Clinical trial NCT02351882: Safety and Efficacy of Nabilone in Alzheimer's Disease
Official title: Safety and Efficacy of Nabilone in Alzheimer's Disease: a Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Alzheimer Disease
Agitation
Weight Loss
Pain
Oxidative Stress
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
First posted: 2015-01-30
Enrollment: 38
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in agitation; Cohen-Mansfield Agitation Inventory (CMAI)
timeFrame: baseline (0 weeks) to 14 weeks
Secondary outcomes:
measure: Change in neuropsychiatric symptoms; Neuropsychiatric Inventory (NPI)
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in cognition; Standardized Mini-mental State Examination (sMMSE)
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in cognition; Severe Impairment Battery (SIB)
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in cognition; Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in clinical representation; Alzheimer's Disease Cooperative Study - The Clinician Global Impression (ADCS - CGIC)
timeFrame: 2 to 14 weeks
Other outcomes:
measure: Change in pain; Pain Assessment In Advanced Dementia (PAINAD)
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in nutritional status; Mini Nutritional Assessment - Short Form (MNA-SF)
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in heart rate
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in levels of blood biomarkers
timeFrame: baseline (0 weeks) to 14 weeks
measure: Change in blood pressure
timeFrame: baseline (0 weeks) to 14 weeks
Locations:
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: Sunnybrook Research Institute
name: Krista L. Lanctôt, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre
name: Nathan Herrmann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruthirakuhan MT, Herrmann N, Gallagher D, Andreazza AC, Kiss A, Verhoeff NPLG, Black SE, Lanctot KL. Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer's disease: Study protocol for a cross-over randomized controlled trial. Contemp Clin Trials Commun. 2019 May 23;15:100385. doi: 10.1016/j.conctc.2019.100385. eCollection 2019 Sep.
citation: Herrmann N, Ruthirakuhan M, Gallagher D, Verhoeff NPLG, Kiss A, Black SE, Lanctot KL. Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease. Am J Geriatr Psychiatry. 2019 Nov;27(11):1161-1173. doi: 10.1016/j.jagp.2019.05.002. Epub 2019 May 8.
citation: Ruthirakuhan M, Herrmann N, Andreazza AC, Verhoeff NPLG, Gallagher D, Black SE, Kiss A, Lanctot KL. 24S-Hydroxycholesterol Is Associated with Agitation Severity in Patients with Moderate-to-Severe Alzheimer's Disease: Analyses from a Clinical Trial with Nabilone. J Alzheimers Dis. 2019;71(1):21-31. doi: 10.3233/JAD-190202.
citation: Ruthirakuhan M, Herrmann N, Andreazza AC, Verhoeff NPLG, Gallagher D, Black SE, Kiss A, Lanctot KL. Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation. J Geriatr Psychiatry Neurol. 2020 Jul;33(4):175-184. doi: 10.1177/0891988719874118. Epub 2019 Sep 23.
citation: Bosnjak Kuharic D, Markovic D, Brkovic T, Jeric Kegalj M, Rubic Z, Vuica Vukasovic A, Jeroncic A, Puljak L. Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev. 2021 Sep 17;9(9):CD012820. doi: 10.1002/14651858.CD012820.pub2.
citation: Ruthirakuhan M, Lanctot KL, Vieira D, Herrmann N. Natural and Synthetic Cannabinoids for Agitation and Aggression in Alzheimer's Disease: A Meta-Analysis. J Clin Psychiatry. 2019 Jan 29;80(2):18r12617. doi: 10.4088/JCP.18r12617.