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Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease (THC-AD)

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ClinicalTrials.gov Identifier: NCT02792257
Recruitment Status : Recruiting
First Posted : June 7, 2016
Last Update Posted : August 10, 2022
Mclean Hospital
Miami Jewish Health
Information provided by (Responsible Party):
Johns Hopkins University

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.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: Dronabinol (Marinol®) Drug: Placebo Phase 2

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 their 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease
Actual Study Start Date : March 1, 2017
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Dronabinol

Arm Intervention/treatment
Experimental: 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.
Drug: Dronabinol (Marinol®)
5mg - 10mg daily dose

Placebo Comparator: Placebo
Placebo medication will be administered twice daily.
Drug: Placebo
Daily dose

Primary Outcome Measures :
  1. Symptoms of agitation as measured by the Pittsburgh Agitation Scale [ Time Frame: 3-weeks ]
    Scale will be administered weekly

  2. Symptoms of agitation as measured by the Neuropsychiatric Inventory, Clinician Version [ Time Frame: 3-weeks ]
    Scale will be administered weekly

Secondary Outcome Measures :
  1. Adverse events in Dronabinol treatment as compared to placebo [ Time Frame: 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   60 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02792257

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Contact: John Outen, M.S. 410-550-7385 jouten3@jhmi.edu
Contact: Eleanor Ash, B.A. 617-855-2589 eash@mclean.harvard.edu

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United States, Florida
Miami Jewish Health Recruiting
Miami, Florida, United States, 33137
Contact: Maria Isesalaya, MBA, BS    305-751-8626 ext 64108    misesalaya@miamijewishhealth.org   
Contact: Ricardo Castaneda, PharmD, CCRC    305-751-8626 ext 64199    rcastaneda@miamijewishhealth.org   
Principal Investigator: Marc Agronin, M.D.         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21224
Contact: Mersania Jn. Pierre, B.A.    410-550-9000    mjnpier1@jhmi.edu   
Principal Investigator: Paul Rosenberg, MD         
United States, Massachusetts
McLean Hospital Recruiting
Belmont, Massachusetts, United States, 02478
Contact: Mia Drury, B.A.    617-855-3257    mdrury@mclean.harvard.edu   
Contact: Rozain Ozonsi, B.S.    617-866-2511    rozonsi@mclean.harvard.edu   
Principal Investigator: Brent P Forester, MD, MSc         
North Shore Medical Center Recruiting
Salem, Massachusetts, United States, 01970
Contact: Mia Drury, B.A.    617-855-3257    mdrury@mclean.harvard.edu   
Principal Investigator: Brent Forester, MD, MSc         
Sub-Investigator: Julia Cromwell, MD         
Sponsors and Collaborators
Johns Hopkins University
Mclean Hospital
Miami Jewish Health
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Principal Investigator: Paul Rosenberg Johns Hopkins University
Principal Investigator: Brent Forester Mclean Hospital
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT02792257    
Other Study ID Numbers: IRB00052955
First Posted: June 7, 2016    Key Record Dates
Last Update Posted: August 10, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Within 1 year of study completion
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Johns Hopkins University:
Neuropsychiatric Symptoms
Additional relevant MeSH terms:
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Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Psychomotor Disorders
Psychomotor Agitation
Neurologic Manifestations
Neurobehavioral Manifestations
Physiological Effects of Drugs
Psychotropic Drugs
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Cannabinoid Receptor Agonists
Cannabinoid Receptor Modulators
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Hormones, Hormone Substitutes, and Hormone Antagonists