Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001112752
Ethics application status
Approved
Date submitted
8/08/2022
Date registered
11/08/2022
Date last updated
22/04/2024
Date data sharing statement initially provided
11/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Cannabidiol (CBD) for Clozapine Refractory Schizophrenia (CanCloz)
Scientific title
A Multi-Centre Randomised Placebo Controlled Pilot Study of Cannabidiol for Clozapine Refractory Schizophrenia
Secondary ID [1] 307634 0
None
Universal Trial Number (UTN)
Trial acronym
CanCloz
Linked study record

Health condition
Health condition(s) or problem(s) studied:
schizophenia 327126 0
schizoaffective disorder 327127 0
Obesity 327128 0
Metabolic syndrome 327129 0
Condition category
Condition code
Mental Health 324267 324267 0 0
Schizophrenia
Diet and Nutrition 324268 324268 0 0
Obesity
Metabolic and Endocrine 324269 324269 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will include 88 individuals with schizophrenia or schizoaffective disorder who will be randomised to receive daily 1000mg Cannabidiol or placebo for 12 weeks in addition to their normal routine care. Routine care is defined as 'individualized combinations of psychopharmacology, behavioural interventions, rehabilitation and associated clinical services in keeping with Queensland Health standards of care'.

All unused supplies of study medication (i.e. oral capsules), will be accounted for and documented by the designated Research Pharmacist. Compliance with study medication will be documented at each visit by means of a capsule count.
Intervention code [1] 324085 0
Treatment: Drugs
Comparator / control treatment
This study will use a placebo (MTC oil capsule) adjunct to routine care as a comparator condition.
Control group
Placebo

Outcomes
Primary outcome [1] 332080 0
The Primary outcome measure will be change in positive schizophrenia symptom severity, based on scores of the Positive and Negative Syndrome Scale (PANSS) score (positive scale) using the Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-PANSS).
Timepoint [1] 332080 0
Baseline (week 0), week 4, week 8 and week 12 (primary endpoint) post first dosage.
Secondary outcome [1] 412653 0
Metabolic syndrome will be assessed as a composite of pathology blood results HbA1c, HDL, LDL, triglycerides and waist circumference determined using a measuring tape, blood pressure determined using a digital blood pressure monitor and hip waist ratio
Timepoint [1] 412653 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [2] 412654 0

Liver function tests assessed by blood results
Timepoint [2] 412654 0

Baseline(week 0), and week 12 post-first dosage
Secondary outcome [3] 412655 0

Diet and appetite (Food Craving Inventory) will be assessed as a composite outcome.
Timepoint [3] 412655 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [4] 412656 0
Change in body weight in kg's and will be conducted by research assistants using calibrated digital scales
Timepoint [4] 412656 0
Baseline (week 0), week 4, week 8 and week 12 post-first dosage
Secondary outcome [5] 412657 0
Depression will be assessed using the Calgary Depression Scale.
Timepoint [5] 412657 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [6] 412658 0
Anxiety will be assessed using the HAM-A scale
Timepoint [6] 412658 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [7] 412659 0
Changes in sleep patterns will be assessed using the Pittsburgh Sleep Quality Index scale
Timepoint [7] 412659 0
Baseline (week 0), week 12 post-first dosage
Secondary outcome [8] 412660 0
Changes in physical activity will be assessed using the Simple Physical Activity Questionnaire (SIMPAQ) measure.
Timepoint [8] 412660 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [9] 412661 0
Changes in neurocognition will be assessed using the Brief Assessment of Cognition in Schizophrenia measures.
Timepoint [9] 412661 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [10] 412662 0
Quality of life will be measured using the Australian Quality of Life scale.
Timepoint [10] 412662 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [11] 412663 0
Inteligence Quotient will be measured using the Test of Premorbid Functioning
Timepoint [11] 412663 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [12] 412664 0
Safety and tolerability will be assessed using the Systematic Assessment for Treatment Emergent Events – Systematic Inquiry (SAFETEE-SI) e.g. nausea and diarrhoea.
Timepoint [12] 412664 0
Baseline (week 0), and week 12 post-first dosage
Secondary outcome [13] 434330 0
Change in schizophrenia symptom severity based off the total Positive and Negative Syndrome Scale (PANSS) score using the Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-PANSS).
Timepoint [13] 434330 0
Secondary outcome [14] 434331 0
Change in schizophrenia symptom severity based off the total Positive and Negative Syndrome Scale (PANSS) score using the Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-PANSS).
Timepoint [14] 434331 0
Baseline (week 0), week 4, week 8 and week 12 post first dosing

Eligibility
Key inclusion criteria
1. Aged between 18 and 64 years (inclusive).
2. Fulfil the DSM-IV criteria for schizophrenia or schizoaffective disorder, based on the Diagnostic Interview for Psychosis (DIP)
3. Total PANSS score greater than or equal to 60
4. Have received oral clozapine for a period of at least 18 weeks with a clozapine level of greater than 350mg/ml
5. Agree to participate, has capacity to consent and able to follow the study instructions and procedures.
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy, lactation, or if sexually active, no effective contraception (applies to both male and female participants)
2. Clinical blood test findings that might compromise participant safety or confound the trial results
3. Active current substance misuse including amphetamine and cannabis use
4. Other prescribed cannabinoids
5. Severe disturbance, such that the person is unable to comply with either the requirements of informed consent or the treatment protocol
6. Any concomitant disease or condition that according to the investigator’s assessment makes the patients unsuitable for trial participation
7. Cessation of clozapine

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)
An independent Biostatistician will generate the randomisation list which will be provided to the designated Research Pharmacist only.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised to one of the treatment groups, using a computer-generated randomization table. Participants will receive either active treatment or placebo in a 1:1 ratio.
Treatment group allocation ratios may change as a result of interim analyses. Allocation ratios will only change after approval from the DSMB.
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 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The effect of CBD relative to placebo on the outcome of 12-week positive-PANSS score will be analysed using a Mixed Model Repeated Measures (MMRM) with fixed effects for treatment arm, time, study site, and treatment arm * time interaction. A random intercept will be included to account for variation in scores between participants. An unstructured variance-covariance structure will be assumed, and where there are convergence issues, a compound symmetry covariance structure will be used instead. Consistent with a treatment-policy approach (ICH E9 R1), all participant data will be analysed regardless of missed assessment data, withdrawal from treatment arm or the use of rescue medication (i.e., Intention-To-Treat). Suitable contrasts will be used to evaluate the difference in mean total PANSS scores at the primary endpoint, week-12. Missing data will be imputed using Multiple Imputation by Chained Equations (MICE) under an assumption of Missing At Random (MAR). A sensitivity analysis will be conducted using a tipping point analysis and the delta adjustment method (e.g., MICE +/-1 PANSS positive score point increments) to evaluate the robustness of the model to the underlying assumptions of missingness. A further sensitivity analysis will be conducted using an alternative ANCOVA model plus MICE. All other secondary/exploratory outcomes will be analysed using the same approach. Number needed to treat will be calculated based on the proportion of participants in each arm who achieve >20% reduction in total PANSS.
Interim analysis
Three interim analyses will be performed once {25%, 50%, 75%} recruitment, corresponding with {n=22, 44, 66} participants have completed their 12-week assessments. Each interim analysis will provide an opportunity to evaluate whether the trial can be concluded at an earlier stage, rather than progressing until the target sample has been fully recruited. The interim analysis will evaluate the level of efficacy achieved conditional on a linear trajectory of change in PANSS positive scores and an end of trial Cohen’s d effect size =.48 The upper (early efficacy) and lower bounds (early futility) and their corresponding mean difference at interim analysis are summarised in 2. Conditional power at each interim analysis will be evaluated using bootstrap resampling (n=10,000). Exceeding the lower or upper bounds will be non-binding and all results of the interim analysis will be provided to the DSMB for further evaluation.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
12/09/2022
Actual
14/06/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
88
Accrual to date
22
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 22925 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 22926 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 22927 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 22928 0
Caboolture Hospital - Caboolture
Recruitment hospital [5] 22929 0
Ipswich Hospital - Ipswich
Recruitment hospital [6] 22930 0
Gold Coast University Hospital - Southport
Recruitment hospital [7] 22931 0
Robina Hospital - Robina
Recruitment hospital [8] 22932 0
Logan Hospital - Meadowbrook
Recruitment hospital [9] 22933 0
Redland Hospital - Cleveland
Recruitment postcode(s) [1] 38232 0
4029 - Herston
Recruitment postcode(s) [2] 38233 0
4032 - Chermside
Recruitment postcode(s) [3] 38231 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 38238 0
4131 - Meadowbrook
Recruitment postcode(s) [5] 38239 0
4163 - Cleveland
Recruitment postcode(s) [6] 38236 0
4215 - Southport
Recruitment postcode(s) [7] 38237 0
4226 - Robina
Recruitment postcode(s) [8] 38235 0
4305 - Ipswich
Recruitment postcode(s) [9] 38234 0
4510 - Caboolture

Funding & Sponsors
Funding source category [1] 311898 0
Hospital
Name [1] 311898 0
Princess Alexandra Hospital
Country [1] 311898 0
Australia
Funding source category [2] 311999 0
University
Name [2] 311999 0
The University of Sydney
Country [2] 311999 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Sir Fred Schonell Drive St Lucia, QLD 4072
Country
Australia
Secondary sponsor category [1] 313379 0
None
Name [1] 313379 0
Address [1] 313379 0
Country [1] 313379 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311333 0
Metro South HREC
Ethics committee address [1] 311333 0
37 Kent Street,
Woolloongabba QLD 4102
Australia
Ethics committee country [1] 311333 0
Australia
Date submitted for ethics approval [1] 311333 0
07/06/2022
Approval date [1] 311333 0
24/06/2022
Ethics approval number [1] 311333 0
HREC/2022/QMS/83530

Summary
Brief summary
The study will be a randomised, placebo-controlled double-blind parallel-group trial; over a 12 week period. The primary objective in this study is to determine the impact of a 12 week treatment of CBD on the PANSS positive score in patients with clozapine refractory schizophrenia compared to placebo. Specifically, it is hypothesised those participants allocated to the active arm CBD treatment will have meaningful difference in PANSS positive score of at least 1.8 at week 12 compared to individuals taking placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120750 0
Prof Dan Siskind
Address 120750 0
Metro South Addiction and Mental Health Service
228 Logan Road Woolloongabba QLD 4102
Country 120750 0
Australia
Phone 120750 0
+61 7 3317 1040
Fax 120750 0
Email 120750 0
d.siskind@uq.edu.au
Contact person for public queries
Name 120751 0
Prof Dan Siskind
Address 120751 0
Metro South Addiction and Mental Health Service
228 Logan Road Woolloongabba QLD 4102
Country 120751 0
Australia
Phone 120751 0
+61 7 3317 1040
Fax 120751 0
Email 120751 0
d.siskind@uq.edu.au
Contact person for scientific queries
Name 120752 0
Prof Dan Siskind
Address 120752 0
Metro South Addiction and Mental Health Service
228 Logan Road Woolloongabba QLD 4102
Country 120752 0
Australia
Phone 120752 0
+61 7 3317 1040
Fax 120752 0
Email 120752 0
d.siskind@uq.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
There will be no IPD sharing for this project. Group data analysis will be conducted and this data will be used for all publications


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16850Study protocol    384423-(Uploaded-08-08-2022-10-43-37)-Study-related document.docx
16851Ethical approval    384423-(Uploaded-08-08-2022-10-43-15)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.