Safety and Efficacy of Nabilone in Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT02351882
• Recruitment Status: Completed
• First Posted: January 30, 2015
• Last Update Posted: June 25, 2020
• Sponsor: Sunnybrook Health Sciences Centre
• Information provided by (Responsible Party): Sunnybrook Health Sciences Centre

Tracking Information

• First Submitted Date: November 17, 2014
• First Posted Date: January 30, 2015
• Last Update Posted Date: June 25, 2020
• Study Start Date: January 2015
• Actual Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2015)

Change in agitation; Cohen-Mansfield Agitation Inventory (CMAI) [ Time Frame: baseline (0 weeks) to 14 weeks ]

A 29-point scale that measures agitation in two dimensions, verbal and physical, each of which having two poles, aggressive and non-aggressive.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 14, 2016)

• Change in neuropsychiatric symptoms; Neuropsychiatric Inventory (NPI) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  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.
• Change in cognition; Standardized Mini-mental State Examination (sMMSE) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Used to describe cognitive impairment.
• Change in cognition; Severe Impairment Battery (SIB) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Used to describe cognitive impairment for severe AD.
• Change in cognition; Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Used to describe cognitive impairment for moderate AD.
• Change in clinical representation; Alzheimer's Disease Cooperative Study - The Clinician Global Impression (ADCS - CGIC) [ Time Frame: 2 to 14 weeks ]
  The ADCS-CGIC is used to measure overall clinically significant change in patients.

Original Secondary Outcome Measures (submitted: January 27, 2015)

• Change in neuropsychiatric symptoms; Neuropsychiatric Inventory (NPI) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  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.
• Change in cognition; Mini-mental State Examination (MMSE) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Used to describe severity of cognitive impairment.
• Change in cognition; Impairment Battery (SIB) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  The SIB is directed towards individuals who are too impaired to complete standard neuropsychological tests.
• Change in cognition; Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  The ADAS-Cog is a validated assessment of cognitive performance in mild to moderate AD patients.

Current Other Pre-specified Outcome Measures (submitted: March 8, 2018)

• Change in pain; Pain Assessment In Advanced Dementia (PAINAD) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  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.
• Change in nutritional status; Mini Nutritional Assessment - Short Form (MNA-SF) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  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.
• Change in heart rate [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Heart rate will be assessed at weeks 0 to 14 to monitor safety.
• Change in levels of blood biomarkers [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Biomarkers will be obtained from blood work.
• Change in blood pressure [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Blood pressure will be assessed at weeks 0 to 14 weeks to monitor safety.

Original Other Pre-specified Outcome Measures (submitted: January 27, 2015)

• Change in pain; Pain Assessment In Advanced Dementia (PAINAD) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  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.
• Change in nutritional status; Mini Nutritional Assessment - Short Form (MNA-SF) [ Time Frame: baseline (0 weeks) to 14 weeks ]
  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.
• Change in heart rate [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Heart rate will be assessed at weeks 0 to 14 to monitor safety.
• Change in clinical representation; Alzheimer's Disease Cooperative Study - The Clinician Global Impression (ADCS - CGIC) [ Time Frame: 2 to 14 weeks ]
  The ADCS-CGIC is used to measure overall clinically significant change in patients, will be flagged for consideration of removal from the study.
• Change in Inflammatory and Oxidative/Nitrosative Stress (O and NS) biomarkers [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Cytokine and lipid levels will be obtained from blood work.
• Change in blood pressure [ Time Frame: baseline (0 weeks) to 14 weeks ]
  Blood pressure will be assessed at weeks 0 to 14 weeks to monitor safety.

Descriptive Information

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

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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Alzheimer Disease
• Agitation
• Weight Loss
• Pain
• Oxidative Stress

Intervention

• 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).
• 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).

Study Arms

• 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.
  Intervention: Drug: Nabilone
• 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.
  Intervention: Drug: Placebo

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 8, 2019): 38
• Original Estimated Enrollment (submitted: January 27, 2015): 40
• Actual Study Completion Date: March 2019
• Actual Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT02351882
• Other Study ID Numbers: 318-2013
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sunnybrook Health Sciences Centre
• Original Responsible Party: Same as current
• Current Study Sponsor: Sunnybrook Health Sciences Centre
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Krista L. Lanctôt, PhD; Sunnybrook Research Institute
• Principal Investigator: Nathan Herrmann, MD; Sunnybrook Health Sciences Centre

• PRS Account: Sunnybrook Health Sciences Centre
• Verification Date: June 2020