Effects of THC-Free CBD Oil on Agitation in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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This is a randomized, double-blinded, placebo-controlled, crossover trial that aims to 1) determine the efficacy of THC-free cannabidiol (CBD oil) in reducing the severity of agitation among participants and 2) determine whether THC-free CBD oil can reduce the burden on caregivers and increase the participants' quality of life.

Detailed Description
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Individuals with Alzheimer's and other forms of dementia often go through a period of significant behavioral and psychological symptoms of dementia (BPSD). It is estimated that up to 90% of persons with dementia (PWD) experience behavior problems at some point. BPSDs can be challenging for both unpaid family caregivers as well as paid caregivers. Family caregivers provide the bulk of care for PWD and number over 15 million. One of the most common types of BPSDs is agitation with a prevalence of up to 87%, based on a recent systematic review. Agitation can lead to impaired daily functioning, prolongation of hospitalization, reduced time to institutionalization, and is associated with higher mortality. Additionally, agitated behavior is associated with increased injury to both patients and caregivers. Based on the 2018 Alzheimer's disease drug development pipeline report almost 70% of clinical trials related to BPSD are dedicated to agitation behavior. Finding ways to address agitation is necessary to improve overall quality of life for PWD and their caregivers. Currently, there are no medications available specifically for the treatment of BPSDs. The use of benzodiazepines, antipsychotics and mood stabilizing agents are common, but the risks and side effects often outweigh any benefits. Several small studies have investigated the use of cannabinoids in the treatment of pathology and symptomology of Alzheimer's disease (AD), as well as treatment of the agitation component of BPSD. A handful of these studies showed that the symptoms of BPSD were decreased with the use of cannabinoids. However, due to small sample sizes, study design, and short trial duration of these studies, the efficacy of these agents on BPSD cannot be confirmed. In addition, cannabinoids have demonstrated anti-oxidant and anti-inflammatory effects, and both processes have been indicated as major contributors to the neurologic effects of AD. Some evidence exists that agitation is related to this neuroinflammatory process. This study will examine the effects of cannabinoids on the behavioral and psychological symptoms of individuals with a dementia diagnosis.

Official Title
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Effects of THC-Free CBD Oil on Agitation in Patients With Alzheimer's Disease

Conditions
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Alzheimer Disease, Dementia, Major Neurocognitive Disorder With Aggressive Behavior

Intervention / Treatment
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* Drug: THC-free CBD Oil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males/females over 50 years old. Have a diagnosis of dementia due to AD or mixed AD with another type of dementia. A Mini-Mental State Exam score (MMSE) between 4 and 28 inclusive. Presence of agitation with a Neuropsychiatric Inventory (NPI)-agitation/aggression subscore > 3. Participants and their informal caregivers must be fluent in English (includes reading, writing, and speech) and able to give informed consent. For patients treated with cognitive-enhancing medications (cholinesterase inhibitors (ChEI) and/or memantine), the dosage must be stable for at least 1 month (30 days). If the ChEI and/or memantine has been discontinued, patients may enroll after 15 days. Eligible caregivers must either live with the participant or have a minimum of 4 hours of daily contact with them. Exclusion Criteria: Diagnosis of non-AD or non-mixed dementias. Very mild dementia or advanced dementia (MMSE: greater than 28 or less than 4). NPI-agitation-aggression score < 3. Having a serious or unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease which might confound assessment of safety outcomes as determined by the study physician. Presence or history of other serious psychiatric disorders or neurological conditions (e.g. psychotic disorders, bipolar disorder or schizophrenia). Current abuse of/dependence on marijuana, current drug abuse, current alcohol abuse. Having seizure disorders. Pregnant or breastfeeding Indication of baseline delirium as determined by the Confusion Assessment Method (CAM). Current use of lithium. Inability to swallow CBD oil softgels. Changes in dosage of anti-depressives within 4 weeks before randomization and during the study. Changes in dosage of antipsychotics or benzodiazepines within 1 week prior to randomization and during the study. Contraindications to CBD oil (history of hypersensitivity to any cannabinoid). Frequent falling due to orthostatic hypotension. Use of tricyclic antidepressants (TCA), fluoxetine, and/or carbamazepine. -Patients who reside in nursing homes.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hemp-based CBD oil Gelcaps<br>The intervention consists of 6 weeks oral administration of CBD oil Gelcaps, starting at a dosage of 15 mg twice per day with up titration to 45 mg twice per day. At any given dose, if participants develop side effects, the dosage will be reduced to the previous dose. | Drug: THC-free CBD Oil<br>* Hemp-based CBD oil Gelcaps<br>|
| Placebo Comparator: Oral placebo Gelcaps<br>Participants in the control group will receive oral placebo Gelcaps that are identical in appearance to the CBD oil Gelcaps. Dosing will be identical to the intervention arm. | Drug: Placebo<br>* Placebo Gelcaps<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in agitation and aggression. | Change in agitation and aggression will be measured by the Cohen-Mansfield Agitation Inventory (CMAI), a validated 29-item questionnaire to assess agitation. Each item is rated on a 7-point scale ranging from 1 Never to 7 Several times per hour. Higher scores indicate greater agitation. | Every two weeks for 15 weeks during study enrollment. | 
| Change in caregiver burden. | Change in caregiver burden will be measured by the Zarit Burden Interview (ZBI), a validated 22-item questionnaire to assess caregiver burden. Each item is rated on a 5-point Likert scale that ranges from 0 Never to 4 Nearly always, with the sum of scores ranging between 0-88. Higher scores indicate greater burden. | Three times during the 15 weeks of study enrollment. | 
| Change in the participant's quality of life. | Change in the participant's quality of life will be measured by the Quality-of-life assessment in dementia (DEMQOL-proxy), a validated 32-item questionnaire to assess the health related quality of life of people with dementia. Each item is rated on a 4-point scale ranging from 1 A lot to 4 Not at all. Higher scores indicate a healthier quality of life. | Three times during the 15 weeks of study enrollment. | 
| Change in caregiver's quality of life. | Change in the caregiver's quality of life will be measured by the Measurement of quality of life in family carers of people with dementia (C-DEMQOL), a validated 30-item questionnaire to assess the quality of life for carers of someone with dementia. Each item is rated on a 5-point scale ranging from 1 Completely to 5 Not at all. Higher scores indicate a healthier quality of life. | Three times during the 15 weeks of study enrollment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of change in neuropsychiatric symptoms. | Assessment of change in neuropsychiatric symptoms for the participant will be measured by the Neuropsychiatric Inventory (NPI), a validated questionnaire that assesses dementia-related behavioral symptoms. The NPI examines 12 sub-domains of behavioral functioning. Each sub-domain is rated on the frequency of the symptoms using a 4-point scale with 1 Occasionally and 4 Very frequently, the severity of the symptoms using a 3-point scale with 1 Mild and 3 Marked, and the distress the symptom causes them on a 5-point scale with 1 Not at all and 5 Very severely or extremely. | Three times during the 15 weeks of study enrollment. | 
| Assessment of change in cognitive skills. | Assessment of change in cognitive skills for the participant will be measured by the Mini Mental State Exam (MMSE), a validated 30-item questionnaire used to measure cognitive impairment among the elderly. A 30-item, clinician-administered assessment of orientation, attention, calculation, learning and memory, language, and visuospatial skills. Each correct response is summed to produce a total score out of 30 possible points. | Three times during the 15 weeks of study enrollment. | 
| The effect of CBD oil on sleep quantity measured by Fitbit | The effect of CBD oil on sleep quality will be measured for the participant and caregiver using the actigraphy function of fit bit. These measures include the amount of total sleep, amount of rapid eye movement (REM) sleep and the amount of deep and light sleep. | Measured on a daily basis during the 15 weeks of study enrollment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psychomotor agitation, Agitation, Aggression, Neuropsychiatric symptoms, CBD Oil, Cannabinoids, Caregiver burden, Sleep quality, Behavioral and Psychological Symptoms of Dementia, Neurocognitive disorders, Cannabidiols