Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease (THC-AD)
Primary Purpose
Alzheimer's Disease
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dronabinol (Marinol®)
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Alzheimer's Disease focused on measuring Alzheimer's, Dementia, Cannabinoids, Agitation, Neuropsychiatric Symptoms
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of Dementia due to AD
- 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.
- Clinically significant severity of agitation defined by NPI-C Agitation or NPI-C Aggression > 4.
- Able to give informed consent, or deemed to lack such capacity by clinical team and legally authorized representative consents.
- Must be fluent in English and/or Spanish (includes reading, writing, and speech)
- 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.
- Must be 60-95 years old
- Must begin enrollment in study within one week of being determined eligible
Exclusion Criteria:
- Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease, which might confound assessment of safety outcomes.
- Seizure disorder
- Baseline delirium as determined by Confusion Assessment Method (CAM) and Diagnostic and Statistical Manual of Mental Disorders (DSM) -5 criteria
- Current use of lithium
- Inability to swallow a pill
Sites / Locations
- Miami Jewish HealthRecruiting
- Johns Hopkins UniversityRecruiting
- McLean HospitalRecruiting
- Tufts Medical CenterRecruiting
- North Shore Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Dronabinol
Placebo
Arm Description
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.
Placebo medication will be administered twice daily.
Outcomes
Primary Outcome Measures
Symptoms of agitation as measured by the Pittsburgh Agitation Scale
Scale will be administered weekly
Symptoms of agitation as measured by the Neuropsychiatric Inventory, Clinician Version
Scale will be administered weekly
Secondary Outcome Measures
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.
Full Information
NCT ID
NCT02792257
First Posted
May 26, 2016
Last Updated
October 23, 2023
Sponsor
Johns Hopkins University
Collaborators
Mclean Hospital, Miami Jewish Health, National Institute on Aging (NIA), Tufts Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT02792257
Brief Title
Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease
Acronym
THC-AD
Official Title
Pilot Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2017 (Actual)
Primary Completion Date
May 31, 2024 (Anticipated)
Study Completion Date
May 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
Mclean Hospital, Miami Jewish Health, National Institute on Aging (NIA), Tufts Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer's Disease
Keywords
Alzheimer's, Dementia, Cannabinoids, Agitation, Neuropsychiatric Symptoms
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
160 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Dronabinol
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo medication will be administered twice daily.
Intervention Type
Drug
Intervention Name(s)
Dronabinol (Marinol®)
Intervention Description
5mg - 10mg daily dose
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Daily dose
Primary Outcome Measure Information:
Title
Symptoms of agitation as measured by the Pittsburgh Agitation Scale
Description
Scale will be administered weekly
Time Frame
3-weeks
Title
Symptoms of agitation as measured by the Neuropsychiatric Inventory, Clinician Version
Description
Scale will be administered weekly
Time Frame
3-weeks
Secondary Outcome Measure Information:
Title
Adverse events in Dronabinol treatment as compared to placebo
Description
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
3-weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
95 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of Dementia due to AD
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.
Clinically significant severity of agitation defined by NPI-C Agitation or NPI-C Aggression > 4.
Able to give informed consent, or deemed to lack such capacity by clinical team and legally authorized representative consents.
Must be fluent in English and/or Spanish (includes reading, writing, and speech)
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.
Must be 60-95 years old
Must begin enrollment in study within one week of being determined eligible
Exclusion Criteria:
Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease, which might confound assessment of safety outcomes.
Seizure disorder
Baseline delirium as determined by Confusion Assessment Method (CAM) and Diagnostic and Statistical Manual of Mental Disorders (DSM) -5 criteria
Current use of lithium
Inability to swallow a pill
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mersania Jn Pierre, B.A.
Phone
410-550-4969
Email
mjnpier1@jhmi.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Rosain Ozonsi, B.A.
Phone
617-866-2511
Email
rozonsi@mclean.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Rosenberg
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Brent Forester
Organizational Affiliation
Tufts Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Miami Jewish Health
City
Miami
State/Province
Florida
ZIP/Postal Code
33137
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Victoria Petrulla
Phone
305-751-8626
Ext
64108
Email
vpetrulla@miamijewishhealth.org
First Name & Middle Initial & Last Name & Degree
Mariolga Aymat
Phone
305-751-8626
Ext
64103
Email
maymat@miamijewishhealth.org
First Name & Middle Initial & Last Name & Degree
Marc Agronin, M.D.
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21224
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mersania Jn Pierre, B.A.
Phone
410-550-4969
Email
mjnpier1@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Paul Rosenberg, M.D.
Facility Name
McLean Hospital
City
Belmont
State/Province
Massachusetts
ZIP/Postal Code
02478
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rosain Ozonsi, B.S.
Phone
617-866-2511
Email
rozonsi@mclean.harvard.edu
First Name & Middle Initial & Last Name & Degree
Andre Nguyen, B.S.
Phone
617-855-3257
Email
anguyen@mclean.harvard.edu
First Name & Middle Initial & Last Name & Degree
James M. Wilkins, M.D., DPhil
Facility Name
Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Todd Laffaye, B.A.
Phone
860-385-3866
Email
todd.laffaye@tuftsmedicine.org
First Name & Middle Initial & Last Name & Degree
Brent P. Forester, M.D., MSc.
Facility Name
North Shore Medical Center
City
Salem
State/Province
Massachusetts
ZIP/Postal Code
01970
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rosain Ozonsi, B.A.
Phone
617-866-2511
Email
rozonsi@mclean.harvard.edu
First Name & Middle Initial & Last Name & Degree
James M. Wilkins, M.D., DPhil
First Name & Middle Initial & Last Name & Degree
Julia Cromwell, M.D.
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Time Frame
Within 1 year of study completion
IPD Sharing Access Criteria
Investigators will send a proposal to the principal investigators (Drs. Rosenberg and Forester) who will decide if the proposal is satisfactory and if so, send the information listed above.
Citations:
PubMed Identifier
34629131
Citation
Cohen LM, Ash E, Outen JD, Vandrey R, Amjad H, Agronin M, Burhanullah MH, Walsh P, Wilkins JM, Leoutsakos JM, Nowrangi MA, Harper D, Rosenberg PB, Forester BP. Study rationale and baseline data for pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's dementia (THC-AD). Int Psychogeriatr. 2021 Oct 11:1-6. doi: 10.1017/S1041610221001150. Online ahead of print.
Results Reference
derived
PubMed Identifier
34532852
Citation
Bosnjak Kuharic D, Markovic D, Brkovic T, Jeric Kegalj M, Rubic Z, Vuica Vukasovic A, Jeroncic A, Puljak L. Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev. 2021 Sep 17;9(9):CD012820. doi: 10.1002/14651858.CD012820.pub2.
Results Reference
derived
PubMed Identifier
33660625
Citation
Solomon HV, Greenstein AP, DeLisi LE. Cannabis Use in Older Adults: A Perspective. Harv Rev Psychiatry. 2021 May-Jun 01;29(3):225-233. doi: 10.1097/HRP.0000000000000289.
Results Reference
derived
Learn more about this trial
Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease
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