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Trial registered on ANZCTR


Registration number
ACTRN12618000078257
Ethics application status
Approved
Date submitted
1/12/2017
Date registered
18/01/2018
Date last updated
29/01/2019
Date data sharing statement initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to evaluate an oral medicinal cannabis extract compared with placebo for the treatment of insomnia.
Scientific title
A study to evaluate the efficacy of sublingual cannabinoid based medicine
extract compared with placebo for the treatment of Insomnia.
Secondary ID [1] 293315 0
ZTL-INS-201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Insomnia 305404 0
Condition category
Condition code
Neurological 304841 304841 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial is a randomised double-blind placebo controlled cross-over study evaluating the efficacy of an oral medicinal cannabis extract (ZTL-101) containing cannabinoids for improving sleep in people with insomnia.
Each investigational product dose (0.5 mL of ZTL-101) is self-administered sublingually once daily at night one hour before bedtime for 14 days.
Adherence to the intervention treatment is monitored using the sleep diary where daily doses are recorded and return of any unused investigational product to the study site at the end of the 14 day treatment period.
Wash-out period between treatments is 1 week.
Intervention code [1] 299577 0
Treatment: Drugs
Comparator / control treatment
Placebo: Contains same excipient sunflower oil as the investigational product but does not contain cannabinoids.

Placebo (0.5mL) is also self-administered sublingually once daily at night one hour before bedtime for 14 days.
Control group
Placebo

Outcomes
Primary outcome [1] 303902 0
Insomnia symptoms as measured by the Insomnia Severity Index questionnaire
Timepoint [1] 303902 0
ISI assessments by an Investigator team member on enrolment and at the end of the 14 day baseline period on the morning following night 14, and post treatment periods of investigational product/placebo at the end of each of the 14 day treatment periods, with morning following night 14 (day 15) as the primary endpoint.
Secondary outcome [1] 340398 0
Objective measure of sleep, Sleep Onset Latency (SOL), determined using polysomnography (PSG) at the end of each 2 week baseline/investigational product/placebo periods (night 14) and actigraphy (nights 1 to 14).
Timepoint [1] 340398 0
*Measured using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14).
*Least Squares Mean SOL measured using actigraphy for each of the nights during baseline/investigational product/placebo periods (nights 1 to 14).

Secondary outcome [2] 340399 0
Objective measure of sleep, Wake After Sleep Onset (WASO), determined using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14) and actigraphy (nights 1 to 14).
Timepoint [2] 340399 0
*Measured using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14).
*Least Squares Mean WASO measured using actigraphy for each of the nights during baseline/investigational product/placebo periods (nights 1 to 14).
Secondary outcome [3] 340400 0
Objective measure of sleep, Total Sleep Time (TST), determined using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14) and actigraphy (nights 1 to 14).
Timepoint [3] 340400 0
*Measured using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14).
*Least Squares Mean TST measured using actigraphy for each of the nights during baseline/investigational product/placebo periods (nights 1 to 14).
Secondary outcome [4] 341169 0
Objective measure of sleep, Sleep Efficiency (SE), determined using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14) and actigraphy (nights 1 to 14).
Timepoint [4] 341169 0
*Measured using PSG at the end of each 2 week baseline/investigational product/placebo periods (night 14).
*Least Squares Mean SE measured using actigraphy for each of the nights during baseline/investigational product/placebo periods (nights 1 to 14).
Secondary outcome [5] 341170 0
Quality of sleep outcome measures assessed as follows:
*REM versus NREM sleep patterns including slow-wave sleep patterns and percentage of time in all sleep stages as measured by PSG on night 14 at the end of each 2 week periods (baseline/investigational product/placebo).
Timepoint [5] 341170 0
*PSG measured at the end of each 2 week baseline/investigational product/placebo periods (night 14).
Secondary outcome [6] 341171 0
*Quality of sleep outcome measure, presence and severity of sleep apnea (apnea-hypopnea index, AHI), as assessed by PSG on night 14 at the end of each 2 week periods (baseline/investigational product/placebo).
Timepoint [6] 341171 0
*PSG measured at the end of each 2 week baseline/investigational product/placebo periods (night 14).
Secondary outcome [7] 341172 0
*Quality of sleep outcome measure, periodic limb movements (PLM), as assessed by PSG on night 14 at the end of each 2 week periods (baseline/investigational product/placebo).
Timepoint [7] 341172 0
*PSG measured at the end of each 2 week baseline/investigational product/placebo periods (night 14).
Secondary outcome [8] 341173 0
Quality of sleep outcome measures assessed as follows:
*Subjective perceptions of sleep latency, duration, WASO, efficiency and quality as documented in the daily sleep diary for each of the 14 nights during baseline/investigational product/placebo periods (nights 1 to 14).
Timepoint [8] 341173 0
*Self-reporting daily in the sleep diary for each of the 14 nights during baseline/dosing/placebo periods (nights 1 to 14).
Secondary outcome [9] 341174 0
Quality of life outcome measure assessed as follows:
*Quality of life as measured by the Q-les-Q questionnaire subsequent to end of each of the 2 week baseline/investigational product/placebo periods on the morning of Day 15.
Timepoint [9] 341174 0
*Questionnaire measured by an investigator team member in the sleep clinic at the end of each of the 2 week periods baseline/investigational product/placebo on the morning of Day 15.
Secondary outcome [10] 341175 0
Quality of life outcome measure assessed as follows:
*Quality of life as measured by the Work and Social Adjustment Scale questionnaire subsequent to end of each of the 2 week baseline/investigational product/placebo periods on the morning of Day 15.
Timepoint [10] 341175 0
*Questionnaire measured by an investigator team member in the sleep clinic at the end of each of the 2 week periods baseline/investigational product/placebo on the morning of Day 15.
Secondary outcome [11] 341907 0
*Self-reported measure of mood, stress, and anxiety as assessed by the Depression, Anxiety, Stress Scale questionnaire subsequent to end of each of the 2 week baseline/investigational product/placebo periods on the morning of Day 15 .
Timepoint [11] 341907 0
*Questionnaire measured by an investigator team member in the sleep clinic at the end of each of the 2 week periods baseline/investigational product/placebo on the morning of Day 15.
Secondary outcome [12] 341908 0
*Self-reported measure of attitudes and beliefs about sleep as measured by the Dysfunctional Beliefs About Sleep questionnaire subsequent to end of each of the 2 week baseline/investigational product/placebo periods on the morning of Day 15.
Timepoint [12] 341908 0
*Questionnaire measured by an investigator team member in the sleep clinic at the end of each of the 2 week periods baseline/investigational product/placebo on the morning of Day 15.
Secondary outcome [13] 341909 0
*Self-reported measure of fatigue as measured by the multidimensional fatigue inventory questionnaire subsequent to end of each of the 2 week baseline/investigational product/placebo periods on the morning of Day 15.
Timepoint [13] 341909 0
*Questionnaire measured by an investigator team member in the sleep clinic at the end of each of the 2 week periods baseline/investigational product/placebo on the morning of Day 15.

Eligibility
Key inclusion criteria
a) Has provided a dated informed consent form signed by them; and
b) Is willing to comply with all study procedures and be available for the duration of the study; and
c) Male or female aged 25 – 70 years ; and
d) Presence of chronic insomnia defined as self-reported difficulty initiating (latency to persistent sleep >30 min) and/or maintaining sleep (>30 mins awake, or waking >30 mins before desired waking time)) on three or more nights per week) for at least 3 months; and
e) Insomnia Severity Index score >10
Minimum age
25 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a) Untreated cardiovascular disease, arrhythmias (other than well controlled atrial fibrillation), hypertension or severe heart failure; or
b) History of allergies particularly to plant-based products containing terpenes, ie flavours and aromatic natural oils for example citrus, mango, lavender, thyme, cedarwood and pine products; or
c) Known hypersensitivity to cannabinoids; or
d) Currently regularly using (greater than or equal to 3 nights/days per week) psychotropic or CNS-active drugs (including cannabis, opioids, benzodiazepines); or
e) Inability to refrain from use of psychotropic or CNS-active drugs (including cannabis, opioids, benzodiazepines) for at least one week prior to and duration of study; or
f) Inability to refrain from use of Cytochrome P450 inhibitors for at least one week prior to and duration of study. Examples include macrolide antibiotics (erythromycin, clarithromycin), azole antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), protease inhibitors (ritonavir, telaprevir, boceprevir), calcium channel blockers (amlopdipine), high cholesterol medication (gemfibrozil), cyclosporine, danazol, tachycardia medication (amiodarone), hypertension medication (verapamil, diltiazem), niacin (vitamin B3 greater than 1g/ day), grapefruit juice; or
g) Untreated metabolic disorders such as diabetes; or
h) Presence of severe depression, severe anxiety or other severe psychopathologic conditions based on self-report or depression scores on the DASS greater than or equal to 21, or anxiety scores on the DASS greater than or equal to 16; or
i) History of suicide attempt or current suicide ideation (response greater than 0 to Question 9 of PHQ-9); or
j) History of seizures or epilepsy; or
k) History of drug or alcohol abuse; or
l) Insomnia associated with sleep apnea (AHI greater than 15 events/hour) or movement disorders such as restless legs, periodic limb movement (PLM) (greater than 30 events/hour or greater than 5 events/hour with associated PLM arousals); or
m) Are currently participating in a formal behavioural therapy program to facilitate sleep; or
n) Current cannabis use (less than 2 months prior); or
o) Pregnancy or lactation; or
p) Inability to refrain from greater than 2 standard drinks/day of alcohol consumption for study duration; or
q) Inability to refrain from greater than 400mg/day of caffeine consumption for study duration; or
r) Shift workers or other workers and athletes who require testing and screening for cannabis products as part of their employment; or
s) Any person required to drive within 10 hours of dose, or those with a self-reported history of falling asleep while driving; or
t) Current delayed sleep phase syndrome where wake up time is regularly later than 8.00am.

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)
This is a double blind study where participants are randomly allocated to a coded investigational product or placebo product (A or B). The code is known only to the supplier and an independent study monitor.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants are randomised to either investigational product (A/B) or placebo product(A/B) first using randomisation software and based on the order of participant enrolment.
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
Baseline measurements are carried out for 2 weeks (14 nights) before the first of the 2 week treatment phases (investigational product or placebo) and a 1 week washout period is included between the first and second treatment phases.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
At the completion of data collection, measures of insomnia, sleep quality and quality of life will be analysed using a linear mixed effects model, with fixed effects of treatment (baseline, placebo, investigational product) and a random effect of individual. Data not normally distributed will undergo appropriate transformation prior to analysis.

Recruitment
Recruitment status
Not yet 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)
WA
Recruitment postcode(s) [1] 18067 0
6009 - Crawley

Funding & Sponsors
Funding source category [1] 297939 0
Commercial sector/Industry
Name [1] 297939 0
Zelda Therapeutics Limited
Address [1] 297939 0
Level 45, 108 St Georges Tce, Perth WA, 6000
Country [1] 297939 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zelda Therapeutics Limited
Address
Level 45, 108 St Georges Tce, Perth WA, 6000
Country
Australia
Secondary sponsor category [1] 297019 0
None
Name [1] 297019 0
Address [1] 297019 0
Country [1] 297019 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298984 0
Bellberry Limited
Ethics committee address [1] 298984 0
129 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 298984 0
Australia
Date submitted for ethics approval [1] 298984 0
24/03/2017
Approval date [1] 298984 0
21/08/2017
Ethics approval number [1] 298984 0
2017-03-226

Summary
Brief summary
Insomnia is the most common sleep disorder. Australian surveys have shown that 13-33% of the adult population have regular difficulty getting to sleep or staying asleep.
Previous studies have shown the benefit of synthetic delta-t-tetrahydrocannabinol (THC) and medical cannabis for a range of sleep disorders, however these trials were mainly targeted to investigate outcomes in other conditions such as pain and multiple sclerosis.
The aim of this study is to provide preliminary evidence for orally delivered medical cannabis for the treatment of sleep disorders due to insomnia.
This trial will enrol 24 participants aged (25-70) inclusive who have insomnia defined as self-reported difficulty initiating and/or maintaining sleep for 3 or more nights per week for at least 3 months. Participants will also be screened with a clinically validated questionnaire for insomnia by an Investigator team member before being recruited into the trial.
Participants involvement in the trial will be for approximately 8-11 weeks (depending on their availability to take the assessments). After completing a series of health asessments and questionnaires relating to their sleep, participants will commence the trial with a 2 week period of baseline measures (without investigational product or placebo) where they will need to wear a wrist-worn device to measure their quantity and quality of their sleep, as well as complete a sleep diary. On the final night of the 2 week period (night 14) they will have an overnight sleep study at the sleep centre site using a non-invasive measuring device to measure sleep patterns and assessments with questionnaires about their sleep by the Investigator team. Following a 1 week break, participants will be randomly allocated (by chance) to receive investigational product or placebo. Each of the treatment phases of both investigational product and placebo will be for 2 week periods including a 1 week break in between the treatments. The same requirements including measurements and assessments as per the baseline will be requried for each of the 2 week periods of investigational product and placebo.
This trial will provide information on the efficacy of medical cannabis for the treatment of sleep disorders due to insomnia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78894 0
Prof Peter Eastwood
Address 78894 0
Director, Centre for Sleep Science
School of Anatomy, Physiology and Human Biology,
The University of Western Australia
35 Stirling Highway, Crawley WA 6009
Country 78894 0
Australia
Phone 78894 0
+61 8 6457 1706
Fax 78894 0
Email 78894 0
Peter.Eastwood@health.wa.gov.au
Contact person for public queries
Name 78895 0
Dr Kathleen Maddison
Address 78895 0
Manager, Centre for Sleep Science
School of Anatomy, Physiology and Human Biology,
The University of Western Australia
35 Stirling Highway, Crawley WA 6009
Country 78895 0
Australia
Phone 78895 0
+61 8 6488 8689
Fax 78895 0
Email 78895 0
kathleen.maddison@uwa.edu.au
Contact person for scientific queries
Name 78896 0
Dr Jennifer Walsh
Address 78896 0
Research Fellow, Centre for Sleep Science
School of Anatomy, Physiology and Human Biology,
The University of Western Australia
35 Stirling Highway, Crawley WA 6009
Country 78896 0
Australia
Phone 78896 0
+61 8 6488 8689
Fax 78896 0
Email 78896 0
Jennifer.Walsh@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
under discussion
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable