Examining its benefits of Medicinal cannabis among older residential care recipients diagnosed with dementia: A study protocol for an N-of-1 randomised trial


 Background: Dementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65-years and above. More effective ways to manage dementia symptoms is needed as current treatment options (anti-depressant and antipsychotic) can be ineffective and associated with substantial side-effects, including increased rate of mortality. Medicinal cannabis has shown to inhibit some symptoms associated with dementia and the adverse effects are often minimal, yet little research has explored the use of this medication among this population. Aim. To monitor any effects in behaviour, Quality of life (QOL), and discomfort caused by pain when administering a purified dose of medicinal cannabis oil (3:2 THC:CBD). Methods/Design: We will carry out an 18-week randomised, double-blinded, crossover, N-of 1 trial that consists of two, 6-week treatment cycles and two, 2-week washout periods (between both cycles, and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups, and receive a dose of either medicinal cannabis oil or placebo for the first treatment cycle and receive the opposite medication for the second. A number of standardised validated questionnaires will be collected on seven occasions, and completed by the participants, aged-care staff, and nominated next of kin or family member. Participant heart rate and blood pressure will be monitored weekly and their body composition and weight will be monitored fortnightly by a research nurse in order to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions towards medicinal cannabis, and to inform proposed focus groups consisting of the aged care staff and next of kin. Discussion: The study design has been informed by medical professionals and key stakeholders including those working within the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.

aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.

Background
Dementia is a collection of symptoms that progressively declines the cognitive and functional ability of the brain (1) and affects memory, intellect, rationality, social skills, and physical functioning (2). The symptoms associated with dementia present themselves in a variety of ways and can include depression, frustration, clinginess, forgetfulness, wandering, sexual aggression, hoarding, sleep disturbances and 'the sundowner effect ' Medicinal cannabis has been shown to improve dementia symptoms such as aggression and agitation (12,13), and appears safer to prescribe compared to pharmacotherapies (3) as the adverse effects are often minimal (14). For example, Weier and Hall (15) found sedation to be the only adverse effect among dementia patients prescribed either cannabinoids or pharmacotherapies. While periods of euphoria, somnolence, and tiredness were observed among those prescribed Dronabinol (a synthetically derived cannabis product; 16), only a small number of adverse events (6 out of 98) related to the administration of cannabinoids compared to the placebo which led to the continuation of this treatment as the adverse events were similar to those manifested by the placebo (14). However, well-designed randomised, double-blinded, placebo-control trials need to be completed to understand the preferred formulation, safety profile, drug-drug 4 interactions and true efficacy to examine the effects of medicinal cannabis (17,18), which will allow for greater generalisability of these results (19).
Studies assessing the safety and efficiency of medicinal cannabis have shown many benefits among other neurodegenerative diseases, such as Parkinson's disease (32,33), Epilepsy and Psychotic disorders and Post-Traumatic Stress Disorder (17,34), Schizophrenia and Anxiety (12), spasticity due to Multiple Sclerosis (35) with the use of medicinal cannabis reducing Benzodiazepine prescriptions by 45% (36). However, only a handful of studies have investigated the use of medicinal cannabis in dementia patients (13,14,22).

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The pharmacodynamics and pharmacokinetics of THC (weeks 1-6; 0.75 mg, weeks 7-12; 1.5 mg) administered to 10 participants with dementia was safe and well tolerated (14), with positive effects in mental state, dementia severity, behavioural symptoms such as delusions, irritability, and sleep and caregiver distress observed with THC (2.5mg) administration among 11 dementia patients (22). Studies reporting the use of Dronabinol (2.5mg daily) found improvements in anorexia and body weight, and less disturbed behaviours (16), such as agitation and motor behaviours with no adverse effects observed (37). Retrospective observations of Dronabinol administration among 40 hospitalised patients' indicated improvements in agitation and aggressive, sleep duration, and meal consumption (13). Two independent case studies monitoring the effects of Nabilone (maximum dose of 0.5mg, twice daily for six weeks) among elders with dementia found improvements in severe agitation and aggression (38), psychomotor activity, smiling, as well as positive experiences from family members (39). No changes in the number of falls or balance (with eyes open) were reported among 18 participants administered 1.5mg of oral THC twice daily (40), with recommendations suggesting higher doses (THC 1.5mg three times daily) and longer study durations (great than three weeks) needed to understand the true effects on behavioural symptoms including QOL and activities of daily living (41). Therefore, further research in this area is needed as many beneficial outcomes have been reported, although dosing, samples size, patient cohort (two to 50 participants) and outcomes have varied in what are generally small studies with poor experimental design.

Aims
The primary aim of the present study will be to examine changes in behavioural and neuropsychiatric symptoms of dementia (BPSD) among those who will be administered a purified medicinal cannabis oil. In addition, two secondary aims of this study will include 6 examining QOL and discomfort caused by pain among those with dementia.

Methods
This study has approval from the Human Ethics Research Committee at the University of Notre Dame Australia. The study will utilise a randomised, double-blinded, crossover, placebo-control, N-of-1 trial that will include a parallel mixed methods study design. The research methodology for this trial is similar to a Phase II randomised control trial, however the two-treatment cycles and N-of-one approach will allow for each participant to take part in both the control and the treatment arms (42). N-of-1 trial protocols have been recommended for dementia patients as this allows for a pragmatic individualistic patient care approach, accuracy in documenting individuals as a responder or a nonresponder to a particular medication, and is a safe approach to monitor the effects of a new medication among those who may already be taking two or more medications (43). In addition, residential aged-care staff and next of kin perceptions towards the use of medicinal cannabis oil will be evaluated via surveys administered prior to, and on completion of the study. At the end of the second treatment cycle the residential agedcare staff and family members will be asked to participate in a follow-up focus group to gather more in-depth information around individual's perceptions before and after the administration of medicinal cannabis. Each participant will be in the trial for approximately 4 months (16-weeks), but the duration of the study will last over 12 months in order to recruit of participants from a number of aged care facilities.

Participants and setting
Participants will be recruited through residential aged-care facilities. Residential agedcare facilities within Australia are government funded organisations that provide additional support for families who may have a family member suffering from dementia whereby many move from their residential homes into a residential aged-care facility so 7 they can be monitored and provided with additional care. A two-sided calculation achieves 81% power when the total sample size of a 2x2 cross-over design is 40 [M = 6 (SD = 13)], and the significance level is 0.05. We will recruit 50 participants to allow for a 20% attrition rate. Participants will be eligible to participate if they live in a residential aged-care facility, are aged 65-years or older, have a diagnosis of dementia, are able to speak English, are known as compliant to taking medication, are not bed ridden, and are able to provide informed consent. Participants will be excluded if they have certain health conditions such as Frontotemporal or Lewy body dementia, other comorbities such as Epilepsy, Anorexia nervosa, comorbid psychiatric conditions, Parkinson's disease, congestive heart failure, history of myocardial infarction or anginal pain, history of stroke, liver disease, renal disease or taking medications such as Primidone, Phenobarbital, Carbamazepine, Rifampicin, Rifabutin, Troglitazone, Hypericum perforatum, and valproic acid that may interact with cannabis metabolism.
The pre-/post-surveys and focus group discussions are an exploratory qualitative component of this study and thus a definitive sample size calculation cannot been determined at this exploratory stage. We estimate that six focus groups comprising of six to eight participants, including two groups of residential care staff, activity staff (direct care staff who monitor daily activities and social engagement), and family members will ensure data saturation has been reached. Written informed consent will be obtained from all participants, including the residential aged-care staff and the next of kin.

Rigor
Residential aged-care staff usually work within the aged-care setting for at least three months and therefore are likely to be working in the same facility for the duration of the 4-month trial. The same aged-care staff will monitor the same participant(s) for the duration of the study and report any changes on the participant's behalf. To be classified 8 as a residential care staff, the individual must spend at least two occasions per week with the participant.

Recruitment
The residential aged-care clinical and general managers who have established relationships with the participants and their next of kin will promote the study to those they feel would be eligible to participate. This will be done through face to face conversations.

Randomisation
Randomisation for this study will use a computer generated random number list developed in Microsoft Excel. Randomisation will occur using a 1:1 ratio of those allocated to the placebo (n = 25) versus the treatment group (n = 25) to ensure an equal distribution is achieved for the first and second treatment cycles. Concealment of group allocation will be the responsibility to the lab technician bottling and manufacturing the product in a Good Manufacturing Practice (GMP) certified international laboratory. The lab technician will stop the randomisation by copying the group allocations, and then follow this sequence for each participant who enrols into the study. The primary researcher will enrol participants into the study and provide the lab technician with the participants first and last name. The pharmacist will receive the bottled medication with the participants name and a unique identification code. The lab technician will regenerate the group allocation so each participant receives the opposite medication for the second treatment cycle.

Blinding
This is a double-blinded study. Therefore, the lab technician will be the only individual who will know the group allocation for the participants. This is to ensure that the pharmacist, aged-care staff, medical practitioners, research nurse, family members, participants, and researchers are all blinded to the participant's group allocation. Once the study is complete, the lab technician will unbind and provide the primary researcher with a list of participants and their group allocation in order to conduct the analysis.

Procedure
The study will run for 18-weeks comprising of a 2-week 'Eligibility period' for screening and clinical assessment, and a 16-week "Experimental phase" comprising of two, 6-week arms of treatment and placebo separated by a 2-week washout period between the treatment arms, and a 2-week washout period following the completion of the second arm

Eligibility period
Individuals who express interest in participating in the study will initially be screened based on the inclusion criteria (described above). Following the initial screening process, potential participants will then undergo a thorough clinical investigation by a geriatrician to ensure they have the cognitive capacity to provide informed consent using the Mini-Mental State Examination (MMSE). The MMSE (44) is the most widely used cognitive outcome measure to assess the severity of cognitive performance. It comprises of 11items, where a total score out of 30 can be calculated to assess the severity of dementia (25-30 questionably significant, 20-25 mild, 10-20 moderate, 0-10 severe). Those who seem suitable, will be revisited by the geriatrician one week after the cognitive tests and will confirm the participant has understood the purpose of the trial and recalled the details of the study. Then the primary researcher will invite the eligible participants into the study and ask them to complete the Consent Form and provide some demographic and baseline details including age, sex, education level, weight, medical history including comorbid illnesses, and prescribed medication. The participants will then be randomly allocated into treatment Group A or B and receive either medical cannabis oil or placebo for the first 6-week treatment cycle. No adjustments will be made to the participants currently prescribed medications.

Experimental phase
This phase of the study will take 16-weeks to complete. To minimize the risk of adverse events and variation in the maximum tolerated dose of medicinal cannabis oil, each participant will receive one dose on the first and second days (2pm) and two doses (9am and 2pm) for the reminder of both treatment arms. The dose will be administered by a registered nurse along with a small meal (e.g. morning and afternoon tea). The participant will gradually receive an increased dose (titration) of the medication over several weeks as shown in Table 1. During these weeks, the participants will record the presence of, and change in, any potential adverse events that may be associated with the medication after the first dose, each afternoon where the dose is increased, and again on their final day of medication. If an adverse event is noted, the participant will revert to their previous, best tolerated dose using the adverse events and safety protocol listed below.
An upper limit of 50mg/day of THC will be permitted in those who do not have any adverse events from the medication. Once a participant has reached their maximum tolerated dose (or a total of 50mg/daily of THC), they will continue to receive that dose until the cessation of the 6-week period. The placebo group will follow a similar titration process using the indicated volumes shown in Table 1. They will continue to receive an increase in the volume of medication until they record an onset of an adverse event, at which time they will continue to take that volume of placebo until the end of the 6-week placebo arm.
Insert Table 1 about here.

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The medicinal cannabis oil, "CogniCann", will be provided in a sealed 10ml glass spray bottle which contains a mix of THC and CBD in a 3:2 ratio (25 mg/ml THC, 17 mg/ml CBD) in a Medium-Chained Triglycerides oil base. Each press of the vial will accurately dispense 100 µl of oil that contains 2.5mg of THC. A total of 50mg/day of THC and 34mg/day of CBD can be administered for 4-5 days from one 10ml glass spray bottle.
CogniCann can be stored at room temperature (below 25°C) for a total of 4 weeks. A certificate of analysis will be provided for each batch upon delivery.
The placebo will be administered in the same 10ml glass spray bottle and collected following the procedures describe above. The placebo will comprise of a Terpene based oil that contains Esters that mimic the smell and taste of cannabinoids.
The bottles of medication will be provided to the residential aged-care facilities by the affiliated pharmacist. The bottles will be delivered every week and collected again 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 of THC allows for each bottle to hold 2-3 weeks of the medication). As participants begin to reach a higher dose (titration phase, see Table 1 above), 2 bottles will be provided on a weekly basis, so each participant will have sufficient medication to last for 7 days.

Data collection
The aged-care staff, resident participants with dementia, and nominated next of kin will complete a total of four outcome measures on seven occasions throughout the study. The questionnaires will take approximately 20 minutes to complete, and will completed three

Adverse Events and safety protocol
An adverse events protocol will be put into place to minimise any potential harm or risks of receiving additional medication (14). This will include participants reporting if they have experienced any adverse events one hour after the increased dose has been administered (Appendix A). 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. 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. At the beginning of the titration phase a caregiver will be vigilant in monitoring any acute adverse events such as dizziness, discoordination with a danger of falls and injury and extreme fatigue. Any adverse events recorded will be reported to a facility line manager, which will then be communicated to staff during shift changes.
Additional safety monitoring will be completed by a research nurse who will meet with each participant to discuss their adverse event records and measure their heart rate and blood pressure twice a week. In addition, the participants weight and non-invasive body composition measures such as lean body mass, bone mass and body fat percentage and 13 fat mass will be measured once a week using a portable scale.

Process evaluation outcomes:
The one page pre-and post-surveys will be administered to aged-care staff and next of kin at the beginning of the first treatment cycle and at the end of the second treatment cycle. These surveys comprise of seven to nine questions regarding individual's perceptions towards medicinal cannabis oil use and the symptoms of dementia they find most challenging. A total of six questions will be asked during the focus group discussions. These questions relate to positive and negative observations among those taking medicinal cannabis oil, changes in perceptions, knowledge and benefits around the use of medicinal cannabis use.

Quantitative
The questionnaire results completed on behalf of the aged-care staff, participants and family members will be analysed using SPSS version 25 (IBM Inc. 2018). The proxyresponses 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. NPI-NH is the primary outcome measure for this study. All other measures (CMAI, QOL-AD, and Abbey Pain Assessment) have been included for secondary analysis. The CMAI will be analysed using the reliability change methodology in comparison to the NPI-NH to allow for small changes to be reported (50). Alpha will be set at .05. In the instance where a participant withdraws half-way through a treatment cycle, the information collected prior to their withdrawal will retain within the study as their personal information will have been de-identified.

Qualitative
QSR NVivo 12 will be used for qualitative data management and assistance in the analysis of both of the pre-and post-surveys and focus groups. Qualitative 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 thematically analysed by repeated readings and subsequent open coding process followed by line by line coding to identify key themes. To avoid bias, a triangulated approach including reflectivity by the primary researcher during the interview process, member checking to establish confirmability and verbatim quotes to establish credibility will be used. The primary researcher and the research team at the University of Notre Dame Australia will only have access to the final data set. The data will be stored on the University computers on a locked storage drive.

Discussion
There are a number of strengths in our study. First, all participants will have a medical 16 diagnosis of dementia. This ensures that the diagnosis is in line with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V; 52). Second, the residential aged care staff spend a large amount of time with the participants, so they will be able to observe small changes and lead to accuracy in recording of the results. Where possible, these results will also be compared with the participant and their next of kin to examine similarities and differences. Beattie et al. (53) published a protocol paper outlining a national project to collect multiple QOL perspectives from the care staff, family members and those living with dementia. Comparisons between proxy and self-report QOL scores have shown a linear relationship between reporters, with the residents often rating their QOL higher than the care staff (54,55).
As an additional precautionary step, two separate questionnaires assessing behavioural symptoms have been included to ensure the smallest effects of medicinal cannabis oil are observed. A strict safety protocol and monitoring of adverse events will also be followed to ensure participant safety, which has been included due to the average age of the participants, additional medications currently prescribed, and the likelihood of having a comorbid condition. Weier and Hall (56) suggest the therapeutic benefits of medicinal cannabis are observed among dementia patients when administered alongside adjacent therapy or medication. In addition, the dose of medication will be titrated to ensure each participant receives their best, tolerated dose and minimizes the onset of any adverse events. This process of 'start low and go slow' is reflective in other studies as well as government documentation for Queensland Health (57,58). Educational training with the aged-care staff will be completed before the first participant is recruited to prevent unexpected issues arising during the trial and to make sure they are familiar with the structure of the overall research protocol as well as the questionnaires.
This study has utilised a holistic approach to gain more in-depth information around BPSD and to capture staff and family member's perceptions towards medicinal cannabis. The inclusion of the qualitative phase is important as little research has been completed to understand personal views towards cannabis use and the effects thereof in this setting.
This approach allows the researchers to understand the perceived strengths and challenges around the use of cannabis within an institutional setting. Many symptoms associated with dementia such as wandering, agitation, aggression, and psychotic behaviours contribute to fatigue and burnout experienced by many caregivers (59). Feast, Moniz-Cook, Stoner, Charlesworth, and Orrell (60) reviewed the relationship between BPSD and informal caregivers (child-adult or spousal caregivers) well-being and found depressive behaviours, agitation and aggression, apathy including irritability, aberrant motor behaviours and delusions were the most distressing symptoms for caregivers.
A number of challenges have been identified in the proposed study. First, receiving informed consent from participants with dementia may be difficult as cognitive decline results in the loss of short-term memory (1). This may lead to difficulty in recruiting participants into the trial and excluding those who do not have the capacity to give informed consent and yet they are potentially those who exhibit a greater number of behavioural occurrences. However, those who experience mild to moderate dementia still exhibit symptoms such as depression and anxiety, and both verbal and physical agitation (2). Due to the irreversible progression of cognitive impairment, the associated compilations and comorbidities, and frailty of the participants, may lead to participants dropping out of the study. To accommodate this, we have included a 20% increase to the sample size. It is also difficult to know if the selected questionnaires chosen for this study are suitable and sensitive enough to measure the changes attributed to the use of medicinal cannabis oil, as no 'gold standard' exists to measure BPSD. Therefore, both the NPI-NH and the CMAI have been selected to account for the small effects. The pharmacodynamics of the medication will be monitored during the treatment cycles through the use of non-invasive body composition measures, and monitoring heart rate, blood pressure and weight. These measures will be collected by a research nurse external to the aged care facilities to improve the feasibility of the study, and to avoid additional work placed onto the aged-care staff and to ensure that each participant is receiving their, best tolerated dose.

Trial Status
The trial has been registered with the Australian New Zealand Clinical Trials Registry. The registration number is ACTRN12619000474156 and was registered in 21 March 2019.
Recruitment will begin in July, 2019. The approximate date that the recruitment will be including the residents and their family members will need to consent to participate. The results gathered beyond this protocol paper will be presented on the total sample, not on individual cases and all participants will be given a unique identification number to deidentify their information.

Availability of data and materials
Not applicable.

Supplementary Files
Appendix A relationship between behavioral and psychological symptoms (BPSD) and caregiver well-being. International Psychogeriatrics. 2016;28 (11) AE will be recorded one hour after drug administration on days of dose increase (days highlighted in red) and on the last day of the treatment period