TRIAL OF DRONABINOL ADJUNCTIVE TREATMENT OF AGITATION IN ALZHEIMER'S DISEASE (AD) (THC-AD)

Abstract

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging. Neuropsychiatric symptoms (NPS) in AD are a major cause of burden to patients, caregivers, and society and are near-universal at some point in the AD course. One of the most troubling of these symptoms is agitation (Agit-AD), typified by a variety of problem behaviors including combativeness, yelling, pacing, lack of cooperation with care, insomnia, and restlessness. There is a great need for better interventions that target Agit-AD, a major source of patient disability as well as caregiver burden and stress, particularly in the case of moderate to severe agitation. Dronabinol (Marinol®) is synthetic tetrahydrocannabinol (THC, one of the predominant biochemical constituents of cannabis), which produces anxiolytic, antidepressant, and anti-inflammatory effects and is FDA approved for anorexia and nausea. This pilot trial could open the door to re-purposing dronabinol as a novel and safe treatment for Agit-AD with significant public health impact. Methods THC-AD is a three-week placebo-controlled, double-blind, randomized clinical trial of dronabinol (10?mg QD) in 80 inpatients, assisted living facility (ALF), or nursing home residents with severe Agit-AD. Capsules of dronabinol contain 2.5?mg per dose (5?mg daily) during Week 1, then increase to 5?mg per dose (10?mg daily) for Weeks 2 and 3. The half-life of dronabinol is ∼4?hours, so study medication is administered BID at 08:00 and 14:00 to maximize daytime coverage for agitation and to minimize sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation as determined by the Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), and being 60-95?years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes include a change in the Pittsburgh Agitation Scale and NPI-C Agitation/Aggression subscales. Secondary outcomes include measures of agitation, cognition, sleep, and global functioning as determined by the following assessments: the NPI-C, Cohen Mansfield Agitation Inventory, Clinical Global Impression of Change, Activities of Daily Living, Mini-Mental State Examination (MMSE), Severe Impairment Battery (8 item), and subjective and observer-rated drug effects. Safety outcomes include monitoring for adverse events (AEs), weekly health assessments, EKG changes, incident delirium (Confusion Assessment Method), and changes in laboratory values. DNA specimens are collected to explore the possibility that cannabinoid receptor polymorphisms may affect response to dronabinol. Serum samples are collected to examine the association of peripheral markers of inflammation with agitation and response to dronabinol. Concomitant medications are limited to currently used antipsychotics, antidepressants, and benzodiazepines, as well as anticonvulsant therapy when not used for seizure disorder, with lorazepam 0.75?mg QD total daily allowed as rescue medication, and can be administered orally or intramuscularly. Additionally, PRN trazodone in doses up to 100?mg total daily dose are allowed for agitation and insomnia. Results We began recruitment in March, 2017 and have enrolled 27 out of 80 participants (mean age 76.96?years, 77.8% female, 85.2% Caucasian, mean total education completed 13.84?years, 55.6% family history of memory impairment). Study participants are significantly cognitively impaired (mean baseline MMSE of 6.69), agitated (mean NPI-C Agitation subtotal 15.19, mean NPI-C Aggression subtotal 6.48) and in reasonable overall health (General Medical Health Rating, 51.9% good and 40.7% fair.) The pace of recruitment is behind initial projections due to a number of factors including adaptation of inpatient units to a culture of research, cost of study medication post clinical trial, difficulty swallowing over-encapsulated pills, prior or current treatment with dronabinol and patient acuity leading to protocol deviations. To meet our recruitment target, we are launching our trial at additional locations (including ALF and nursing homes) and we have expanded the inclusion criteria to increase the maximum age at study entry to 95?years. We have not encountered adverse events or regulatory issues that suggest a rationale to change our study protocol. Conclusions AD is a fatal disease which robs an individual of their memory and personality. Agitation is one of the most common behavioral manifestations of AD and is associated with greater caregiver burden and shorter time to institutionalization. Current treatments for Agit-AD have a plethora of safety limitations, and there is a particularly acute need for interventions for severe Agit-AD in advanced dementia. One important question for treatment development is whether Agit-AD represents a specific target for intervention or a nonspecific syndrome shared with many other diseases. This clinical trial may enable us to understand if targeting the cannabinoid system will be an effective approach to treat this public health issue. This research was funded by: National Institute of Aging, R01AG050515