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Trial registered on ANZCTR


Registration number
ACTRN12618000545268
Ethics application status
Approved
Date submitted
23/03/2018
Date registered
12/04/2018
Date last updated
13/03/2019
Date data sharing statement initially provided
11/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised, Double Blind, Placebo-Controlled Trial of Medicinal Cannabis in Adults with Tourette's Syndrome
Scientific title
A Randomised, Double Blind, Placebo-Controlled, Crossover Trial of Tetrahydrocannabinol and Cannabidiol for the treatment of Tourette’s Syndrome
Secondary ID [1] 294438 0
Nil Known
Universal Trial Number (UTN)
U1111-1211-3260
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tourette's Syndrome 307184 0
Condition category
Condition code
Neurological 306299 306299 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Adults with Tourette's Syndrome will participate in a randomised, double-blinded, placebo-controlled, crossover clinical trial. Each participant will complete two 6-week periods of treatment with either active drug or placebo, with an intervening washout of 4-weeks. The order of presentation of active drug versus placebo will be randomly allocated and counterbalanced in a 1:1 ratio between groups. The active drug will be an oral solution containing 5mg/ml tetrahydrocannabinol (THC) and 5mg/ml cannabidiol (CBD). The placebo will be an inert oil. Initial dosing will be 1ml daily, increasing up to a maximum of 4ml daily in divided doses. Dose titration will be overseen by the lead investigator based on standardised evaluation of tic severity. Criteria for dose escalation will be a decrease of less than 2 points, no change or increased tic severity score on the Yale Global Tic Severity Scale. Dose increases will be at the rate of 1ml per week. Participants will be required to return empty bottles of medication at each visit in order to receive a further supply.
Intervention code [1] 300729 0
Treatment: Drugs
Comparator / control treatment
The placebo will be an excipient-matched oil with no active drug.
Control group
Placebo

Outcomes
Primary outcome [1] 305303 0
The difference in mean tic severity as assessed by the Yale Global Tic Severity Scale between active and placebo periods of treatment.
Timepoint [1] 305303 0
Assessed at baseline and then at week 2, week 4 and week 6 following commencement of the study drug in each treatment period (active drug and placebo). The primary endpoint will be week 6, compared to baseline.
Secondary outcome [1] 344802 0
The difference in mean tic severity as assessed by the Modified Rush Video-Based Rating Scale between active and placebo periods of treatment.
Timepoint [1] 344802 0
Assessed at baseline and then at week 2, week 4 and week 6 following commencement of the study drug in each treatment period (active drug and placebo).
Secondary outcome [2] 344803 0
The difference in mean obsessive-compulsive symptoms as assessed by the Yale-Brown Obsessive-Compulsive Scale between active and placebo periods of treatment.
Timepoint [2] 344803 0
Assessed at baseline and then at week 2, week 4 and week 6 following commencement of the study drug in each treatment period (active drug and placebo).
Secondary outcome [3] 344804 0
The difference in mean depressive symptoms as assessed by the Montgomery-Asperg Depression Rating Scale between active and placebo periods of treatment.
Timepoint [3] 344804 0
Assessed at baseline and then at week 2, week 4 and week 6 following commencement of the study drug in each treatment period (active drug and placebo).
Secondary outcome [4] 344805 0
The difference in mean anxiety symptoms as assessed by the Hamilton Anxiety Rating Scale between active and placebo periods of treatment.
Timepoint [4] 344805 0
Assessed at baseline and then at week 2, week 4 and week 6 following commencement of the study drug in each treatment period (active drug and placebo).
Secondary outcome [5] 344806 0
The difference in mean cognitive performance (on measures of processing speed, executive functioning and working memory) as assessed by the Cambridge Cognition (Cantab) cognitive tests (Reaction Time Task, Multitasking Test and Spatial Working Memory) between active and placebo periods of treatment.
Timepoint [5] 344806 0
Assessed at baseline and at the conclusion of each treatment period (6-weeks after commencement of study drug in each treatment period).
Secondary outcome [6] 344807 0
The difference in mean quality of life scores as assessed by the Quality of Life Enjoyment & Satisfaction Questionnaire between active and placebo periods of treatment.
Timepoint [6] 344807 0
Assessed at baseline and at the conclusion of each treatment period (6-weeks after commencement of study drug in each treatment period).
Secondary outcome [7] 344808 0
Adverse Event (AE) Recording with a comparison between active and placebo treatments. All AEs will be recorded between the time of consent and the final study assessment. Each participant will be monitored regularly by the investigator and study personnel for AEs occurring throughout the study. Particular attention will be given to dizziness, nausea, dry mouth, sedation, confusion and hallucinations.
Timepoint [7] 344808 0
Each study visit post consent.
Secondary outcome [8] 344815 0
The difference in mean serum cannabinoid and endocannabinoid markers as assessed by laboratory analysis of blood samples taken from participants during the active and placebo treatment periods.
Timepoint [8] 344815 0
At baseline and at week 4 of each treatment period.

Eligibility
Key inclusion criteria
Confirmed diagnosis of Tourette's syndrome with a tic severity score greater than 20 on the Yale Global Tic Severity Scale.
Must agree not to drive a motor vehicle during the trial.
Able to give written and informed consent.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of epilepsy.
History of multiple sclerosis.
History of an additional movement disorder such as Parkinson's disease.
History of dementia..
Pregnancy and breastfeeding.
Recreational cannabis smoker (participants must have a negative drug screen at study entry).
Current treatment with deep brain stimulation.
Current drug or alcohol abuse (excluding tobacco).
Any history of psychosis.
Diagnosis of bipolar disorder.
History of any previous high-lethality suicide attempt, history of any suicide attempt in the last 12-months or at high-risk of suicide in the opinion of the screening clinician.
Currently using antipsychotic or dopamine-depleting agents as treatment for Tourette's syndrome. Participants who have undergone a successful 4 week washout of current exclusionary therapies overseen by the Investigator will be eligible.
Allergy to tetrahydrocannabinol and cannabidiol or the tablet excipients.
Taken another study (experimental) drug within the past 30 days.

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 statistician at QIMR Berghofer Medical Research Institute will conduct randomisation. Randomisation will proceed in blocks of 6 to ensure balance across treatment groups. Active and placebo treatments will be labelled with a code that will be held by the statistician and will not be revealed to investigators or participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation.
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
Each participant will complete two 6-week periods of treatment with either active drug or placebo, with an intervening washout of 4-weeks.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The sample size calculation was performed under the assumption of a 2-group active drug versus placebo study. This was informed by data from randomised, placebo-controlled trials of antipsychotic medication for Tourette's Syndrome. For a mean difference in total tic score from baseline to 6-weeks of 9 (effect size 0.9) assuming a common standard deviation of 10, 5% type 1 error rate (two-sided) and power of 80% we estimated 21 participants per treatment group (total participants 42). Conservatively estimating a 10% drop out rate translated to 23 participants per group). In the current crossover methodology a total of 24 participants is proposed to allow for counterbalancing.

Analysis will be on an intention to treat basis. The primary outcome is change in total tic score of the Yale Global Tic Severity Scale (YGTSS) across each 6 week treatment period. We are interested in comparing the difference in the change in tic score between active and placebo treatment. Data will be analysed using a linear mixed effects model on an intention to treat basis. This will enable adjustment for missing data, should this occur. Period and carryover effects will be examined in the model. A secondary analysis will examine the difference in total tic score from baseline to 6 weeks between periods for each participant using an independent 2-sample t-test, or Mann-Whitney U test if the variable is not normally distributed. Period effects will be accounted for using the Hills-Armitage approach.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 299067 0
Hospital
Name [1] 299067 0
Wesley Medical Research Institute
Address [1] 299067 0
Level 8, East Wing
The Wesley Hospital
451 Coronation Drive
Auchenflower
QLD
4066
Country [1] 299067 0
Australia
Primary sponsor type
Hospital
Name
Wesley Medical Research Insititute
Address
Level 8, East Wing
The Wesley Hospital
451 Coronation Drive
Auchenflower
QLD
4066
Country
Australia
Secondary sponsor category [1] 298305 0
None
Name [1] 298305 0
Address [1] 298305 0
Country [1] 298305 0
Other collaborator category [1] 280042 0
University
Name [1] 280042 0
Lambert Initiative for Cannabinoid Therapeutics, University of Sydney
Address [1] 280042 0
University of Sydney
Brain and Mind Centre
94 Mallett Street
Camperdown
NSW
2050
Country [1] 280042 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300000 0
UnitingCare Health HREC
Ethics committee address [1] 300000 0
UnitingCare Health Human Research Ethics Committee
Ground Floor Moorlands House
The Wesley Hospital
451 Coronation Drive, Auchenflower QLD 4066
PO Box 499 Toowong QLD 4066
Ethics committee country [1] 300000 0
Australia
Date submitted for ethics approval [1] 300000 0
Approval date [1] 300000 0
19/01/2018
Ethics approval number [1] 300000 0
1744

Summary
Brief summary
Tourette’s syndrome (TS) is a neurological disorder that develops in childhood and often continues into adulthood. Individuals with TS make involuntary movements and vocalisations (known as tics), which may be painful, embarrassing and functionally impairing. There is no cure for TS, but certain medications (particularly antipsychotics) are effective at suppressing tics when taken continuously. Unfortunately, these medications have significant and independently-disabling side effects, which limit their acceptability for many sufferers.

The human body has its own (‘endogenous’) cannabinoid neurotransmitter system, which facilitates communication between nerve cells in the brain. This system is implicated in the control of normal movement and the development of movement disorders such as TS. The ‘endocannabinoid’ system could therefore be a new therapeutic target for tic suppression. There is some early evidence to support the effectiveness of cannabinoids in TS, but well-designed clinical trials have yet to be conducted.

We plan to use an oral formulation of medicinal cannabis containing two cannabinoids: tetrahydrocannabinol and cannabidiol. This formulation does not intoxicate or cause the unpleasant psychiatric effects of ‘street’ cannabis.

We predict that treatment with tetrahydrocannabinol and cannabidiol will significantly reduce tics, when compared to placebo, as well as improving psychiatric and cognitive symptoms associated with TS. We also predict that this formulation will be well tolerated, without psychiatric side effects, and will not lead to craving or intoxication. Therefore, this study may support the development of a new, safe and effective treatment for TS, with potential applications to other neurological disorders.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82222 0
Dr Philip Mosley
Address 82222 0
Neurosciences Queensland
Level 1, St Andrews Place
33 North Street
Spring Hill
QLD
4000
Country 82222 0
Australia
Phone 82222 0
+61738393688
Fax 82222 0
+61738393588
Email 82222 0
p.mosley@uq.edu.au
Contact person for public queries
Name 82223 0
Dr Philip Mosley
Address 82223 0
Neurosciences Queensland
Level 1, St Andrews Place
33 North Street
Spring Hill
QLD
4000
Country 82223 0
Australia
Phone 82223 0
+61738393688
Fax 82223 0
+61738393588
Email 82223 0
p.mosley@uq.edu.au
Contact person for scientific queries
Name 82224 0
Dr Philip Mosley
Address 82224 0
Neurosciences Queensland
Level 1, St Andrews Place
33 North Street
Spring Hill
QLD
4000
Country 82224 0
Australia
Phone 82224 0
+61738393688
Fax 82224 0
+61738393588
Email 82224 0
p.mosley@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
What supporting documents are/will be available?
No other documents available
Summary results
No Results