Dronabinol for Agitation in Dementia Crossover Trial

Study Overview
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Brief Summary
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The goal of this clinical trial is to study the effects of dronabinol in US Veterans with agitation related to moderate to severe dementia. The main goals of the study are: To evaluate the efficacy of dronabinol for the treatment of agitation in moderate to severe dementia compared to placebo To evaluate the safety of dronabinol in the treatment of agitation in moderate to severe dementia compared to placebo Fifty (50) subjects will be given either dronabinol or placebo for 8 weeks. All subjects will then undergo a washout phase for 3 weeks, followed by the crossover intervention (i.e. subjects who received placebo during the first phase will receive dronabinol during the second phase, and vice versa). Thus, all participants will be taking dronabinol at some point during the study. During the study, subjects will undergo evaluations for: Agitation Cognitive changes Physical changes (i.e. labs, ekg, physical exam)

Detailed Description
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The investigators will conduct a phase IIa study to evaluate the efficacy and safety of dronabinol in the treatment of agitation related to dementia in the US Veteran population. Specific Aim 1 - To evaluate the efficacy of dronabinol (target dose 5 mg bid) for the treatment of agitation in dementia. Hypothesis: Dronabinol improves clinically significant agitation in moderate to severe dementia. Approach: The investigators will conduct a 6-week, double-blind, placebo-controlled, crossover, exploratory study of 50 Veterans suffering from moderate to severe dementia and clinically significant agitation with the Cohen Mansfield Agitation Inventory (CMAI) total score as the main outcome measure. Impact: The potential benefit of dronabinol in agitation will be evaluated. Specific Aim 2 - To evaluate the safety of dronabinol in the treatment of agitation in moderate to severe dementia. Hypothesis: Dronabinol is safe for the treatment of agitation in moderate to severe dementia. Approach: Outcomes of safety monitoring are to be measured by physical examination, vital signs with weight, adverse event reports, electrocardiogram, safety labs including complete metabolic panel (CMP), complete blood count (CBC), urinalysis (UA), and treatment compliance. Impact: The potential adverse effects of the 5 mg dose of dronabinol will be evaluated. Exploratory Aims - The investigators will also evaluate the effect of dronabinol on neuropsychiatric symptoms, caregiver distress, cognition, weight, nutritional status, pain, and inflammation.

Official Title
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Single-site, Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Dronabinol for the Treatment of Agitation in Outpatient With Dementia

Conditions
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Dementia Moderate, Dementia Severe, Agitation,Psychomotor, Behavioral Symptoms

Intervention / Treatment
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* Drug: Dronabinol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: US Veteran who is not pregnant or unable to become pregnant Diagnosis of Major Neurocognitive Disorder (aka dementia) of any type Functional Assessment Staging Test (FAST) score of 5 or higher Presence of clinically significant agitation and/or irritability with an NPI subscale score greater than or equal to 4 If treated with cholinesterase inhibitors or memantine, dosage must be stable for 3 months, or if discontinued they may enroll after 1 month Must be able to swallow capsules Must meet International Psychogeriatric Association's provisional definition of agitation in dementia. Must have decisional capacity to sign informed consent or have a legally authorized representative available to provide consent Must have an available study partner who spends at least 10 hours per week with the subject. Exclusion Criteria: Psychotropic medication changes (i.e. concomitant antidepressants, antipsychotics) less than 1 month prior to study randomization Contraindications to dronabinol (hypersensitivity or allergy to any cannabinoid or sesame oil) Use of cannabinoids (including over the counter products such as CBD or medical cannabis) or other illicit drugs in the past 3 months History of psychotic symptoms due to another psychiatric illness other than dementia int he past 2 years. Unstable current psychiatric disorder or neurologic condition (i.e. unstable depression, bipolar disorder, epilepsy, etc.) other than agitation or psychosis due to dementia. Suicidal ideations in the past 3 months or attempts in the past year Clinically significant delusions and/or hallucinations which are considered by the PI's to be a contraindication for dronabinol use Taking 1 or more medications which in the judgement of the PI's can be contraindicated with the use of dronabinol Unstable or uncontrolled medical conditions including cardiovascular system issues (i.e. angina, cardiac arrhythmias, recurrent syncope, hypertension, etc) as judged by the PI's.

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
Interventional Model Description: Eligible subjects will be randomization to either dronabinol or placebo (1:1 assignment ratio) for a total of 8 weeks (1 week of titration, followed by 6 weeks of treatment at target dose, followed by 1 week of taper). All subjects will then undergo a 3-week placebo washout phase, followed by the crossover intervention for 8 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dronabinol First<br>Participants will take Dronabinol 2.5 mg capsules twice daily for 1 week, followed by dronabinol 5 mg twice daily for 6 weeks, followed by dronabinol 2.5 mg twice daily for 1 week. They will then undergo a 3-week washout period, followed by placebo capsules twice daily for 8 weeks. | Drug: Dronabinol<br>* All participants will take both dronabinol and placebo at different points in the study in this crossover design trial.<br>* Other names: Marinol;|
| Experimental: Placebo First<br>Participants will take matching placebo capsules twice daily for 8 weeks, followed by a three week washout period. They will then begin taking dronabinol 2.5 mg capsules twice daily for 1 week, followed by dronabinol 5 mg twice daily for 6 weeks, followed by dronabinol 2.5 mg twice daily for 1 week. | Drug: Dronabinol<br>* All participants will take both dronabinol and placebo at different points in the study in this crossover design trial.<br>* Other names: Marinol;|

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-item scale to assess 4 dimensions of agitation across a range of frequencies during the previous two weeks. Scores range from 29-203, where higher scores indicate greater agitation severity. | Baseline (0 weeks) to 18 weeks | 
| Safety and tolerability, Treatment Emergent Adverse Events | We will compare the frequency of reported adverse events using Common Terminology Criteria for Adverse Events version 4.0 | Baseline (0 weeks) to 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in agitation, Neuropsychiatric Inventory (NPI) | This scale provides a comprehensive evaluation of neuropsychiatric symptoms in the previous month across 12 domains of behavior. Total scores range from 0-144, where higher scores reflect a greater level of neuropsychiatric symptom burden. | Baseline (0 weeks) to 18 weeks | 
| Change in caregiver distress, Neuropsychiatric Inventory - Caregiver distress score | Caregiver distress is rated for each positive neuropsychiatric symptom domain on a scale of 0 (not distressing at all) to 5 (extremely distressing). Thus total scores range from 0-60 on for the 12 domains. | Baseline (0 weeks) to 18 weeks | 
| Clinically perceptible effect of dronabinol on agitation, modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADAS-CGIC) | This modified version of the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change assesses ites specific to agitation in Alzheimer's disease to produce a global rating of change in agitation and a measure of clinical significance. Scores range from 1 to 7 where 1 = marked improvement, 4 = no change, and 7 = marked worsening) | Baseline (0 weeks) to 18 weeks | 
| Change in cognition, standardized Mini Mental Status Examination (sMMSE) | The standardized version of the original MMSE is a 30 point scale to measure global cognition, where lower scores indicate greater cognitive impairment. | Baseline (0 weeks) to 18 weeks | 
| Change in cognition, Alzheimer's Disease Assessment Scale - Cognitive Section (ADAS-Cog) | This scale includes 11 items, 8 of which are performance based and 3 are ratings of language impairment. Scores range from 0-70, where higher scores indicate greater impairment. This scale will be administered to subjects scoring greater than or equal to 12 on the sMMSE. | Baseline (0 weeks) to 18 weeks | 
| Change in cognition, Severe Impairment Battery | The severe impairment battery is a measure of cognition developed for the evaluation of patients whose dementia severity is such that they cannot complete conventional neuropsychological testing. It will be administered to anyone with an sMMSE score less than 12. Scores range from 0 to 133, where lower scores indicate greater impairment. | Baseline (0 weeks) to 18 weeks | 
| Change in nutritional status, prealbumin | Assessed by changes in prealbumin (mg/dl) | Baseline (0 weeks) to 18 weeks | 
| Change in nutritional status, weight | Assessed by changes in weight (kg) | Baseline (0 weeks) to 18 weeks | 
| Change in pain, Pain Assessment in Advanced AD (PAIN-AD) scale | The PAIN-AD scale is a 5-item rater observed scale to measure pain in patients with dementia. Scores range from 0-10, where higher scores suggest a higher level of pain. | Baseline (0 weeks) to 18 weeks | 
| Change in blood pressure | Blood pressure (mm Hg) will be monitored every 2 weeks | Baseline (0 weeks) to 18 weeks | 
| Change in heart rate | Heart rate will be monitored in beats per minute (bpm) every 2 weeks to monitor safety. | Baseline (0 weeks) to 18 weeks | 
| Change in QTc interval on Electrocardiogram (EKG) | EKGs will be monitored at each study visit to assess changes in QTc interval and monitor safety | Baseline (0 weeks) to 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia, Agitation, Behavioral and Psychological Symptoms of Dementia