing the medication and placebo, in combination with the trial pharmacists at both sites. Trial pharmacists will not have contact with participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Eligible participants will be randomised in a 1:1 ratio between groups using variable block randomisation to help maintain blinding, with subjects stratified by study site.
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
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/05/2024
Actual
14/05/2024
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
250
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 24543 0
The Langton Centre - Surry Hills
Recruitment hospital [2] 24544 0
St George Hospital - Kogarah
Recruitment hospital [3] 24545 0
NSLHD Drug and Alcohol Service - St Leonards
Recruitment hospital [4] 24546 0
Drug and Alcohol Clinical Services, Hunter New England Local Health District - Newcastle
Recruitment hospital [5] 24547 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [6] 24548 0
Turning Point Drug and Alcohol Centre - Richmond
Recruitment hospital [7] 24549 0
Cumberland Hospital - Westmead
Recruitment postcode(s) [1] 40137 0
2010 - Surry Hills
Recruitment postcode(s) [2] 40141 0
2050 - Camperdown
Recruitment postcode(s) [3] 40139 0
2065 - St Leonards
Recruitment postcode(s) [4] 40143 0
2145 - Westmead
Recruitment postcode(s) [5] 40138 0
2217 - Kogarah
Recruitment postcode(s) [6] 40140 0
2300 - Newcastle
Recruitment postcode(s) [7] 40142 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 313354 0
Government body
Name [1] 313354 0
National Health and Medical Research Council
Country [1] 313354 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Camperdown, NSW 2006
Country
Australia
Secondary sponsor category [1] 315103 0
None
Name [1] 315103 0
Address [1] 315103 0
Country [1] 315103 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312576 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 312576 0
Research Ethics and Governance Office,
Sydney Local Health District
Level 11, KGV Building Missenden Road
Camperdown NSW 2050
Ethics committee country [1] 312576 0
Australia
Date submitted for ethics approval [1] 312576 0
29/11/2022
Approval date [1] 312576 0
03/02/2023
Ethics approval number [1] 312576 0
X22-0394 & 2022/ETH02467

Summary
Brief summary
The study is a parallel group double-blind Phase 3 randomised control trial comparing a 12-week treatment period of oral Cannabidiol (CBD) (400mg daily, Experimental) to Placebo (Control). The research hypothesis is that CBD, compared to placebo, will achieve significant reductions in cannabis use, as measured by number of self-reported cannabis-free days and urinary THC-COOH levels, among treatment-seeking patients with moderate-severe CUD.
Participants will be treatment-seeking clients recruited from study sites under conditions of informed consent. Participants will be randomly allocated to either CBD or placebo (1:1 ratio, double blind conditions), and attend every 3 weeks (weeks 1-12) for (a) clinical review with study doctor, (b) dispensing of medication, (c) collection of urine drug screen and (d) a research interview with an independent researcher. Participants will have up to 4 sessions of Cognitive Behavioural Therapy-based counselling over the 12 weeks. Final research interview will occur at week 24, 12 weeks after the study intervention. Additional qualitative research interviews will be conducted with Aboriginal participants in a sub-study examining their perspectives of treatment. Sample size is 250 participants, with approximately 125 randomised to each condition. It is estimated that approximately 20% of participants (n=50) will be Aboriginal. The study will use an intention to treat between-group analysis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125150 0
Prof Nicholas Lintzeris
Address 125150 0
The Langton Centre,
591 South Dowling Street,
Surry Hills, NSW 2010
Country 125150 0
Australia
Phone 125150 0
+61 4 1926 1675
Fax 125150 0
Email 125150 0
nicholas.lintzeris@health.nsw.gov.au
Contact person for public queries
Name 125151 0
Dr Anjali Bhardwaj
Address 125151 0
The Langton Centre,
591 South Dowling Street,
Surry Hills, NSW 2010
Country 125151 0
Australia
Phone 125151 0
+61 2 9332 8777
Fax 125151 0
Email 125151 0
cbd-cud.study@sydney.edu.au
Contact person for scientific queries
Name 125152 0
Dr Anjali Bhardwaj
Address 125152 0
The Langton Centre,
591 South Dowling Street,
Surry Hills, NSW 2010
Country 125152 0
Australia
Phone 125152 0
+61 2 9332 8777
Fax 125152 0
Email 125152 0
cbd-cud.study@sydney.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
All data will be de-identified and only available to the study committee. No IPD will be available to the public as per NHMRC and University of Sydney data confidentiality guidelines.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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