Safety and Efficacy of Nabilone in Alzheimer's Disease

Study Overview
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Brief Summary
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Alzheimer's disease (AD) is commonly associated with behavioural changes such as agitation. Severe agitation is important to treat because it not only increases progression of AD and physical health problems (increased falls and weight loss), but it also decreases quality of life and increases caregiver stress. Currently prescribed treatments (i.e., antipsychotics) for agitation in AD do not work in everybody and when they do work the effect is small and they increase the risk of harmful side effects, including death. As a result, there is an urgent need for safer medication options. The cannabinoid nabilone can now be prescribed in capsule form for appetite and pain killing effects. Nabilone's calming effects may benefit those with agitation, and help the weight loss and untreated pain frequently associated with agitation. Through a clinical trial, the investigators hope identify the benefits of nabilone in the treatment of agitation in AD. The investigators objective is to determine whether nabilone is an efficacious and safe treatment for agitation, as well as having benefits for pain, weight and behavioural symptoms. This will be a 14 week clinical trial (participants take nabilone for 6 weeks, placebo for 6 weeks (order randomized) with 1 week between treatments). The investigators will assess and compare agitation, weight, pain, memory, behaviour and safety. Nabilone is a new class of medication that may be a safe and effective treatment for agitation in AD, with added benefits on appetite and pain. Reducing these symptoms would increase quality-of-life and reduce caregiver stress.

Detailed Description
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Objectives: The investigators objective is to provide pilot data addressing whether the ∆9-tetrahydrocannabinol (THC) analogue nabilone is a pharmacological option for managing agitation, a particularly difficult to treat neuropsychiatric symptom (NPS), as well as having benefits for pain, weight and overall NPS, and gather double-blind information on tolerability and safety. This group of symptoms is particularly prevalent in patients with moderate to severe AD. Rationale: The high prevalence and impact of agitation in patients with moderate to severe Alzheimer's disease (AD) makes this neuropsychiatric symptom (NPS) a key determinant of decreased quality of life. Associated with agitation are weight loss, and pain, both of which lead to additional loss of quality of life. Agitation frequently necessitates use of antipsychotics, which, while well-studied, have modest efficacy and severe side effects including increased mortality. With the development of synthetic THC analogues, the therapeutic potential of cannabinoids can now be evaluated. Cannabinoids can be prescribed as capsules to treat anorexia and pain in certain patient groups. In addition to these potentially beneficial effects on appetite and pain, a recent study suggested positive effects of nabilone on agitation in dementia. Importantly, in addition to psychotropic effects, emerging evidence suggests neuroprotective (inhibit Aβ-induced microglial activation and excitotoxicity) and anti-inflammatory abilities, which can decrease oxidative stress, in stark contrast to the negative effects of antipsychotics. As such, this system is of high potential relevance in agitated patients with AD. Research Plan: This will be a randomized cross-over study comparing 6 weeks of nabilone and placebo, with a 1 week placebo washout preceding each treatment phase in Long-term care (LTC) patients, and outpatients with moderate to severe AD and agitation. Study outcomes will be measured at baseline and end of treatment for each treatment phase. The primary outcome measure will be the Cohen-Mansfield Agitation Inventory (CMAI). The secondary outcomes will be the weight (kg), overall NPS (Neuropsychiatric Inventory (NPI)), NPI agitation/aggression subscale, nutrition (Mini Nutritional Assessment - Short Form (MNA-SF), body mass index (BMI), skin fold thickness), pain (The Pain Assessment In Advanced Dementia (PAINAD)), cognition (Mini-Mental State Examination (MMSE); Severe Impairment Battery (SIB)) and clinical significance (Alzheimer's Cooperative Study-Clinician Global Impression of change (ADCS-CGIC). Safety (heart rate, blood pressure, and adverse events) will also be assessed at every visit.

Official Title
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Safety and Efficacy of Nabilone in Alzheimer's Disease: a Pilot Study

Conditions
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Pain, Alzheimer Disease, Agitation, Weight Loss, Oxidative Stress

Intervention / Treatment
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* Drug: Nabilone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥55 years of age Diagnostic and Statistical Manual (DSM) -V criteria for Major Neurocognitive Disorder due to AD. Patients with both Major Neurocognitive Disorder due to AD and Major Vascular Neurocognitive Disorder (i.e., mixed AD and cerebrovascular disease) will also be included. Currently in moderate-to-severe stage of dementia (Mini-Mental Status Examination (MMSE) ≤24) Presence of clinically significant agitation (Neuropsychiatric Inventory (NPI) agitation subscale ≥3) If treated with cognitive-enhancing medications (cholinesterase inhibitors and/or memantine), dosage must be stable for at least 3 months. If the ChEI and/or memantine has been discontinued, they may enroll after 1 month. Exclusion Criteria: Change in psychotropic medications less than 1 month prior to study randomization (e.g., concomitant antidepressants) Contraindications to nabilone (history of hypersensitivity to any cannabinoid) Current or past significant cardiovascular disease (e.g. uncontrolled hypertension, ischemic heart disease, arrhythmia and severe heart failure) Presence or history of other psychiatric disorders or neurological conditions (e.g. psychotic disorders, schizophrenia, stroke, epilepsy), previous or current abuse of/dependence on marijuana

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nabilone<br>Participants randomized into the nabilone arm will be prescribed nabilone for 6 weeks. After one-week placebo washout, they will be taking placebo for an additional 6 weeks. | Drug: Nabilone<br>* Participants randomized to nabilone treatment arm, will undergo a one-week placebo washout, followed by 6 weeks of nabilone treatment (weeks 1-6). Participants will then receive a one-week placebo washout (week 7), before receiving 6 weeks of placebo treatment (weeks 8-14).<br>|
| Placebo Comparator: Placebo<br>Participants randomized into the placebo arm will be receiving placebo for 6 weeks. After one-week placebo washout, they will be prescribed nabilone for an additional 6 weeks. | Drug: Placebo<br>* Participants randomized to placebo arm, will undergo a one-week placebo washout, followed by 6 weeks of drug matched placebo (weeks 1-6). Participants will then receive a one-week placebo washout (week 7), before receiving 6 weeks of nabilone treatment (weeks 8-14).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in agitation; Cohen-Mansfield Agitation Inventory (CMAI) | A 29-point scale that measures agitation in two dimensions, verbal and physical, each of which having two poles, aggressive and non-aggressive. | baseline (0 weeks) to 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in neuropsychiatric symptoms; Neuropsychiatric Inventory (NPI) | A widely used assessment of behaviour disturbances in dementia, including: apathy, agitation, delusions, hallucinations, depression, euphoria, aberrant motor behaviour, irritability, disinhibition, anxiety, sleeping, and eating. The frequency and severity of these symptoms are judged on a 4-point and 3-point scale, respectively. A 5-point scale is used to evaluate caregiver distress. | baseline (0 weeks) to 14 weeks | 
| Change in cognition; Standardized Mini-mental State Examination (sMMSE) | Used to describe cognitive impairment. | baseline (0 weeks) to 14 weeks | 
| Change in cognition; Severe Impairment Battery (SIB) | Used to describe cognitive impairment for severe AD. | baseline (0 weeks) to 14 weeks | 
| Change in cognition; Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) | Used to describe cognitive impairment for moderate AD. | baseline (0 weeks) to 14 weeks | 
| Change in clinical representation; Alzheimer's Disease Cooperative Study - The Clinician Global Impression (ADCS - CGIC) | The ADCS-CGIC is used to measure overall clinically significant change in patients. | 2 to 14 weeks |