Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000474156
Ethics application status
Approved
Date submitted
13/03/2019
Date registered
22/03/2019
Date last updated
29/03/2021
Date data sharing statement initially provided
22/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Medicinal cannabis use among dementia patients
Scientific title
Medicinal cannabis and dementia: Effects on behavioural symptoms among older residential care recipients.
Secondary ID [1] 294928 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dementia 307888 0
Condition category
Condition code
Neurological 306937 306937 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a parallel mixed methods design that includes a randomised, double blinded, crossover, N-of-1, placebo-control trial. This is similar to a phase II randomised control trial:

Arm 1:
Placebo

Arm 2:
Medicinal Cannabis oil

This trial will run for 16 weeks. In a crossover design a number of treatment cycles occur where each participant will receive the placebo and the medicinal cannabis oil during one treatment cycle. This trial will include two, six-week treatment cycles. For the first six week treatment cycle, participants will be randomised into the placebo group (Arm 1) or medicinal cannabis oil (Arm 2) group. After the first six week treatment cycle, a two-week washout period will occur. During the second treatment cycle those who took the medicinal cannabis oil (Arm 2) in the first treatment cycle will take the placebo (Arm 1) during the second treatment cycle and vis versa. After the second treatment cycle, an additional two-week washout period will occur to monitor the participants as they will no longer be taking any additional medication.

The 16 week will comprise of two, six-week treatment cycles, with a two, two-week wash out periods. The mode of administration will be through an oral spray. The dose, will be increased from 2.5mg/day (1 spray) until the participant reaches their best, tolerated dose or a maximum of 50mg/day (20 sprays). The dose will be increased approximately every three days and on the days the dose has been increased, the resident will record the presence of any adverse events one hour after the dose has been administered. Following the recording of any moderate to severe adverse events (determined as ‘Somewhat worse’ [moderate] or ‘Much worse’ [severe] on the participants adverse event record) that has not ameliorated by the time for the next dose, the participant will receive the previous, best tolerated dose. If the effects of the adverse event(s) have disappeared or become milder, and do not interfere with the participant’s daily function or well-being, the caregivers may increase their dose at the indicated rate. Recurrence of adverse events after two attempts to increase the dose will result in the participant remaining at their previous, best tolerated dose for the remainder of the intervention period. If a participant experiences an adverse event they will stay on the previous dose for another two days before the next dose is increased. A registered nurse will administer the medication with morning and afternoon tea (approximately 9am and 2pm).

The CongiCann bottles will be delievered to the residential aged care facilities by the pharmacists every Monday. The bottles will be collected after 7 days of use (even if they are half full) and returned to the pharmacy where they can determine how much was used (or left) and then dispose of the bottles to meet Therapeutic Goods Administration (TGA) requirements. At the start of the titration phase, 1 bottle will be administered for each participant (as the lower dose of 2.5mg allows for each bottle to hold 2-3 weeks of the medication). As participants being to reach a higher dose (titration phase, see Table 1 below), 2-3 bottles will be provided on a weekly basis, so each participant will have sufficient medication to last for 7 days.

In addition, a process of evaluation will be completed where residential staff and family members will complete pre- (beginning of the first treatment cycle) and post- (end of the second treatment cycle) surveys about their perceptions towards medicinal cannabis oil. At the end of the second treatment cycle, focus groups will be completed with residential care staff and family members.
Intervention code [1] 301242 0
Treatment: Drugs
Comparator / control treatment
Each individual will be their own comparator/control in the N-of-1 crossover study as each participant will receive the placebo and the medicinal cannabis during one treatment cycle. This methodology has been selected as the participants are likely to be already be taking multiple medications and are likely to have comorbid conditions, This will ensure participant safety and be able to monitor who is a responder and a non-responder to the medication. The placebo group will receive an increased dose of placebo, or until they reach an upper limit of 50ml/day, The placebo will be administered following the same titration method as described above [2.5mg/day = 1 spray - 50mg/day = 20 sprays).

The oil base of the placebo is a terpene oil with esters mimicking the smell and flavor of cannabis.
Control group
Placebo

Outcomes
Primary outcome [1] 319469 0
The Neuropsychiatric Inventory Questionnaire-Nursing Homes (NPI-NH; Cummings et al., 1997) measures 12 neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, anxiety, euphoria/ elation, apathy/ indifference, disinhibition, irritability, aberrant motor behaviour, night time disturbances and appetite changes). The primary outcome will derived from the total score of all 12 domain scores to examine the total number of behavioural symptoms. The higher the score, the greater the presence of behavioural symptoms present.
Timepoint [1] 319469 0
The NPI-NH will be collected at seven time points throughout the study. This will be completed three times during the first treatment arm [baseline (Day 0), after maximum tolerated dose has been reached (Day 24), at the end of the treatment cycle (Day 42)], three times during the second treatment arm [baseline (Day 56), After maximum tolerated dose has been reached (Day 80), End of the treatment cycle (Day 97)] and once following the two-week washout period after the second treatment arm (Day 112).
Secondary outcome [1] 347033 0
The Cohen-Mansfield Agitation Inventory (CMAI; Cohen-Mansfield, 1996) will be collected to assess behavioral changes. The CMAI is a 29 item questionnaire and examines three behavioral factors (aggressive behaviour, physically nonaggressive behaviour and verbally agitated behavior). A total score is calculated, from a 7-point Likert scale [Never (1), Less than once a week (2), Once or twice a week (3), Several times a week (4), Once or twice a day (5), Several times a day (6), Several times an hour (7)] with a higher score indicating greater changes in behavior.
Timepoint [1] 347033 0
The CMAI will be collected at seven time points throughout the study at the same time as the NPI-NH. This will be completed three times during the first treatment arm [baseline (Day 0), after maximum tolerated dose has been reached (Day 24), at the end of the treatment cycle (Day 42)], three times during the second treatment arm [baseline (Day 56), After maximum tolerated dose has been reached (Day 80), End of the treatment cycle (Day 97)] and once following the two-week washout period after the second treatment arm (Day 112).
Secondary outcome [2] 347034 0
Quality of life Alzheimer’s disease (QOL-AD; Logsdon, Gibbons, McCurry, & Teri, 2002) will be used to identify if any changes in QOL occur. The QOL-AD consists of 13-items,using a 4-point Likert scale [poor (1), fair (2), good (3) and excellent (4)] and is designed for both self and proxy report. An overall total QOL score is derived, with a higher score indicating a higher QOL
Timepoint [2] 347034 0
The QOL-AD will be collected at seven time points throughout the study at the same time as the NPI-NH. This will be completed three times during the first treatment arm [baseline (Day 0), after maximum tolerated dose has been reached (Day 24), at the end of the treatment cycle (Day 42)], three times during the second treatment arm [baseline (Day 56), After maximum tolerated dose has been reached (Day 80), End of the treatment cycle (Day 97)] and once following the two-week washout period after the second treatment arm (Day 112).
Secondary outcome [3] 347035 0
The Abbey Pain Assessment Scale (APAS; Abbey et al., 2004) will be used to assess the participants level of pain. The APAS assesses pain by examining vocalization, facial expression, change in body language, behavioural change, physiological change, and physical change. This questionnaire uses a 4-point Likert scale [Absent (0), Mild (1), Moderate (2), Severe (3)] and a total score of 18 is calculated. The severity of pain is indicated as mild (3-7), moderate (8-13) and severe (14+).
Timepoint [3] 347035 0
The APAS will be collected at seven time points throughout the study at the same time as the NPI-NH. This will be completed three times during the first treatment arm [baseline (Day 0), after maximum tolerated dose has been reached (Day 24), at the end of the treatment cycle (Day 42)], three times during the second treatment arm [baseline (Day 56), After maximum tolerated dose has been reached (Day 80), End of the treatment cycle (Day 97)] and once following the two-week washout period after the second treatment arm (Day 112).
Secondary outcome [4] 347036 0
The participants heart rate will be monitored by a research nurse using a stethoscope.
Timepoint [4] 347036 0
The participants heart rate and blood pressure will be monitored twice a week and their weight and non-invasive body composition measure will be taken once a week by a research nurse. Adverse events will be reported one hour after the dose of the medication has been increased.
Secondary outcome [5] 368301 0
The participants blood pressure will be monitored by a research nurse using a blood pressure cuff and stethoscope.
Timepoint [5] 368301 0
twice a week during both treatment cycles (approximate every Monday and Thursday)
Secondary outcome [6] 368302 0
The participants weight will be monitored by a research nurse using a scale.
Timepoint [6] 368302 0
measured once a week (approximately every Monday)
Secondary outcome [7] 368303 0
The participants body composition (using a scale) to measure lean body mass, bone mass and fat mass.
Timepoint [7] 368303 0
This will be measured once a week (approximately every Monday).
Secondary outcome [8] 368304 0
Adverse events will be monitored by the participants each time they receive a higher dose of medication. If moderate to severe adverse events are recorded [determined as ‘Somewhat worse’ (moderate) or ‘Much worse’ (severe) on the participants adverse event record] and these events have not ameliorated by the time for the next dose, the participant will use the previous, best tolerated dose, or if the effects of the adverse event(s) have disappeared or become milder, and do not interfere with the participant’s daily function or well-being, the caregivers may increase their dose at the indicated rate. For example, some adverse events may include, drowsiness, dizziness, dry mouth, lured vision).
Timepoint [8] 368304 0
This will be measured each time the dose of medication is increased (approximately every three days). (day 1, 3, 6, 9, 12, 15, 18, 21, 24, 27... etc...).
Secondary outcome [9] 368305 0
pre surveys will be completed by the primary carer and family members to assess their perceptions towards medicinal cannabis before the medication is being administered. These surveys have been designed specifically for this study.
Timepoint [9] 368305 0
This will be completed before the first dose of medication is administered (Days 0)
Secondary outcome [10] 368306 0
post surveys will be completed by the primary carer and family members to assess their perceptions towards medicinal cannabis at the after of the treatment. These surveys have been designed specifically for this study.
Timepoint [10] 368306 0
This will be completed after the last dose of medication has been administered in the second treatment arm. (Day 98)
Secondary outcome [11] 368307 0
Focus groups with the primary carers and the family members will be used to assess their perceptions before and after the use of medicinal cannabis and will be used to gather more in-depth information from the pre and post surveys.
Timepoint [11] 368307 0
Completed after the last dose is administered in the second treatment arm (Day 98)

Eligibility
Key inclusion criteria
Live within a residential aged care facility,
• Aged 65 year or older,
• Have a diagnosis of dementia, and display at least 3 behavioural symptoms associated with dementia
• Able to speak English,
• Known compliance to taking medication, and
• Not bed ridden.

Note those with mild dementia will be able to consent to participant in the study themselves. Those with moderate-to-severe dementia, their next of kin can consent on their behalf if they wish, but will need to speak with an independent medical practitioner prior to their involvement in the study (This is in keeping with the recent changes made to the Western Australian Guardianship and Administration Act of 1990).
Minimum age
65 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
To minimize the likelihood of an adverse event, people with certain health conditions or on some medications will be excluded from the study. These include:
-Diagnosed of one or more of the following conditions:
-Frontotemporal or Lewy body dementia
-Neurodegenerative disease (Epilepsy or recurrent seizure, Anorexia nervosa)
-Significant psychiatric disorder other than BPSD associated with underlying condition
-Parkinson’s disease
-Significant cardiovascular disease (eg arrhythmias, fibrillation, CHF, angina) clinically uncontrolled in the last year Significant cardiovascular disease (eg arrhythmias, fibrillation, CHF, angina) clinically uncontrolled in the last year
-History of myocardial infarction with manifestations of active cardiac ischemia in the last year
-Clinical event of a stroke within the last 6 months
-Significant liver disease or presence of hepatic encephalopathy (where there are grounds to suspect liver disease excluded as per Child-Pugh classification B or C)
-Significant renal impairment (where there are grounds to suspect kidney disease excluded as per calculated GFR beneath 60ml/min)
-Taking medications that may interact with cannabis metabolism such as Primidone, Phenobarbital, Carbamazepine, Rifampicin, Rifabutin, Troglitazone, Hypericum perforatum, and valproic acid.

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)
Concealment of group allocation is achieved by giving the responsibility for sequence generation and group allocation to product sponsor supplier who is independent of the study and its investigators.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
For this study, simple randomisation using the randomisation function in Excel will be used to randomize the group allocations for each participants.

The product supplier will be instructed by the research team to create a consecutive list of 25 individuals in the placebo group and 25 in the medicinal cannabis oil group for the first treatment cycle, and send individual bottles for each participant to the pharmacist with the name of each participant, and a unique identification code on the bottles. The supplier will be responsible for regenerating the list of participants and place each into the opposite group for the second treatment cycle.
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
A parallel mixed methods design will also be used among the residential aged care staff including the activity staff and family members as they will be asked to complete pre and post surveys about their perceptions of medicinal cannabis and be asked to participant in a follow-up focus groups.

The questionnaire results will be completed by the aged-care facility staff or the research nurse, and where possible the participants and family members.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
For the crossover N-of-1 trial, a power calculation using a two-sided t-test achieves 81% power to infer that the mean difference is not 0.000 when the total sample size of a 2x2 cross-over design is 40, the actual mean difference is 6.000, the standard deviation of the differences is 13.000, and the significance level is 0.0500. A sample size of 50 participants accounts for a 20% attrition rate.

The quantitative results will be analyzed using SPSS version 25. The proxy-responses from the aged-care staff will be the main responses considered for analysis. Where available, participants and family responses will be included for secondary analysis. To examine group differences, the participants will be categorised according to their treatment cycle group allocation (Group A or Group B). Descriptive statistics will be derived. Each variable will be tested for normality and where appropriate non-parametric tests will be used. The seven data collection points will be examined to see if any changes in behavior, QOL or pain have occurred over the duration of both treatment cycles.

The process evaluation outcome is an exploratory component of this study therefore the total number of pre- and post- surveys completed by the residential aged care staff and family members is unknown. We estimate that a total of six focus groups will be appropriate to reach data saturation.

QSR NVivo 11 will be used for data management and storage, and assist in the analysis of both of the pre-and post-surveys and focus groups. Content analysis will be used to analyse the surveys to assess similarities and differences between responses. The focus groups will be transcribed verbatim and the transcripts will be read repeatedly and analysed first using open coding followed by line by line coding to thematically analyse the results.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
7/01/2019
Actual
26/02/2020
Date of last participant enrolment
Anticipated
9/08/2021
Actual
Date of last data collection
Anticipated
29/11/2021
Actual
Sample size
Target
50
Accrual to date
23
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 22688 0
6148 - Rossmoyne
Recruitment postcode(s) [2] 22689 0
6157 - Bicton
Recruitment postcode(s) [3] 22690 0
6164 - Success
Recruitment postcode(s) [4] 27763 0
6069 - Ellenbrook
Recruitment postcode(s) [5] 27764 0
6018 - Innaloo
Recruitment postcode(s) [6] 33581 0
6007 - West Leederville

Funding & Sponsors
Funding source category [1] 299509 0
Commercial sector/Industry
Name [1] 299509 0
MGC pharmaceuticals Ltd
Country [1] 299509 0
Australia
Primary sponsor type
University
Name
University of Notre Dame Australia
Address
19 Mouat street, Fremantle, WA, 6959
Country
Australia
Secondary sponsor category [1] 298809 0
Commercial sector/Industry
Name [1] 298809 0
MGC pharmaceuticals Ltd
Address [1] 298809 0
1202 Hay Street, West Perth, WA, 6005
Country [1] 298809 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300409 0
University of Notre Dame Human Research Ethics Committee
Ethics committee address [1] 300409 0
Ethics committee country [1] 300409 0
Australia
Date submitted for ethics approval [1] 300409 0
10/04/2018
Approval date [1] 300409 0
08/08/2018
Ethics approval number [1] 300409 0
018091F

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

Contacts
Principal investigator
Name 83570 0
Dr Amanda Timler
Address 83570 0
The University of Notre Dame Australia
19 Mouat street, Fremantle, WA, 6959
Country 83570 0
Australia
Phone 83570 0
+61 8 9433 0795
Fax 83570 0
Email 83570 0
[email protected]
Contact person for public queries
Name 83571 0
Amanda Timler
Address 83571 0
University of Notre Dame Australia
19 Mouat street, Fremantle, WA, 6959
Country 83571 0
Australia
Phone 83571 0
+61 8 9433 0795
Fax 83571 0
Email 83571 0
[email protected]
Contact person for scientific queries
Name 83572 0
Amanda Timler
Address 83572 0
University of Notre Dame Australia
19 Mouat street, Fremantle, WA, 6959
Country 83572 0
Australia
Phone 83572 0
+61 8 9433 0795
Fax 83572 0
Email 83572 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
SourceTitleYear of PublicationDOI
EmbaseUse of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: Study protocol for a double-blind randomised crossover trial.2020https://dx.doi.org/10.1186/s13063-020-4085-x
EmbaseNAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia (NACTOPAISD): Clinical trial protocol.2022https://dx.doi.org/10.1016/j.biopha.2022.113488
EmbaseTherapeutic properties of multi-cannabinoid treatment strategies for Alzheimer's disease.2022https://dx.doi.org/10.3389/fnins.2022.962922
N.B. These documents automatically identified may not have been verified by the study sponsor.