Alzheimer's Disease
Conditions
Keywords
Alzheimer's, Dementia, Cannabinoids, Agitation, Neuropsychiatric Symptoms
Brief summary
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. This pilot trial could open the door to re-purposing Dronabinol (Marinol®) as a novel and safe treatment for Agit-AD with significant public health impact.
Detailed description
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging, affecting an estimated 5.2 million Americans and predicted to increase to 13.8 million by 2050. AD affects both cognition and emotion. 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 with \> 97% of AD patients having at least one symptom reported on the Neuropsychiatric Inventory (NPI). 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. In community-based samples, Agit-AD is common. Agit-AD is associated with greater caregiver burden and shorter time to institutionalization, and there is a particularly acute need for interventions for severe Agit-AD in advanced dementia. While there are currently no FDA approved medications for Agit-AD, psychotropic medications are widely prescribed off-label to treat Agit-AD. The most commonly used classes of medications prescribed for off-label treatment are antipsychotics and antidepressants. The evidence to date for efficacy remains mixed. Antipsychotics appear to have some degree of efficacy, but the effects are not highly replicable and it's use is associated with increased mortality in elderly patients with dementia. Antidepressants (particularly selective serotonin reuptake inhibitors, (SSRI)s) appear to have fewer and less severe adverse effects compared to antipsychotics, as well as no known mortality risks, but are not without limitation. Therefore, exploration of alternative treatments for Agit-AD, particularly severe cases, is timely and warranted. Dronabinol (Marinol®) is FDA-approved for the treatment of anorexia/weight loss in AIDS and for nausea/emesis associated with chemotherapy, which is now being used off-label for Agit-AD. Dronabinol is a synthetic oral formulation of delta-9-tetrahydrocannabinol (THC), a psychoactive constituent of the cannabis plant that acts as a partial agonist at the Type 1 (CB1) and Type 2 (CB2) endocannabinoid receptors. This pharmacology is appropriate for targeting Agit-AD because CB1 receptor agonism can produce anxiolytic and antidepressant effects and CB2 receptor agonism can be anti-inflammatory. The mechanism by which dronabinol exerts its effects on agitation and aggression in patients with dementia may occur through its action at the CB1 and/or the CB2 receptor. Agonists at the CB1 receptor in the brain improve anxiety and depression in humans as well as animal models. Dronabinol is an effective agonist at the CB1 receptor, which is generally specific to neurons and localized predominantly on the presynaptic terminal where it inhibits glutamatergic, dopaminergic and other neurotransmitter release. The CB1 receptor effects has been observed to mediate the observed anxiolytic and antidepressant effects of THC. Dronabinol is also an agonist at CB2, a potent anti-inflammatory receptor localized on activated microglia. Patients with AD have increased central and peripheral inflammation, likely as a result of the accumulation of beta-amyloid. Increased inflammation may have a number of behavioral effects that could drive the agitation and aggression in dementia patients. Dronabinol's effects at the CB2 receptor therefore could also produce changes in behavior in AD patients by reducing inflammation.
Interventions
DRUGDronabinol (Marinol®)
5mg - 10mg daily dose
DRUGPlacebo
Daily dose
Sponsors
Mclean Hospital
Miami Jewish Health
National Institute on Aging (NIA)
Tufts Medical Center
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Dementia due to AD 2. Presence of Agit-AD as defined by the provisional criteria from the International Psychogeriatric Association (IPA). The definition requires the presence of cognitive impairment, evidence of emotional distress, one of three observable types of behavior (excessive motor activity, verbal aggression, physical aggression), requires that the behavior cause excess disability, and notes that the behaviors cannot be solely attributable to another disorder such as psychiatric illness, medical illness, or effects of substance use. 3. Clinically significant severity of agitation defined by NPI-C Agitation or NPI-C Aggression \> 4. 4. Able to give informed consent, or deemed to lack such capacity by clinical team and legally authorized representative consents. 5. Must be fluent in English and/or Spanish (includes reading, writing, and speech) 6. Must be admitted to clinical sites associated with McLean Hospital, Johns Hopkins University, and Miami Jewish Health Services as an inpatient/long term care resident during the study duration (3 weeks) OR be able to travel to these locations to enroll as an outpatient. 7. Must be 60-95 years old 8. Must begin enrollment in study within one week of being determined eligible
Exclusion criteria
1. Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease, which might confound assessment of safety outcomes. 2. Seizure disorder 3. Baseline delirium as determined by Confusion Assessment Method (CAM) and Diagnostic and Statistical Manual of Mental Disorders (DSM) -5 criteria 4. Current use of lithium 5. Inability to swallow a pill
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Up to 3 weeks | The Pittsburgh Agitation Scale (PAS) is a tool used to assess the severity of agitation in patients, particularly with dementia. The minimum score is 0 and the maximum score is 16. A higher number means a worse outcome, meaning more agitation. |
| Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Up to 3 weeks | The Neuropsychiatric Inventory Clinician Version (NPI-C) is an assessment tool used to evaluate neuropsychiatric symptoms in patients, particularly those with dementia. The minimum score is 0 and the max is 426. Higher scores indicate worse outcomes, meaning more agitation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | Up to 3 weeks | All Adverse Events (AE) s occurring after randomization and during the 3-week treatment period, regardless of adherence to study treatment, will be recorded at all contacts. |
Countries
United States
Participant flow
Recruitment details
There were 84 enrolled participants at 5 clinical research sites. Most of the recruitment was at three sites (Johns Hopkins, McLean, and Miami).
Pre-assignment details
84 subjects signed consents to be screened for eligibility. 9 participants signed consents but did not meet the eligibility criteria to start the study (screen failures). 75 subjects were randomized to treatment groups in the study.
Participants by arm
| Arm | Count |
|---|---|
| Dronabinol Study medication will be administered twice daily. Capsules of dronabinol will contain 2.5 mg per dose (5mg daily) during Week 1, then increase to 5 mg per dose (10mg daily) for Weeks 2 and 3.
Dronabinol (Marinol®): 5mg - 10mg daily dose | 37 |
| Placebo Placebo medication will be administered twice daily.
Placebo: Daily dose | 38 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Allergy | 0 | 1 |
| Overall Study | Excessive Agitation | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Not Feeling Well | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
Baseline characteristics
| Characteristic | Dronabinol | Total | Placebo |
|---|---|---|---|
| Activities of Daily Living (ADL) Checklist | 25.4 units on a scale STANDARD_DEVIATION 20.3 | 23.2 units on a scale STANDARD_DEVIATION 19.8 | 21.1 units on a scale STANDARD_DEVIATION 19.2 |
| Age, Customized Mean Age | 79.1 years STANDARD_DEVIATION 7.3 | 78.5 years STANDARD_DEVIATION 7.5 | 77.9 years STANDARD_DEVIATION 7.7 |
| Cohen Mansfield Agitation Inventory (CMAI) | 30.5 units on a scale STANDARD_DEVIATION 7.9 | 29.7 units on a scale STANDARD_DEVIATION 8.5 | 28.9 units on a scale STANDARD_DEVIATION 9.1 |
| Confusion Assessment Method (CAM) 0, Alert | 32 Participants | 68 Participants | 36 Participants |
| Confusion Assessment Method (CAM) 1, Lethargic | 3 Participants | 4 Participants | 1 Participants |
| Confusion Assessment Method (CAM) 1, Vigilant | 2 Participants | 3 Participants | 1 Participants |
| Current Antidepressant No | 30 Participants | 43 Participants | 13 Participants |
| Current Antidepressant Yes | 7 Participants | 32 Participants | 25 Participants |
| Current Antipsychotic No | 17 Participants | 37 Participants | 20 Participants |
| Current Antipsychotic Yes | 20 Participants | 38 Participants | 18 Participants |
| Education | 14.1 years STANDARD_DEVIATION 2.9 | 13.8 years STANDARD_DEVIATION 3.2 | 13.6 years STANDARD_DEVIATION 3.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 67 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mini Mental State Examination (MMSE) | 9.1 units on a scale STANDARD_DEVIATION 7.8 | 8.6 units on a scale STANDARD_DEVIATION 6.8 | 8.2 units on a scale STANDARD_DEVIATION 5.7 |
| NPI-C Agitation/Aggression | 21.9 units on a scale STANDARD_DEVIATION 9.7 | 20.4 units on a scale STANDARD_DEVIATION 10.5 | 19.0 units on a scale STANDARD_DEVIATION 11.2 |
| NPI-C Caregiver Distress | 89.8 units on a scale STANDARD_DEVIATION 57.4 | 85.4 units on a scale STANDARD_DEVIATION 65.4 | 81.2 units on a scale STANDARD_DEVIATION 72.9 |
| NPI-C Disinhibition | 7.4 units on a scale STANDARD_DEVIATION 7.3 | 6.6 units on a scale STANDARD_DEVIATION 7.1 | 5.8 units on a scale STANDARD_DEVIATION 7 |
| NPI-C Irritability | 10.3 units on a scale STANDARD_DEVIATION 7.6 | 10.3 units on a scale STANDARD_DEVIATION 8.8 | 10.3 units on a scale STANDARD_DEVIATION 9.9 |
| NPI-C Sleep | 3.3 units on a scale STANDARD_DEVIATION 5.1 | 3.5 units on a scale STANDARD_DEVIATION 5 | 3.6 units on a scale STANDARD_DEVIATION 4.9 |
| NPI-C Total | 76.7 units on a scale STANDARD_DEVIATION 34.2 | 76.5 units on a scale STANDARD_DEVIATION 41.8 | 76.4 units on a scale STANDARD_DEVIATION 48.6 |
| Pittsburgh Agitation Scale (PAS) | 7.1 units on a scale STANDARD_DEVIATION 4.1 | 6.3 units on a scale STANDARD_DEVIATION 4.2 | 5.6 units on a scale STANDARD_DEVIATION 4.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 7 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 35 Participants | 67 Participants | 32 Participants |
| Severe Impairment Battery (SIB) | 11.9 units on a scale STANDARD_DEVIATION 7.4 | 12.3 units on a scale STANDARD_DEVIATION 6.8 | 12.6 units on a scale STANDARD_DEVIATION 6.3 |
| Sex: Female, Male Female | 22 Participants | 49 Participants | 27 Participants |
| Sex: Female, Male Male | 15 Participants | 26 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 38 |
| other Total, other adverse events | 21 / 37 | 20 / 38 |
| serious Total, serious adverse events | 2 / 37 | 0 / 38 |
Outcome results
Primary
Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version
The Neuropsychiatric Inventory Clinician Version (NPI-C) is an assessment tool used to evaluate neuropsychiatric symptoms in patients, particularly those with dementia. The minimum score is 0 and the max is 426. Higher scores indicate worse outcomes, meaning more agitation.
Time frame: Up to 3 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dronabinol | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 0 | 76.68 score on a scale | Standard Deviation 34.19 |
| Dronabinol | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 1 | 59 score on a scale | Standard Deviation 37.95 |
| Dronabinol | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 2 | 55.56 score on a scale | Standard Deviation 41.73 |
| Dronabinol | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 3 | 52.38 score on a scale | Standard Deviation 38.21 |
| Placebo | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 3 | 51.06 score on a scale | Standard Deviation 46.9 |
| Placebo | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 0 | 76.37 score on a scale | Standard Deviation 48.62 |
| Placebo | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 2 | 56.59 score on a scale | Standard Deviation 47.38 |
| Placebo | Symptoms of Agitation as Measured by the Neuropsychiatric Inventory, Clinician Version | Week 1 | 56.54 score on a scale | Standard Deviation 48.07 |
Comparison: Efficacy is assessed by fitting a longitudinal linear GEE model with the co primary outcomes and with time, treatment arm, and their interaction. Analyses are adjusted for site and for use of antidepressants and antipsychotics at baseline. The treatment by week interaction is the coefficient of interest and represents the difference in change in outcome per week between the two arms.p-value: 0.09495% CI: [-2.73, 0.21]Regression, Linear
Primary
Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale
The Pittsburgh Agitation Scale (PAS) is a tool used to assess the severity of agitation in patients, particularly with dementia. The minimum score is 0 and the maximum score is 16. A higher number means a worse outcome, meaning more agitation.
Time frame: Up to 3 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dronabinol | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 2 | 5.73 score on a scale | Standard Deviation 4.67 |
| Dronabinol | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 0 | 7.14 score on a scale | Standard Deviation 4.12 |
| Dronabinol | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 3 | 4 score on a scale | Standard Deviation 3.52 |
| Dronabinol | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 1 | 5.69 score on a scale | Standard Deviation 4.36 |
| Placebo | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 3 | 5.13 score on a scale | Standard Deviation 4.44 |
| Placebo | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 0 | 5.55 score on a scale | Standard Deviation 4.18 |
| Placebo | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 2 | 5.22 score on a scale | Standard Deviation 4.24 |
| Placebo | Symptoms of Agitation as Measured by the Pittsburgh Agitation Scale | Week 1 | 4.97 score on a scale | Standard Deviation 3.81 |
Comparison: Efficacy is assessed by fitting a longitudinal linear GEE model with the co primary outcomes and with time, treatment arm, and their interaction. Analyses are adjusted for site and for use of antidepressants and antipsychotics at baseline. The treatment by week interaction is the coefficient of interest and represents the difference in change in outcome per week between the two arms.p-value: 0.01595% CI: [-1.328, -0.152]Regression, Linear
Secondary
Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo
All Adverse Events (AE) s occurring after randomization and during the 3-week treatment period, regardless of adherence to study treatment, will be recorded at all contacts.
Time frame: Up to 3 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 1 AEs | 10 Participants |
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 3 AE | 3 Participants |
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 0 AEs | 16 Participants |
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 4 AE | 1 Participants |
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 2 AE | 6 Participants |
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 8 AE | 1 Participants |
| Dronabinol | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 5 AE | 0 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 8 AE | 0 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 5 AE | 1 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 0 AEs | 18 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 1 AEs | 11 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 2 AE | 5 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 3 AE | 1 Participants |
| Placebo | Number of Participants With Adverse Events in Dronabinol Treatment as Compared to Placebo | 4 AE | 2 Participants |
p-value: 0.5795% CI: [0.73, 1.79]Regression, Logistic