This study has approval from the Human Ethics Research Committee at the University of Notre Dame Australia. The study will utilise a parallel mixed methods study design. The research methodology for this study is a Phase II randomised placebo-control cross over trial. The design will include, a 2-week eligibility (assessment) period, two, 6-week-treatment cycles to allow for each participant to take part in both the control and the treatment cycles, and two, 2-week washout periods (one between both treatment cycles and the other after the second treatment cycle). The 6-week treatment cycles have been selected based on the safety, pharmacodynamics, and pharmacokinetics completed by Ahmed et al. (14), and a 2-week washout period has been shown to be safe and an appropriate length of time for cannabis to metabolise in older individuals (43).
In addition, residential aged-care staff and next of kin perceptions towards the use of CBM 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 aged-care 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 CBM. Each participant will be in the trial for approximately 4 months (18-weeks), but the duration of the study will last over 12 months in order to recruit participants from a number of aged care facilities.
Participants and setting
Participants will be recruited through residential aged-care facilities. Residential aged-care 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 they can be monitored and provided with additional care. The PASS 2019 Power Analysis and Sample Size Software (NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass, 2019) was used to derive the sample size. The Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) is the primary outcome measure. Total sample size for a 2x2 cross-over design assuming a two-sided t-test to detect a mean difference of 6 on the NPI-NH scale with a standard deviation of 13 (for the difference) is 40 for a power of 80% and significance level of 5%. Fifty participants will be recruited 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 mild diagnosis of dementia [indicated by a score of >20 on the Mini Mental State Assessment (MMSE)], 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 comorbidities 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 be determined at this stage. We estimate that six focus groups comprising of six to eight participants, including two groups of residential care staff, activity staff (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.
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 as a residential care staff, the individual must spend at least two occasions per week with the participant. The same registered nurse will administer the medication for both treatment cycles.
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 performed through face to face conversations.
The randomisation process for this study will be done by creating a random number list using a 1:1 ratio allocation to ensure equal number of cases in the both the placebo (n = 25) and treatment group (n = 25) using Microsoft Excel. The determination of participant allocation will be completed by the laboratory manager in the drug manufacturing laboratory with each case being provided with a unique identification (ID) number (1-50). The primary researcher, who is responsible for recruitment, will provide the lab manager with the participants name to be sequentially matched again the next available ID number. The laboratory will provide the pharmacy with both CBM and placebo in identical bottles labelled with the ID but the medical practitioner and research team members will not know the order of treatment until the completion of the study. The pharmacist will place the participants name on the bottle before distributing the bottles to the aged care facilities.
This is a double-blinded study. Therefore, the lab manager 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/next of kin, participants, and researchers are all blinded to the participant’s group allocation. Once the study is complete, the lab manger will un-blind the information by providing the primary researcher with a list of participants and their group allocation in order to conduct the analysis.
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 cycles of treatment and placebo separated by a 2-week washout period between the treatment cycles, and a 2-week washout period following the completion of the second arm (Figure 1).
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 MMSE. The MMSE (44) is the most widely used cognitive outcome measure to assess the severity of cognitive performance. It comprises of 11-items, 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 CBM oil or placebo for the first 6-week treatment cycle. No adjustments will be made to the participants currently prescribed medications.
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 CBM 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 cycles. The dose will be administered by a registered nurse along with a small meal (e.g. morning and afternoon tea) and the rate of titration will be monitored by the pharmacist to ensure it is appropriate for each individual. The participant will gradually receive an increased dose (titration) of the medication over several weeks as shown in Table 1. During these weeks, the participant along with the care staff 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 cycle.
Management and administration of medication
The CBM 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 CBM.
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.
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 take approximately 20 minutes to complete, and will be completed three times during the first treatment arm [baseline (Day 0), after maximum tolerated dose has been reached (Day 24), and 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), and the end of the treatment cycle (Day 97)] and once following the two-week washout period after the second treatment arm (Day 112). The questionnaires will be administered by the primary researcher.
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 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 registered nurse 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 staff member at the aged care facility 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 fat mass will be measured once a week using a portable scale. In addition, a nurse-led review will be completed two days into the washout periods to monitor the participant’s withdrawal symptoms once no more medication is being administered.
The Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH; 45) is a questionnaire that 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 frequency and severity of each symptom is rated (4-point and 3-point Likert scales). A total score can be calculated by adding the first 10 domains together, all 12 domain scores can be summed in special circumstance where neurovegetative symptoms are of interest, and a carer disruptiveness score [summing the disruptiveness score of the 10 (or 12) behavioural domains] can be calculated. The NPI-NH can be completed in approximately 10 minutes.
The Cohen Mansfield Agitation Inventory (CMAI) is designed to assess agitation cross three domains. Namely, physically aggressive behaviour, physically non-aggressive behaviour and verbally agitated behaviour (46). The CMAI comprise of 29-items and uses 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)] and measures four subscales: Aggressive Behaviour, Physical Non-aggressive Behaviour, Verbally Agitated Behavior, and Hiding and Hoarding. A total score of 203 is calculated, with a higher score indicating a higher frequency in behavioural occurrence and takes approximately 5 minutes to complete.
The Quality of life-Alzheimer’s Disease (QOL-AD) is designed to measure aspects important towards an individual’s QOL. 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 (47). The QOL-AD measures four domains (Physical, Mental Health, Social, and Function) and can be completed with people with a wide range of dementia severity (48). A total score out of 52 is calculated, with a larger score indicating a higher QOL. The self-report version can be completed in about 10-15 minutes, and the proxy-report in about 5 minutes. A composite score can also be calculated (participant QOL-AD x 2 + carer QOL-AD x 3).
The Abbey Pain Assessment Scale comprise of six items, assessing vocalization, facial expression, change in body language, and behavioural, physiological, and physical change (49). 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+) and can be completed in less than 5 minutes.
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 CBM 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 CBM oil, changes in perceptions, knowledge and benefits around the use of CBM use.
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 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. For those variables that meet the normality assumption, two sided paired and/or independent t-test will be used to examine group differences within and between groups. If the normality assumption is violated, than non-parametric tests such as Wilcoxon Signed Rank Test will be used. Within-subject differences of the four measurements between the first and second washout periods will be tested using paired t-tests to ensure the washout phase is long enough to rule out any carryover effects (50, 51). All data collection points will be examined using general linear mixed modelling techniques, to see if any changes in behaviour, QOL or pain have occurred over the duration of both treatment cycles. The covariates of weight, average dose of medication, and baseline measures will be controlled for in each model, and any interactions will be tested and reported. The proportion of AEs during the CBM and placebo phase will be tested and reported for each individual. 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 (52). 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 be retained within the study as their personal information will have been de-identified. The data management of the information collected will follow standard university procedures, be stored in a locked cabinet for a period of 15 years, stored on a password protected computer, and backed up regularly in a secured format.
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.