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Trial registered on ANZCTR


Registration number
ACTRN12621001659897
Ethics application status
Approved
Date submitted
18/10/2021
Date registered
1/12/2021
Date last updated
1/12/2021
Date data sharing statement initially provided
1/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot randomised controlled trial testing the efficacy of cannabidiol for anxiety in Tourette Syndrome
Scientific title
A pilot randomised controlled trial testing the efficacy of cannabidiol for anxiety in Tourette Syndrome
Secondary ID [1] 305302 0
Nil known.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tourette Syndrome 323618 0
Anxiety 323619 0
Condition category
Condition code
Mental Health 321152 321152 0 0
Anxiety
Neurological 321153 321153 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo-controlled cross-over trial to assess the efficacy of Cannabidiol (CBD) administered as Epidiolex. Epidiolex is a purified cannabidiol oral solution that will be administered orally or via gastrostomy and nasogastric feeding tubes.

All participants will undergo a screening process. Eligible participants will be randomised to begin either 16-weeks of treatment with CBD or 16-weeks of treatment with placebo. Each treatment block includes 6 weeks of titration, 8 weeks on the maintenance dose and 2 weeks of drug tapering. Following the initial 16-weeks of either treatment or placebo, patients will immediately cross-over and begin a further 16-weeks of the alternative treatment. Allocation to treatment group will be randomised and blinded for both participants and study personnel.

Treatment group A (Epidiolex)
Parents/caregivers will administer the study drug orally/via gastrostomy/via nasogastric tube in two divided doses (12 hours +/- 2 hours) daily. Dosage will be titrated over 6 weeks until maximum or best tolerated dose is reached. Maximum or best tolerated dose will be maintained for 8 weeks. Participants are then titrated down over a two week period, before crossing over to the alternative treatment arm.

Dosing schedule:
Week 1-2: 2.5mg/kg/day via two divided doses
Week 3-4: 5mg/kg/day via two divided doses
Week 5-6: 10mg/kg/day via two divided doses
Week 7-14: 15mg/kg/day
Week 15-16: 5mg/kg/day (Week 15); 2.5mg/kg/day (Week 16)

Four weeks after final dose, participants will be followed up in clinic prior to discharge from the study.

Compliance with study medication will be reviewed at each "in-clinic" appointment. Pharmacy staff will calculate the expected number of bottles (based on participants weight and expected titration schedule) required between clinic visit time points and dispense to the participants accordingly. Participants will be required to return all used and/or any unused bottles of medication to the study site pharmacy where clinical trial pharmacists will complete accountability and adherence calculations. This information will be forwarded to the PI and/or PO for noting.

A new prescription for the study medication will be provided by the PI to the clinical trial pharmacists who will dispense a new supply of study medication to see participants through until their next in-clinic appointment.
Intervention code [1] 321714 0
Treatment: Drugs
Comparator / control treatment
Treatment group B (Placebo)
Parents/caregivers will administer placebo orally/via gastrostomy/via nasogastric tube in two divided doses (12 hours +/- 2 hours) daily. Dosage will be titrated over 6 weeks until maximum or best tolerated dose is reached. Maximum or best tolerated dose will be maintained for 8 weeks. Participants are then titrated down over a two week period, before crossing over to the alternative treatment arm.

Dosing schedule:
Week 1-2: 2.5mg/kg/day via two divided doses
Week 3-4: 5mg/kg/day via two divided doses
Week 5-6: 10mg/kg/day via two divided doses
Week 7-14: 15mg/kg/day
Week 15-16: 5mg/kg/day (Week 15); 2.5mg/kg/day (Week 16)

Placebo suspension is comprised of sesame oil, sucralose and strawberry flavouring.
Control group
Placebo

Outcomes
Primary outcome [1] 328949 0
Any change in the total anxiety score on the Revised Children’s Anxiety and Depression Scale (RCADS) when compared with placebo.
Timepoint [1] 328949 0
Treatment Group A: Assessed periodically at Week 0 (Baseline), Week 6, Week 10 and Week 14.
Treatment Group B: Assessed periodically at Week 0 (Baseline), Week 6, Week 10 and Week 14.
Secondary outcome [1] 400911 0
Any change in quality of life as assessed via the Paediatric Quality of Life Scale when compared with placebo.
Timepoint [1] 400911 0
Treatment Group A: Assessed periodically at Week 0 (Baseline), Week 10 and Week 14.
Treatment Group B: Assessed periodically at Week 0 (Baseline), Week 10 and Week 14.
Secondary outcome [2] 400912 0
Any change in the depression scores on the Revised Children’s Anxiety and Depression Scale (RCADS) depression subscale when compared with placebo.
Timepoint [2] 400912 0
Treatment Group A: Assessed periodically at Week 0 (Baseline), Week 6, Week 10 and Week 14.
Treatment Group B: Assessed periodically at Week 0 (Baseline), Week 6, Week 10 and Week 14.
Secondary outcome [3] 400913 0
Any change in obsessive compulsive behaviour as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale when compared with placebo.
Timepoint [3] 400913 0
Treatment Group A: Assessed periodically at Screening, Week 6, Week 10 and Week 14.
Treatment Group B: Assessed periodically at Screening, Week 6, Week 10 and Week 14.
Secondary outcome [4] 400914 0
Any change in the number of tics as assessed by the Yale Global Tic Severity Scale in Group A (active) when compared with Group B (placebo).
Timepoint [4] 400914 0
Treatment Group A: Assessed periodically at Screening, Week 6 and Week 14.
Treatment Group B: Assessed periodically at Screening, Week 6 and Week 14.
Secondary outcome [5] 400915 0
Any change in problem behaviours as measured by the Strengths and Difficulties Questionnaire when compared with placebo.
Timepoint [5] 400915 0
Treatment Group A: Assessed periodically at Week 0 (Baseline), Week 6, Week 10 and Week 14.
Treatment Group B: Assessed periodically at Week 0 (Baseline), Week 6, Week 10 and Week 14.
Secondary outcome [6] 400916 0
Any change in subjective sleep parameters (including sleep quality, sleep duration and sleep efficiency) as measured by sleep actigraphy device.
Timepoint [6] 400916 0
Treatment Group A: Actigraphy device provided at Screening for 2 weeks of monitoring and re-assessed at Week 10 for 2 weeks of monitoring.
Treatment Group B: Actigraphy device provided at Screening for 2 weeks of monitoring and re-assessed at Week 10 for 2 weeks of monitoring.
Secondary outcome [7] 402653 0
Any changes in the premonitory urges for tics as assessed by the Yale Global Tic Severity Scale in Group A (active) when compared with Group B (placebo).
Timepoint [7] 402653 0
Treatment Group A: Assessed periodically at Screening, Week 6 and Week 14.
Treatment Group B: Assessed periodically at Screening, Week 6 and Week 14.
Secondary outcome [8] 402769 0
Any change in objective sleep parameters (including sleep duration) as measured by a sleep diary.
Timepoint [8] 402769 0
Treatment Group A: Diary provided at Screening for 2 weeks of sleep tracking. Re-assessed during dose maintenance. Diary provided for 2 weeks of tracking at Week 10.
Treatment Group B: Diary provided at Screening for 2 weeks of sleep tracking. Re-assessed during dose maintenance. Diary provided for 2 weeks of tracking at Week 10.

Eligibility
Key inclusion criteria
- Male or female children/adolescents aged 6-17 years old.
- Participants must have a diagnosis of Tourette Syndrome [confirmed by psychiatric diagnosis], and who have either (1) trialled a course of pharmaceutical (e.g. Clonidine), and psychological (e.g. cognitive behavioural therapy) treatment unsuccessfully; or, (2) who have significant contra-indications to standard methods of treatment
- Participants must be experiencing severe symptoms of anxiety as assessed by the PI at screening
- If participants are receiving non-pharmacological educational, behavioural, and/or dietary interventions, they must be stable and have been doing so for 2 months prior to screening.
- Participants must be willing to continue to be reviewed by their primary treating doctor/psychiatrist/paediatrician during the trial.
Minimum age
6 Years
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Use of any cannabis-based product within a month prior to the screening visit (confirmed via urine test at screening).
- Planned use of any cannabis-based product (or other investigational drug) other than that offered in this trial for the planned duration of this trial.
- History of treatment for, or evidence of, drug abuse within the past year.
- History of suicidal behaviour and active intent.
- Participants with pre-existing cardiac conditions or abnormalities.
- Known allergy to CBD or any other cannabinoid and the excipients (ethanol, sucralose, strawberry flavour, sesame oil).
- Participants currently using strong CYP 3A4 inhibitors/inducers or sensitive substrates which may interact with CBD
- Any clinically significant condition or abnormal findings at the Screening Visit that would, in the opinion of the PI, preclude study participation or interfere with the evaluation of the study treatment.
- Participants experiencing acute or progressive neurological disease, psychiatric disorder or severe cognitive abnormalities that are likely to require changes in drug therapy, interfere with the objectives of the trial, or interfere with the ability to adhere to protocol requirements.
- Females who are pregnant, nursing or are planning a pregnancy. Cannabidiol is contraindicated in pregnancy. Females of childbearing potential will require a negative serum pregnancy test before participating in the study. Females of childbearing potential must also be willing to use a suitable contraceptive during the trial if they plan on being sexually active. Urine pregnancy tests will be conducted and must remain negative to be permitted to continue the trial.

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)
Concealed allocation. (double-blind treatment group assignment); To facilitate the double-blinding process, the CBD/placebo will be dispensed by a clinical trials pharmacist who is independent to the PO.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to begin either 14 weeks treatment with CBD (intervention arm), or 14 weeks of treatment with placebo (control arm). Pharmacists will generate a block randomisation plan to assign participants to treatment or control groups according to a randomisation sequence.
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 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Efficacy Analysis: The primary efficacy estimand is the overall difference between treatments (CBD vs placebo) in reduction in total anxiety from Baseline to End of Treatment Group A on the Revised Children’s Anxiety and Depression Scale (RCADS).The statistician responsible for the analysis of outcome data will be blind to group allocation. The primary efficacy analysis will assess average treatment group differences for the primary and secondary outcome measures over the entire study period and will use a likelihood based mixed-effects model, repeated measures approach (MMRM).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2022
Actual
Date of last participant enrolment
Anticipated
1/05/2023
Actual
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 20515 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 35293 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 309672 0
Hospital
Name [1] 309672 0
Children's Health Queensland Hospital and Health Service
Country [1] 309672 0
Australia
Primary sponsor type
Hospital
Name
Children's Health Queensland Hospital and Health Service
Address
Queensland Children's Hospital
501 Stanley Street,
South Brisbane QLD
4101
Country
Australia
Secondary sponsor category [1] 310974 0
None
Name [1] 310974 0
Address [1] 310974 0
Country [1] 310974 0
Other collaborator category [1] 282022 0
Commercial sector/Industry
Name [1] 282022 0
GW Research Limited
Address [1] 282022 0
Sovereign House
Vision Park, Histon
Cambridge
CB24 9BZ
Country [1] 282022 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309440 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 309440 0
Level 7,
Centre for Children's Health Research
62 Graham Street,
South Brisbane QLD 4101
Ethics committee country [1] 309440 0
Australia
Date submitted for ethics approval [1] 309440 0
29/04/2019
Approval date [1] 309440 0
16/05/2019
Ethics approval number [1] 309440 0
HREC/19/QCHQ/51705

Summary
Brief summary
This trial will identify the efficacy of CBD for the treatment of anxiety in children and adolescents with Tourette Syndrome. Forty children and adolescents aged 6 to 17 years will be recruited to a 32-week randomised, double-blind, placebo controlled cross-over trial. Participants will be randomised on a 1:1 basis to either the active group (CBD) or control group (placebo). Following 14 weeks of the trial participants will then cross-over to the alternative group for comparison. It is proposed that while participants are in the active group their levels of anxiety will be significantly lower than when they are in the placebo group. Similarly, it is proposed that participants in the active group will also have significantly less tics, lower levels of depression, decreased obsessive-compulsive behaviours and improved quality of life, sleep and global symptomology.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114166 0
Dr John Down
Address 114166 0
Department of Neurosciences
Queensland Children's Hospital
501 Stanley Street
South Brisbane QLD 4101
Country 114166 0
Australia
Phone 114166 0
+61 07 3068 2580
Fax 114166 0
07 3069 7109
Email 114166 0
[email protected]
Contact person for public queries
Name 114167 0
Emily Milburn
Address 114167 0
Level 6
Centre for Children's Health Research
62 Graham Street
South Brisbane QLD 4101
Country 114167 0
Australia
Phone 114167 0
+61 07 3069 7709
Fax 114167 0
+61 07 3069 7109
Email 114167 0
[email protected]
Contact person for scientific queries
Name 114168 0
John Down
Address 114168 0
Department of Neurosciences
Queensland Children's Hospital
501 Stanley Street
South Brisbane QLD 4101
Country 114168 0
Australia
Phone 114168 0
+61 07 3068 2580
Fax 114168 0
07 3069 7109
Email 114168 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



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.