Safety and Efficacy of Nabilone in Alzheimer's Disease

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

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.

Study Overview

• Status: Completed
• Conditions: Pain; Weight Loss; Alzheimer Disease; Oxidative Stress; Agitation
• Intervention / Treatment: Drug: Nabilone; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nabilone; 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; 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).
Placebo Comparator: Placebo; 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; 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).

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain; Pain Assessment In Advanced Dementia (PAINAD)	The PAINAD is a 5-item observer-rated scale conducted after a 5-minute observation. The scale examines breathing, vocalizations, facial expression, body language, and consolability.	baseline (0 weeks) to 14 weeks
Change in nutritional status; Mini Nutritional Assessment - Short Form (MNA-SF)	The MNA-SF is a structured interview consisting of 6 items that categorizes patients as malnourished, at risk of malnutrition, or of normal nutritional status.	baseline (0 weeks) to 14 weeks
Change in heart rate	Heart rate will be assessed at weeks 0 to 14 to monitor safety.	baseline (0 weeks) to 14 weeks
Change in levels of blood biomarkers	Biomarkers will be obtained from blood work.	baseline (0 weeks) to 14 weeks
Change in blood pressure	Blood pressure will be assessed at weeks 0 to 14 weeks to monitor safety.	baseline (0 weeks) to 14 weeks

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre

Publications and helpful links

General Publications

• 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:CD012820. doi: 10.1002/14651858.CD012820.pub2. Review.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: November 17, 2014
• First Submitted That Met QC Criteria: January 27, 2015
• First Posted (Estimate): January 30, 2015

Study Record Updates

• Last Update Posted (Actual): June 25, 2020
• Last Update Submitted That Met QC Criteria: June 23, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Body Weight; Neurodegenerative Diseases; Body Weight Changes; Dementia; Tauopathies; Weight Loss; Alzheimer Disease; Physiological Effects of Drugs; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; Nabilone
• Other Study ID Numbers: 318-2013