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Trial registered on ANZCTR


Registration number
ACTRN12621000349842
Ethics application status
Approved
Date submitted
15/12/2020
Date registered
26/03/2021
Date last updated
21/05/2024
Date data sharing statement initially provided
26/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Cannabidiol for At Risk for psychosis Youth
Scientific title
The effect of Cannabidiol on positive psychotic symptoms in At Risk for psychosis Youth: A randomised controlled trial
Secondary ID [1] 302838 0
Nil known
Universal Trial Number (UTN)
Trial acronym
CanARY
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ultra-High Risk of Psychosis 319812 0
Condition category
Condition code
Mental Health 317743 317743 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
CanARY is a Randomised Controlled Trial examining the feasibility of Cannabidiol (CBD) as a treatment for young people aged 12 - 25 years who have been identified as Ultra-High Risk of Psychosis. CanARY is a three-arm RCT with a placebo and 2 discrete drug doses randomised to the ratio 1:1:1. The study is double-blind. Participants will be asked to take the study intervention for 12 weeks.
CBD (per oral) – doses of 600mg or 1000mg per day (fixed schedule) for 12 weeks
- All participants will take 2x capsules in the morning and 3x capsules in the evening.
- For the 1000mg group each capsule will contain 200mg active CBD
- For the 600mg group 1x morning capsule will contain 200mg active CBD and 1x will be placebo; 2x evening capsules will each contain 200mg active CBD and 1x will be placebo
- For the placebo group all capsules will be placebo
Both placebo and the active are formulated in hard gelatin capsules, each placebo capsule contains 600mg Softisan 378.
Within the first week, the study doctor will call the participant to monitor compliance and check for any side effects.
Adherence to the study medication will be assessed by pill counts upon return of medication to the Research Assistant. Pill count verification will also be conducted by the pharmacy and a subset of these data by the unblinded monitor. Additionally, medication diaries (mobile applications) and e-reminder systems will be used to facilitate and document treatment adherence. Objective quantification of cannabinoid levels will be obtained via regular urine samples throughout the treatment phase. Where a participant fails to present to the treatment clinic (site) for visits where an intervention is administered, details of this protocol deviation will be recorded in the source documentation with the reason for the failure to present to the clinic explained where possible.

Clinical case management and psychological intervention will be continued as 'Treatment as Usual' in addition to pharmacological intervention. All participants will complete interviews at set time points: baseline, week 4, week 8 and week 12. Participants will also be provided the opportunity to complete a follow-up interview at week 26.

Lead-in
Young people aged 12-25 years who are interested in taking part in the study will be offered an initial appointment with a researcher. At this visit, the young person will be provided with information about the study, including the interventions, research assessments, time commitment, risks and benefits. At the lead-in visit, a researcher will explain the study and provide the participant (and their parent(s)/legal guardian for participants under the age of 18) with a copy of the consent form. If the participant (and their parent(s)/legal guardian for participants under the age of 18) give consent to take part in the trial, the researcher will then complete a demographic questionnaire, the Social and Occupational Functioning Assessment Scale (SOFAS), the Comprehensive Assessment of At-Risk Mental States (CAARMS), and the Structured Clinical Interview for DSM-5 – Schizotypal Personality Disorder Module (SCID-II) with the participant. The researcher will explain that participation in the trial is contingent on inclusion and exclusion criteria to be reviewed at the subsequent Screening visit and the persistence of UHR criteria until the Screening visit. The lead-in visit takes approximately 2 hours.

Screening Visit:
The Screening visit includes a review of the inclusion and exclusion criteria, medical history, physical examination, blood (fasted for 4-10 hours prior) and urine tests, and the CAARMS. A researcher will inform the participant about their eligibility to take part in the trial at the end of the Screening visit or as soon as the study doctor has confirmed the eligibility of the participant. The Screening visit will take approximately 2-3 hours.

Baseline (Week 0)
At the Baseline assessment, the inclusion and exclusion criteria and concomitant medication will be reviewed before the first 4 weeks of the investigational product (IP) is dispensed along with detailed instructions on how to take the IP. Rating scales (CAARMS, Montgomery Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Overall Anxiety Severity And Impairment Scale (OASIS), the Brief Psychiatric Rating Scale (BPRS), Negative Symptoms Inventory-Psychosis Risk (NSI-PR), Treatment Expecation Questionnaire (TEX-Q), the Patient Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD, SOFAS, Clinical Global Impressions Scale (CGI), Assessment of Quality of Life-8D (AQoL-8D), Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), Resource Use Questionnaire (RUQ), COVID-19 questionnaire and Structured Clinical Interview for DSM-5 (SCID-I)) will be completed as part of the Baseline visit and a hair sample will be collected. The Baseline assessment also includes a review of adverse events. The Baseline visit takes approximately 2 – 3 hours.

Week 4
The Week 4 visit includes a review of adverse events and a physical examination, the CAARMS, MADRS, HAM-A, OASIS, BPRS, PROMIS-SD, NSI-PR, SOFAS, CGI, AQoL-8D and ASSIST. The IP will be dispensed and any remaining IP from the Baseline visit returned and medication adherence will be recorded. Blood (fasted for 4-10 hours prior) and urine samples will be collected at this study visit. The Week 4 visit takes approximately 1.5 – 2 hours.

Week 8
The Week 8 visit includes a review of adverse events and completion of the CAARMS, MADRS, HAM-A, OASIS, SOFAS, CGI, AQoL-8D, PROMIS-SD, BPRS, NSI-PR and ASSIST. The IP will be dispensed and any remaining IP from the previous visit returned. Medication adherence will be recorded at the Week 8 visit and a urine sample collected. The Week 8 visit takes approximately 1.5 hours.

Week 12
The Week 12 visit includes a review of adverse events and a physical examination, the CAARMS, MADRS, HAM-A, OASIS, SOFAS, CGI, ASSIST, PROMIS-SD, BPRS, NSI-PR, AQoL-8D, RUQ and SCID-I. Any remaining IP from the Baseline visit returned and medication adherence will be monitored. Blood (fasted for 4-10 hours prior), urine and hair samples will be collected. If the participant is in the PK study, the week 12 main study bloods will be collected at the research clinic at the ‘2 hours prior to final dose’ time point (the first bloods collected on that day). The Week 12 visit takes approximately 2 hours.

Week 26 - Week 104
Give the study duration of 3.5 years, including a recruitment period of 3 years, not all participants will have week 56, week 78 or week 104 data collected. The length of time the young person is followed up for will depend on when the participant is recruited in the study. All participants will be followed-up to complete the week 26 visit. Participants will be asked if they are agreeable to be followed up for the 6 month, 12 month, 18 month and 24 month assessments to provide comprehensive results on the effectiveness and longevity of CBD. Participants can nominate not to complete these assessments.
The follow-up visits (Week 26, 52, 78 and 104) will include a review of adverse events and concomitant medication, and the administration of the CAARMS, MADRS, HAM-A, OASIS, SOFAS, CGI, ASSIST, AQoL-8D, PROMIS-SD, BPRS, RUQ, NSI-PR and SCID-I mood and psychosis modules* (*Week 26 only). These visits will take approximately 1 (Week 26 and 78) and 2 (Week 52 and 104) hours.


Intervention code [1] 319117 0
Treatment: Drugs
Intervention code [2] 319118 0
Prevention
Comparator / control treatment
There will be one placebo group. The placebo group will orally take 2 x tablets in the morning and 3 x tablets in the evening. The placebo tablets are formulated in hard gelatin capsules, each placebo capsule contains 600mg Softisan 378.
Control group
Placebo

Outcomes
Primary outcome [1] 325777 0
Severity of positive psychotic symptoms on the Comprehensive Assessment of At-Risk Mental States (CAARMS)
Timepoint [1] 325777 0
Week 12 post intervention commencement.
Secondary outcome [1] 389114 0
Transition to psychotic disorder will be assessed using the CAARMS
Timepoint [1] 389114 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.

Secondary outcome [2] 390792 0
Depression will be assessed by the Montgomery Asberg Depression Rating Scale (MADRS
Timepoint [2] 390792 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [3] 390793 0
Anxiety symptoms will be assessed by the Hamilton Anxiety Rating Scale (HAM-A) 108 and the Overall Anxiety Severity And Impairment Scale (OASIS
Timepoint [3] 390793 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [4] 390794 0
Sleep quality will be assessed by the Patient Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD)
Timepoint [4] 390794 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [5] 390795 0
General psychopathology will be assessed using the The Brief Psychiatric Rating Scale (BPRS) and the Negative Symptom Inventory-Psychosis Risk (NSI-PR).
Timepoint [5] 390795 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [6] 390796 0
Functioning will be assessed by the Social and Occupational Functioning Assessment Scale (SOFAS)
Timepoint [6] 390796 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [7] 390797 0
Change in clinical presentation and symptoms will be assessed using the the CGI-I scale, which ranges from 1 to 7, with lower scores indicating more improvement, as compared with baseline.
Timepoint [7] 390797 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [8] 390800 0
Quality of life will be measured using the Assessment of Quality of Life – eight dimension (AQoL- 8D) which can be used in both adolescents and adults.
Timepoint [8] 390800 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [9] 390801 0
Cost effectiveness will be measured using the Resource Use Questionnaire (RUQ), This measure has been developed for mental health economic evaluations undertaken in Australia.
Timepoint [9] 390801 0
Week 12 and Week 26 post intervention commencement.
Secondary outcome [10] 390802 0
The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)will be used to assess tobacco, alcohol and illicit substance use.
Timepoint [10] 390802 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [11] 392053 0
Distress associated with positive psychotic symptoms will be assessed using the CAARMS
Timepoint [11] 392053 0
Baseline, Week 4, Week 8, Week 12, Week 26, Week 52 (optional long term follow-up), Week 78 (optional long term follow-up) and Week 104 (optional long term follow-up) post intervention commencement.
Secondary outcome [12] 392057 0
Safety and Tolerability reported according to the Common Terminology Criteria for Adverse Events (CTCAE; version 5)
Timepoint [12] 392057 0
Week 12 post intervention commencement. Adverse events ongoing at week 12 assessment will be followed up at the remaining visits (week 26, week 52, week 78 and week 104) until they have resolved.

Eligibility
Key inclusion criteria

1. Aged 12-25 years (inclusive) at entry;
2. Sufficient fluency in English (for assessment purposes);
3. Ability to provide informed consent (parental/guardian consent will be obtained for participants aged <18 years);
4. Meeting one or more UHR for psychosis groups as defined in Table 1 of the study protocol; and
5. Attenuated psychotic symptoms present in the past month at UHR level as defined in Table 1 of the study protool.
Minimum age
12 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Ultra-High Risk symptoms only present during acute intoxication
2. If prescribed psychotropic medication (e.g. antidepressant medication) the individual must have been on a stable dose for a minimum of 6 weeks prior to randomisation). Antipsychotic medication is not an exclusion criterion. In the case of current antipsychotic use, medication will be tapered and ceased at entry to the study.
3. Pregnancy, lactation, or if sexually active, no effective contraception (applies to both male and female participants)
4. Clinical blood test findings that might compromise participant safety or confound the trial results
5. Acute or unstable systemic medical disorder
6. Psychiatric condition due to a medical condition;
7. Severe disturbance, such that the person is unable to comply with either the requirements of informed consent or the treatment protocol
8. Current acute suicidality/self- harm or aggression/dangerous behaviour
7. Diagnosis of a serious developmental disorder or a documented history of developmental delay or intellectual disability
9. History of a psychotic episode of one week or longer

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)
After the baseline assessment has been completed, the participant will be randomised to one of the three treatment groups. A randomisation list has been generated by an independent, unblinded statistician and passed onto the electronic database technician/designer. Therefore, allocation concealment is performed via central randomisation by a computer, which will then be inputted into the eCRF by the technician. Upon randomisation, an email will be sent directly to the pharmacy specifying which group the participant should be allocated to.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
An independent statistician will conduct the computerised stratified randomisation, with permuted blocks within each stratum. The clinical trial supply company will prepare the product specification file and prepare and label all trial drugs for study sites based on the randomisation sequence. All personnel involved in the study will be blinded to the randomisation sequence throughout the trial, except for the trial pharmacists
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
Double-blind RCT. Neither the researcher determining inclusion in the study or the participant will know which arm they will be allocated to. All personnel involved in the study will be blinded to the randomisation sequence throughout the trial, except for the trial pharmacists.
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary analysis will adopt the intention-to-treat approach and employ analysis of variance to conduct an overall comparison of the three treatment groups in terms of the primary outcome measure, which is severity of positive psychotic symptoms. If this overall comparison is significant, pairwise comparison of the treatments will be conducted using Fisher’s LSD test. As a secondary analysis, baseline outcome score, site, antidepressant treatment (the two stratifying variables in randomisation) and compliance level will be included as covariates. To compare the treatment groups for the secondary outcomes, survival analysis will be used for transition to psychosis, general linear model analysis for psychopathology measures, functioning and quality of life and logistic regression for clinical improvement (dichotomised as yes or no). Generalised linear mixed-effects model analysis will also be used to compare the treatment groups in terms of the longitudinal trajectories of the outcomes. If the amount of missing data is non-trivial, multiple imputation will be considered.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
20/06/2022
Actual
20/06/2022
Date of last participant enrolment
Anticipated
15/04/2025
Actual
Date of last data collection
Anticipated
15/10/2025
Actual
Sample size
Target
405
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment postcode(s) [1] 32044 0
3052 - Parkville
Recruitment postcode(s) [2] 32051 0
6056 - Midland
Recruitment postcode(s) [3] 32052 0
6017 - Osborne Park
Recruitment postcode(s) [4] 32053 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 307260 0
Charities/Societies/Foundations
Name [1] 307260 0
Wellcome Trust (UK)
Country [1] 307260 0
United Kingdom
Primary sponsor type
Other Collaborative groups
Name
Orygen
Address
35 Poplar Rd, Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 308318 0
None
Name [1] 308318 0
Address [1] 308318 0
Country [1] 308318 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307355 0
MELBOURNE HEALTH HUMAN RESEARCH ETHICS COMMITTEE
Ethics committee address [1] 307355 0
Ethics committee country [1] 307355 0
Australia
Date submitted for ethics approval [1] 307355 0
28/01/2020
Approval date [1] 307355 0
29/04/2020
Ethics approval number [1] 307355 0
HREC/60933/MH-2020

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106946 0
Prof Paul Amminger
Address 106946 0
Orygen, 35 Poplar Rd, Parkville VIC 3052
Country 106946 0
Australia
Phone 106946 0
+61 401 846 430
Fax 106946 0
Email 106946 0
[email protected]
Contact person for public queries
Name 106947 0
Paul Amminger
Address 106947 0
Orygen, 35 Poplar Rd, Parkville VIC 3052
Country 106947 0
Australia
Phone 106947 0
+61 401 846 430
Fax 106947 0
Email 106947 0
[email protected]
Contact person for scientific queries
Name 106948 0
Paul Amminger
Address 106948 0
Orygen, 35 Poplar Rd, Parkville VIC 3052
Country 106948 0
Australia
Phone 106948 0
+61 401 846 430
Fax 106948 0
Email 106948 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?
Only meta-data / information about the study will be displayed on the catalogue.
When will data be available (start and end dates)?
Data are currently embargoed. They will be available after the main results have been published for an indefinite time.
Available to whom?
Data will potentially be available to researchers from not-for profit organisations, commercial organisations or other based in any location. All data requests will be considered by the data custodian and the primary sponsor on a case-by-case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted. For further information, see Orygen data management policy.
Available for what types of analyses?
To any type of analyses. Assessed on a case-by-case basis.
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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