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Safety and Efficacy of Nabilone in Alzheimer's Disease

This study is currently recruiting participants.
Verified October 2017 by Sunnybrook Health Sciences Centre
Sponsor:
ClinicalTrials.gov Identifier:
NCT02351882
First Posted: January 30, 2015
Last Update Posted: October 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre
  Purpose

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.


Condition Intervention Phase
Alzheimer Disease Agitation Weight Loss Pain Oxidative Stress Drug: Nabilone Drug: Placebo Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Nabilone in Alzheimer's Disease: a Pilot Study

Resource links provided by NLM:


Further study details as provided by Sunnybrook Health Sciences Centre:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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 Inflammatory, Oxidative/Nitrosative Stress (O and NS) and cholesterol metabolism biomarkers [ Time Frame: baseline (0 weeks) to 14 weeks ]
    Cytokine, OS/NS and cholesterol metabolism 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.


Estimated Enrollment: 40
Study Start Date: January 2015
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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).

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   55 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02351882


Contacts
Contact: Myuri Ruthirakuhan, MSc 4164806100 ext 3185 rutmyuri@sri.utoronto.ca

Locations
Canada, Ontario
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Contact: Myuri Ruthirakuhan, MSc    (416) 480-6100 ext 3185    rutmyuri@sri.utoronto.ca   
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Investigators
Principal Investigator: Krista L. Lanctôt, PhD Sunnybrook Research Institute
Principal Investigator: Nathan Herrmann, MD Sunnybrook Health Sciences Centre
  More Information

Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT02351882     History of Changes
Other Study ID Numbers: 318-2013
First Submitted: November 17, 2014
First Posted: January 30, 2015
Last Update Posted: October 5, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
Alzheimer Disease
Weight Loss
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Body Weight Changes
Body Weight
Signs and Symptoms
Nabilone
Dronabinol
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Hallucinogens
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Cannabinoid Receptor Agonists
Cannabinoid Receptor Modulators