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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02792257
Recruitment Status : Recruiting
First Posted : June 7, 2016
Last Update Posted : August 5, 2021
Sponsor:
Collaborators:
Mclean Hospital
Miami Jewish Health
Information provided by (Responsible Party):
Johns Hopkins University

Tracking Information
First Submitted Date  ICMJE May 26, 2016
First Posted Date  ICMJE June 7, 2016
Last Update Posted Date August 5, 2021
Actual Study Start Date  ICMJE March 1, 2017
Estimated Primary Completion Date May 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2017)
  • Symptoms of agitation as measured by the Pittsburgh Agitation Scale [ Time Frame: 3-weeks ]
    Scale will be administered weekly
  • Symptoms of agitation as measured by the Neuropsychiatric Inventory, Clinician Version [ Time Frame: 3-weeks ]
    Scale will be administered weekly
Original Primary Outcome Measures  ICMJE
 (submitted: June 1, 2016)
  • Symptoms of agitation as measured by the Pittsburgh Agitation Scale [ Time Frame: 3-weeks ]
  • Symptoms of agitation as measured by the Neuropsychiatric Inventory, Clinician Version [ Time Frame: 3-weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2017)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 1, 2016)
Adverse events in Dronabinol treatment as compared to placebo [ Time Frame: 3-weeks ]
All AEs occurring after randomization and during the 3-week treatment period, regardless of adherence to study treatment, will be recorded at all contacts.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease
Official Title  ICMJE Pilot Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Alzheimer's Disease
Intervention  ICMJE
  • Drug: Dronabinol (Marinol®)
    5mg - 10mg daily dose
  • Drug: Placebo
    Daily dose
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Dronabinol (Marinol®)
  • Placebo Comparator: Placebo
    Placebo medication will be administered twice daily.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 1, 2016)
160
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2023
Estimated Primary Completion Date May 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 95 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John Outen, M.S. 410-550-7385 jouten3@jhmi.edu
Contact: Eleanor Ash, B.A. 617-855-2589 eash@mclean.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02792257
Other Study ID Numbers  ICMJE IRB00052955
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: 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.
Responsible Party Johns Hopkins University
Study Sponsor  ICMJE Johns Hopkins University
Collaborators  ICMJE
  • Mclean Hospital
  • Miami Jewish Health
Investigators  ICMJE
Principal Investigator: Paul Rosenberg Johns Hopkins University
Principal Investigator: Brent Forester Mclean Hospital
PRS Account Johns Hopkins University
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP