Clinical trial NCT02792257
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Dementia Cannabinoids Agitation Neuropsychiatric Symptoms
Sponsor: Johns Hopkins University
Start date: 2017-03-01; Completion date: 2024-05-31
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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 2: Placebo medication will be administered twice daily.
Interventions: intervention 1: Dronabinol (Marinol®) intervention 2: Placebo
Intervention descriptions: intervention 1: 5mg - 10mg daily dose intervention 2: Daily dose

Protocol documents:
Prot_SAP_000.pdf: 
Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s 
disease (AD) (THC-AD) 
 
NCT Number- NCT02792257 
Document Date- 7/2/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
2 
 
 
Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s 
disease (AD) (THC-AD) 
 
Principal Investigators:  Brent Forester, MD, MSc, McLean Hospital and Paul Rosenberg, MD, Johns 
Hopkins 
Research Sites:  McLean Hospital, Miami Jewish Health, and Johns Hopkins Hospital 
Coordinating Center: Johns Hopkins University 
Funding: National Institute of Health (NIH) 
 
1. 
Background and Significance: 
 
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 (1). AD affects both 
cognition and emotion. Neuropsychiatric symptoms (NPS) in AD are a major cause of burden to patients, 
caregivers, and society (2,3) 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) (4). The most 
common NPS are agitation, depression and apathy (2,5).   
 
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 (4). In community-based samples, Agit-AD is common: in the Cardiovascular Health Study 
the prevalence of Agit-AD in the past month was 30% (5), and in the Cache County Dementia 
Progression study the 5-year prevalence was > 40% (4).  Agit-AD tends to persist (6) with its prevalence 
increasing with dementia severity (7). Agit-AD is associated with greater caregiver burden (8) and shorter 
time to institutionalization (1,9), 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.   
 
Agit-AD is a specific syndrome and suitable target for intervention research 
 
One of the major challenges in treating Agit-AD has been understanding the precise definition of the 
syndrome of agitation, as clinical manifestations may be varied and overlap with a number of other 
conditions including mood disorders and delirium.  The International Psychogeriatric Association (IPA) 
recently addressed this issue with a consensus definition of Agit-AD derived from opinion leaders on the 
neuropsychiatry of Alzheimer’s disease (10).  The definition requires the presence of cognitive 
impairment, evidence of emotional distress, and one of three of observable behavior (excessive motor 
activity, verbal aggression, physical aggression). It requires that the behaviors cause excess disability, 
and that the behaviors not be solely attributable to another disorder such as psychiatric illness, 
medical illness, or substance use.  The pharmaceutical industry has re-embraced Agit-AD as a target after 
several years hiatus, with are at least three controlled trials of novel medication interventions in the field 
for Agit-AD (clinicaltrials.gov NCT01922258 [brexpiprazole], NCT01584440 [Nuedexta 
(Dextromethorphan/quinidine)], and NCT01735630 [scylloinositol]).  Nuedexta has recently reported 
positive results in a phase II trial but there are no peer-reviewed publications to date. This new definition 
allows for treating Agit-AD as a specific target rather than a non-specific symptom, addressing past 
concerns about “pseudospecificity” of target symptoms (11). 
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
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There is widespread agreement that behavioral therapies should be first-line treatment for Agit-AD 
given their inherent safety. These interventions are being increasingly incorporated into “user-friendly” 
algorithms (12).  However, behavioral interventions are still not widely disseminated, may be less 
effective for the most severe cases of Agit-AD, and significant time and effort may be expended prior to 
observing response.  While behavioral management strategies are inherently safer than medications and 
are being increasingly systematized for wider dissemination (12,13), there clearly remains a role for 
medications, particularly in more severe cases.  
 
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 (3,8,14,15,16) and their use is associated with increased mortality in elderly patients 
with dementia (12,17,18). The latter has prompted an FDA “black-box” warning and caution in the field 
about their use.  Antidepressants (particularly selective serotonin reuptake inhibitors, SSRIs) appear to 
have fewer and less severe adverse effects compared to antipsychotics, as well as no known mortality 
risks, but are not without limitation. In a recent multi-center RCT of citalopram for Agit-AD (CitAD), 
clinical benefit was observed in that study (reviewed in Preliminary Data), but cautions were raised about 
adverse effects (prolonged QTc intervals and cognitive decline) (19).  CitAD participants were largely 
outpatients, and CitAD excluded patients taking antipsychotics and those with severe Agit-AD. Clinical 
response was not observed until 6-9 weeks following medication induction and response was poorer in 
more impaired participants.  Also, only ~40% of patients were characterized as “responders,” indicating a 
large unmet public health need. Therefore, exploration of alternative treatments for Agit-AD, particularly 
severe cases, is timely and warranted. 
 
Dronabinol  
 
Given modest efficacy and concerns about toxicity with current pharmacotherapies, there is a need to 
explore alternatives. 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. 
 
      Dronabinol (Marinol®) is an oral synthetic formulation of delta-9-tetrahydrocannabinol (THC), a 
partial agonist at the cannabinoid receptors (CB1 and CB2) and one of the major psychoactive 
constituents of the cannabis plant.  The endocannabinoid system is widespread throughout the human 
body.  The CB1 receptor is a G-coupled protein receptor primarily located on the spinal cord, peripheral 
nervous system, and in brain areas associated with learning/memory (hippocampus), movement (basal 
ganglia, cerebellum), mood (amygdala), higher-order cognition (frontal cortex), and appetite/reward 
(hypothalamus, nucleus accumbens) among others.  The CB1 receptor modulates the release of most 
major neurotransmitters in the brain, most often inhibiting release.  The CB2 receptor is primarily located 
in the immune system and in the gut, but also is present in the CNS.  Significant first-pass metabolism 
and degradation of THC occurs with the oral route of administration resulting in bioavailability of about 
10-20%.  THC is metabolized to 2 primary metabolites:  11-OH-THC, a psychoactive metabolite of 
approximately equal potency as THC; and THC-COOH, a non-psychoactive metabolite. 
Subjective/physiological effects are dose dependent. Due to THC and its metabolites being highly lipid 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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soluble, blood cannabinoid levels are not necessarily reflective of acute drug effects, particularly 
following oral administration.  
 
Potential mechanisms for benefit of dronabinol in Agit-AD 
 
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 (20,21).  Dronabinol is 
an effective agonist at the CB1 receptor, which is generally specific to neurons and localized 
predominantly on the presynaptic terminal (22) where it inhibits glutamatergic, dopaminergic and other 
neurotransmitter release (23).  The CB1 receptor effects has been observed to mediate the observed 
anxiolytic and antidepressant effects of THC (24). Dronabinol is also an agonist at CB2, a potent anti-
inflammatory receptor localized on activated microglia.  Patients with AD have increased central (7) and 
peripheral (25) inflammation, likely as a result of the accumulation of beta-amyloid.  Increased 
inflammation may have a number of behavioral effects (26) 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.   
 
Dronabinol shows promise as a novel treatment for Agit-AD 
 
Recently there has been renewed interest in potential alternative medical applications of 
cannabis/THC and medical marijuana is now legalized in 23 states and the District of Columbia.  Acute 
effects of THC can include subjective feelings of euphoria, relaxation, and sedation, and clinicians noted 
that THC is well tolerated for its approved indications. Given these subjective effects and relatively 
benign safety profile, investigators have studied THC preparations for the treatment of Agit-AD and there 
are several promising small studies. Volicer et al (27) administered dronabinol 2.5 mg twice daily to 15 
participants with advanced AD and anorexia in a crossover randomized controlled trial (RCT).  They 
observed reduction in Agit-AD measured by the Cohen-Mansfield Agitation Inventory (CMAI) during 
dronabinol exposure. Adverse events (AEs) were few although one participant experienced a generalized 
seizure after a single dose of 2.5 mg.  Patel et al performed a retrospective chart review of 48 residents of 
an assisted living dementia unit who had AD and anorexia (28).  Following treatment with dronabinol 2.5 
mg twice daily, agitation improved in 65%. No clinically significant AEs were attributed to dronabinol 
treatment. Walther et al (29) reported decreased nocturnal motor activity and reduced agitation in 6 
participants with dementia in an open-label trial of dronabinol 2.5 mg daily with no AEs attributed to 
drug exposure. Forester and colleagues published a case series of 40 inpatients at McLean Hospital with 
Agit-AD of advanced severity treated for 7 days with dronabinol (mean dose 7 mg daily) adjunctive to 
other psychotropics (30).  Pittsburgh Agitation Scale (PAS) scores decreased from a mean (SD) of 9.68 
(3.91) to 5.25 (4.17) (p<0.0001), for an effect size of 1.09.  Similar decreases were seen in PAS subscales 
including aberrant vocalization, motor agitation, aggressiveness, and resisting care.  Adverse events were 
no more than mild in severity and dronabinol was well tolerated. At Johns Hopkins, Dr. Rosenberg had 
similarly positive initial clinical results on 11 inpatients with Agit-AD.  However, a recent null trial from 
the Netherlands co-authored by Dr. Rosenberg suggests that dosing greater than 4.5 mg daily may be 
required for therapeutic efficacy (31). In laboratory studies with healthy adults, Dr. Vandrey, observed 
that oral cannabis containing 10 mg THC produced positive drug effects in the absence of cognitive 
impairment or spontaneously reported adverse events (AEs).  These encouraging preliminary results 
support a proof-of-concept RCT of dronabinol for Agit-AD. Because a 4.5 mg/day dose was insufficient 
in a prior study, and 10 mg/day of THC appears to acutely maximize positive effects in healthy adults 
compared with 25 and 50mg, 10 mg daily is a good target dose for both tolerance and efficacy in frail 
elderly adults.  


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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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 “repurposing” dronabinol as a novel and safe treatment for Agit-AD with 
significant public health impact.   
 
2. Specific Aims: 
 
We propose THC-AD:  a three-week placebo-controlled, double-blind, randomized clinical trial of 
dronabinol (10 mg QD) in 80 patients with severe Agit-AD. Concomitant medications will be limited to 
currently used antipsychotics, antidepressants, benzodiazepines, as well as anticonvulsant therapy when 
not used for seizure disorder, with lorazepam 0.75 QD total daily allowed as rescue medication, and can 
be administered orally or intramuscularly. Additionally, these four categories of currently used 
concomitant medications are permitted to be used with PRN trazodone in doses up to 100 mg total daily 
dose for agitation and insomnia.  
 
AIM 1: To compare the efficacy of three weeks of dronabinol adjunctive treatment to placebo in 80 
patients with severe Agit-AD. 
Hypothesis 1: Compared to placebo, dronabinol treatment will be associated with a greater reduction in 
symptoms of agitation as measured by co-primary outcomes of a) PAS b) NPI-C Agitation, Aggression, 
and the sum of Agitation and Aggression. The Cohen-Mansfield Agitation Inventory will be a secondary 
agitation outcome. Psychosocial function, cognition, and sleep will be assessed for potential benefit.  
 
 AIM 2:  To compare the safety of three weeks of dronabinol adjunctive treatment to placebo in 80 
patients with severe Agit-AD.  
Hypothesis 2: Dronabinol treatment will be well tolerated with (AEs) not significantly different than 
placebo, including incident delirium as measured by the Confusion Assessment Method (CAM). 
 
Outcomes:   
 
The primary objective of this proposal is to assess dronabinol as a treatment for moderate to severe 
agitation in AD patients.  The Pittsburgh Agitation Scale (PAS) includes the important elements of other 
agitation measures in a relatively short instrument developed for clinical and research settings. Based on 
our preliminary data demonstrating significant declines in PAS total and subscales, we have chosen the 
PAS to serve as one of two primary outcome measures in addition to the Neuropsychiatric Inventory, 
Clinician Version (NPI-C), an updated version of the original Neuropsychiatric Inventory which is the 
most widely used measure for Agit-AD. The Cohen-Mansfield Agitation Inventory (CMAI), a longer 
instrument providing a rich description of detailed agitation symptoms, will serve as a secondary outcome 
measure, along with measures of global function (CGI-C), sleep, cognition (MMSE and SIB-8), 
subjective and observer-rated drug effects, and adverse events. 
 
 
3. Participant Selection: 
 
We plan to screen approximately 160 patients ages 60-95 with a clinical diagnosis of Alzheimer’s 
Dementia currently experiencing severe agitation symptoms.  We estimate a screen failure rate of 50% for 
a total of 80 participants randomized. Enrolled participants who meet all inclusion and exclusion criteria 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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during the screening visit will proceed to the baseline visit as outlined below. We have included more 
information about recruitment strategies below. 
 
Inclusion Criteria:  
 
1) Diagnosis of Dementia due to AD (by most recent criteria from McKhann et al (32))  
2) Presence of Agit-AD as defined by the provisional criteria from the International Psychogeriatric 
Association (IPA) (10). 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.  
This cutoff has been widely used in Agit-AD trials as evidence of clinically significant agitation, 
for example in CitAD (19,33).  
4) Able to give informed consent, or deemed to lack such capacity by clinical team and legally 
authorized representative consents.  We anticipate that most participants will lack capacity to 
consent and surrogate consent will be obtained in accordance with local state law and hospital 
guidelines. 
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) (34) and DSM-5 
criteria (35) 
4) Current use of lithium 
5) Inability to swallow a pill 
 
 
Delirium:   
 
Delirium is a syndrome of transient cognitive and behavioral change caused by a medical illness or 
medication.  Delirium is an important confound for studies of Agit-AD, as delirium is very common in 
dementia with an estimated lifetime prevalence of 56% (36) and dementia is the strongest risk factor for 
post-operative delirium (37).  It would be poor medical practice to misdiagnose delirium as Agit-AD; the 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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proper treatment for delirium is to address the underlying medical etiology.  We have four interventions 
to address this issue.  As part of routine clinical care, participants will receive thorough medical 
evaluation and management.  This will include physical exam, laboratory tests as appropriate, and 
management of medications.  Given the large range of potential medical conditions that one might 
encounter, it is not possible to specify these interventions in advance; instead, we specify that participants 
will be stabilized medically (as judged by the internist or geriatrician) prior to randomization.  Second, we 
will exclude patients diagnosed at baseline as meeting criteria for delirium using both a structured 
instrument (CAM) and clinical diagnostic criteria (DSM 5).  Third, we will monitor incident delirium as a 
safety outcome using the CAM.  Lastly, we will exclude participants with delirium at baseline, because 
the approach to agitation in these participants is fundamentally different and requires addressing causes of 
delirium itself. 
 
Concomitant medications and rescue medication:  
 
Participants may enter THC-AD taking antidepressants, antipsychotics, benzodiazepines, as well as 
anticonvulsant therapy when not used for seizure disorder.  The dosages of concomitant medication will be 
maintained unchanged through the 3-week RCT unless dose adjustment is required for safety reasons.   
Lithium will not be allowed. Lorazepam (up to 0.75 mg QD; 0.25 mg TID) to be administered orally or 
intramuscularly will be allowed as “rescue medication” for uncontrollable agitation. A similar dose of 
lorazepam (0.25 mg BID) has been used in prior trials (CitAD) without creating undue bias in interpretation 
of outcomes (19). We have increased the dose to 0.25 mg TID in order to safely care for severely agitated 
participants. PRN trazodone in doses up to 100 mg total daily dose will be allowed for agitation and 
insomnia. 
 
We propose to assess the effect of dronabinol on agitation in participants with AD. This is a population 
with high behavioral acuity and severely impaired cognition, as evidenced in our preliminary data.  Given 
this acuity, it is neither safe nor ethical to impose a period of time to stabilize on current psychotropic 
medications, which might make for a more rigorous trial design and longer study duration.  Mandating that 
patients with agitation in AD delay further changes in treatment is clinically unacceptable at the study site 
facilities. We elected to balance concomitant medications (antidepressants, antipsychotics, 
benzodiazepines, as well as anticonvulsants) in the two treatment groups prior to randomization using the 
process of “minimization” (38).  This method allows for balancing important covariates between groups in 
relatively small samples. While minimization requires altering the 1:1 ratio of randomization to maintain 
balance in covariates, treatment assignment is still randomized and study staff is blinded to assignment.  
The alterations in the randomization ratio are usually small and we have used this method in several trials 
without any evidence of unblinding or bias. 
 
Study screen fails: 
 
Participants will be deemed Screen Failures if they fail to meet the inclusion criteria and/or meet any 
exclusionary criteria as outlined above. Participants may also be deemed Screen Failures if, during the 
course of the study, study staff learn that participants have misinformed study staff about the 
inclusion/exclusion criteria and, therefore, no longer meet study selection criteria. 
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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All participants will complete the pre-screening and screening process detailed below. No participants 
will be excluded on the basis of race, ethnicity or sexual orientation. 
 
Participants will be recruited at clinical sites associated with McLean Hospital, Johns Hopkins University, 
and Miami Jewish Health Services.  Referrals will come from physicians on these units following 
standard IRB procedures and maintaining confidentiality per HIPAA standards.  Specifically, referring 
physicians will obtain consent from participants or legally authorized representatives (i.e. family with 
power of attorney or who serve as the patient’s health care proxy) to make the referral.  Then participants 
and/or families will be approached by research staff per standard IRB-approved procedures. 
 
 
4. 
Participant Enrollment: 
 
At the informed consent/screening visit, a member of the study staff will go through the informed consent 
form with the participants, and if appropriate, delegates. The participants and/or legal authorized 
representative will be encouraged to ask any questions they may have regarding study related procedures 
before the consent form is signed. Study staff will provide adequate time for the potential participant to 
consider participation in the study. Study staff will continue to emphasize that participation is voluntary 
and may be stopped at any time after signing consent without affecting their ability to receive treatment at 
McLean Hospital, Johns Hopkins Hospital, Miami Jewish Health, or any other institute. Potential 
participants who decide to participate in the study will document their consent by signing and dating the 
consent. All consents will be obtained by trained study clinicians. 
 
Before participants sign the consent form, an independent clinician will meet with the participants to 
assess their capacity to make informed decisions about participating in this study and complete the 
competency/capacity evaluation form. In the case the participant is deemed unable to give consent for the 
study, a legal representative may consent on their behalf. 
 
While it is customary to include an assent signed by the participant when the participant lacks capacity to 
consent, in this study we will make that optional because many participants will be too impaired to give 
meaningful assent; i.e., they can “sign on the line” but their language skills are too impaired to 
meaningfully assess their comprehension, even to the limited degree required for assent.  We will adhere 
to the crucial ethical principle that research procedures cannot and will not be forced on any participant, 
and point out that study drug must be swallowed and cannot be administered to an unwilling participant.   
 
Once enrolled, participants will receive a copy of their signed consent form. Receipt of the signed consent 
form will be documented on the Documentation of Informed Consent Form. All participants are assigned 
an identification number, according to the chronological order of consent date, which will be used in 
place of their full name on research study documents. Copies of the informed consent form will be placed 
in the participant’s medical record (at McLean, if applicable) with the participant’s permission. 
 
At McLean, participants will receive the “Partners Healthcare Notice for Use and Sharing of Protected 
Health Information” packet, and will be required to sign the “Acknowledgement of Receipt of Privacy 
Notice” form. Participants will be reminded that they can ask questions at any time and that the study is 
completely voluntary. Once consent is received, participants will begin the study assessment. 
 
At Johns Hopkins and Miami Jewish Health, IRB-approved procedures for informing participants and 
their legally authorized representatives of their right to confidentiality of health care information will be 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
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followed.  At Johns Hopkins and Miami Jewish Health, the custom is to include this language in the 
informed consent. 
 
Randomization and blinding:  
 
The investigators will be blind to treatment assignment. The Research Pharmacy will prepare blind 
medication using opaque capsules and randomly assign eligible participants to dronabinol vs. placebo 
treatment. We will use minimization to ensure that treatment groups are balanced with respect to use of 
antidepressant and antipsychotics. This method is preferred over stratification for trials of small sample 
size (38). The goal is have a ratio of drug:placebo close to 1:1 but adjust over time to achieve balance of 
antidepressant and antipsychotic use between the dronabinol and placebo groups. To address concerns 
that future or past randomizations could be predicted based on knowledge of treatment assignment of any 
one participant (relevant to unblinding at the end of the study for ethical reasons), we will use dynamic, 
non-deterministic probabilities of treatment assignments (39). User-friendly software to perform this type 
of minimization has already been developed and used by our research group in several R01-supported 
clinical trials including “Pilot Trial of Carvedilol in AD” and “Venlafaxine for depression in AD”. Note 
that although the odds of assignment to treatment group may vary across the course of the study, 
treatment assignment still remains a randomized process and the investigators remain blind to treatment 
assignment. The Research Pharmacy will keep treatment assignment confidential but have access to 
treatment assignment available on a 24-hour basis. In the event of medical emergency where knowledge 
of treatment assignment is essential to providing safe patient care, the Research Pharmacy will inform 
treating physicians of the treatment assignment. The investigators will be kept blind to treatment 
assignment except in extreme cases. In the event of unmasking, the Research Pharmacist will make a 
report to the DSMB. 
 
Methods for maintaining blinded rating of primary outcomes Frail elderly demented patients are 
notoriously prone to AEs including mood, attention, and subjective effects, and dronabinol is no 
exception to these concerns.  Additionally, the subjective effects may in fact be central to therapeutic 
benefit.  But observation of these effects could lead to inadvertent unmasking of treatment assignment and 
thus to bias in assessing outcomes.  To minimize these issues, we have separated members of the study 
team rating primary outcomes from those rating AEs. Although all members of the team are blinded to 
treatment assignment, this minimizes the possibility that raters of primary outcomes will guess or suspect 
treatment assignment based on AEs, and therefore minimizes the possibility that the rating of primary 
outcomes will be biased by knowledge of AEs.  This is a standard procedure used widely in industry-
sponsored AD trials. 
 
Study drug titration schedule: 
 
Study drug will be supplied as capsules containing dronabinol or inert filler (for placebo).  Study 
medication will be administered at 8 a.m. and 2 p.m.  Capsules of dronabinol will contain 2.5 mg per dose 
(5mg QD) during Week 1, then increase to 5 mg per dose (10mg QD) for Weeks 2 and 3. Commercial 
dronabinol will be overencapsulated and topped off with inert filler to preserve the blind. 
 
The study physicians will remain blinded to treatment assignment. However, if the study physicians opine 
that the study drug has led to adverse events, the study physicians have the option of reducing the dose of 
study drug at his/her discretion.   
 
Rationale for dosing: 
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
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The recently published results of van den Elsen et al (31) reporting null effect of 1.5mg THC TID (4.5mg 
QD) suggest that if THC is to be effective for Agit-AD, this dose is too low.  We observed benefit in our 
observational data with twice daily dosing for a mean total of 7mg QD, but the retrospective, uncontrolled 
study design did not allow a fine-grained look at dose effectiveness.  Our preliminary data in younger 
adults suggests that an acute dose of 10 mg produces mild to moderate positive subjective effects with 
few adverse effects whereas higher doses do not increase positive subjective effects and are associated 
with cognitive impairment and mild-moderate AEs.  Because our target population is frail and likely to be 
more sensitive to drug effects, we believe that a targeted 10 mg (5mg BID) daily dose will to maximize 
both efficacy and maintenance of safety.  The half-life of dronabinol is ~ 4 hours.  Dr. Ryan Vandrey is a 
consultant on the study at Johns Hopkins who specializes in pharmacologic research on controlled 
substances including THC.  Although Dr. Vandrey’s work in younger persons demonstrates subjective 
effects last 6-8 hours total; we propose to dose 6 hours apart to maximize daytime coverage for agitation, 
with dosing at 8 a.m. and 2 p.m.  The morning dose is standardly used in our clinical practice; the 
afternoon dose is timed to target late-afternoon/early evening agitation, a very common cycle in Agit-AD 
(often inappropriately termed “sundowning”). Kevin Hill M.D. will also serve as a consultant on the 
study. Dr. Hill is a national expert on marijuana treatment and policy. 
 
Outpatient Enrollments and Remote Assessments: 
 
Participants who enroll as outpatients will be required to attend a portion of each visit in-person.  Due to 
the COVID-19 pandemic, we will minimize physical interaction between participants and study team 
members by reducing the number of assessments that are completed in-person.  In-person visits will 
include the following precautions: a telephone screening prior to the visit to assess possible COVID-19 
symptoms, minimizing the number of staff members and caregivers involved, wearing personal protective 
equipment, maintaining physical distance, and thorough cleaning of all clinical spaces and instruments 
used during the visit.  Assessments that do not require in-person interaction will be completed remotely in 
order to decrease the length of in-person visits and to enhance safety for all involved, including remote 
consent (see Table 1 below).  Caregivers will be provided instructions on how to complete the remote 
assessments with study clinicians through a HIPAA compliant telemedicine software at a mutually agreed 
upon schedule.  The study team will provide a packet with all necessary information for remote 
assessments during the Baseline visit.  This packet will also include the DICE approach (Describe 
Investigate Create Evaluate) to educate caregivers with techniques to help manage behavioral symptoms 
of AD.  DICE is an algorithmic, evidence-based approach to NPS that includes the following four steps: 
Describe the behavior to derive an accurate characterization and the context of the emergent NPS; 
Investigate possible underlying causes of the NPS; Create and implement a treatment plan for the 
behavior; Evaluate what parts of the treatment and plan were effective (61).   
 
During remote assessments, caregivers will provide information to study clinicians as requested and allow 
them to interact with participants via video.  The study team will complete all assessments shown below 
in Table 1.  The contact format will remain the same for each subject (either in-person or remote for each 
visit during the 3 week enrollment duration).  Caregivers will receive study medication, a schedule for 
medication administration, and a medication log during in-person outpatient visits.  For outpatient 
participants, study staff will also perform a pill count at weeks 1-3 visits. Study clinicians will continue to 
prescribe rescue medications if needed, carefully monitor drug effects, and provide clinical referral or 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
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schedule additional visits if AEs develop.  Study clinicians will provide their contact information and will 
be in frequent communication with caregivers and participants throughout the enrollment duration.  
Caregivers will be well-informed of the possible side effects of dronabinol and will promptly inform 
study clinicians of all observations.   
 
Inpatient Enrollments and Remote Assessments: 
 
As described in the above section on remote assessments for outpatients, research team members will also 
have the option to remotely interview healthcare providers for inpatient enrollments.  For both outpatient 
and inpatient enrollments, study clinicians will have the option to remotely interview subjects and their 
caregivers to discuss the criteria for study enrollment, review the risks and benefits, determine capacity, 
and complete consent.  Interviews will be completed through a HIPAA compliant telemedicine software.  
Only the contact format will change to remote, but the assessment forms will remain the same (remote 
assessments will be identical to in-patient assessments).  The contact format will remain the same for each 
subject (either in-person or remote for each visit during the 3 week enrollment duration). 
 
 Table 1. Outpatient Study Procedures by Visit 
Procedure 
Screening 
 Baseline 
Week 1 
Week 2 
Week 3 
Informed Consent Process 
X 
  
  
  
  
Review of inclusion/exclusion criteria  
X 
  
  
  
  
Demographics 
X 
  
  
  
  
Medical History 
X 
  
  
  
  
Other Medications  
X 
  
  
  
  
Randomization 
  
X 
  
  
  
Study medication dispensing  
  
X 
 
 
  
Coronavirus Impact Scale (CIS) 
 
X 
 
 
 
Unblinding*  
  
  
  
  
X * 
Clinical Instruments 
  
  
  
  
  
Pittsburgh Agitation Scale (PAS) 
  
X 
X 
X 
X 
Neuropsychiatric Inventory, Clinician 
Version (NPI-C) 
  
X 
X 
X 
X 
Cohen-Mansfield Agitation Inventory 
(CMAI) 
  
X 
X 
X 
X 
Modified Alzheimer's Disease Cooperative 
Study- Clinical Global Impression of 
Change (CGI-C) 
  
X 
X 
X 
X 
Alzheimer's Disease Cooperative Study - 
Activities of Daily Living (ADCS-ADL) 
  
X 
X 
X 
X 
Confusion Assessment Method (CAM) 
  
X 
X 
X 
X 
Sleep Assessment (NPI-C Sleep Subscale) 
  
X 
X 
X 
X 
Cognition 
  
  
  
  
  
SIB-8 
  
X 
  
  
X 
Mini Mental State Exam (MMSE) 
  
X 
  
  
X 
Drug Effect 
  
  
  
  
  


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Drug Effect Questionnaire (DEQ) 
  
X 
X 
X 
X 
Medication Side-Effects Questionnaire 
  
X 
X 
X 
X 
Safety and AE monitoring 
  
  
  
  
  
Physical Exam 
 
X 
  
  
  
Neurological Exam 
 
X 
  
  
  
Vital Signs 
  
X 
X 
X 
X 
General Medical Health Rating (GMHR) 
X 
  
  
  
  
Adverse Event Monitoring 
  
X 
X 
X 
X 
ECG 
  
X 
  
  
X 
Blood draw (DNA, Biomarker, CBC, CMP, 
TSH) 
  
X 
  
  
X 
*Only done after all other study procedures are complete. 
 
Outpatient Enrollment – Procedures Color Legend: 
Completed in-person 
Completed remotely via HIPAA compliant video software 
Completed via optional location (in-person or remote) 
 
Unmasking:  
 
Every effort will be made to maintain the masked nature of the trial while taking precautions to optimize 
participant safety. Unmasking of treatment assignment before 3 weeks (“emergency unmasking”) will be 
limited to medical situations in which withholding knowledge of the identity of the drug will lead to 
unreasonable danger or suffering, and will not be necessary for routine management of potential side 
effects. The Research Pharmacy will have 24-hour access to treatment unmasking information. In an 
emergency situation, the study physician may elect to unmask a participant’s treatment assignment. All 
participants will undergo treatment unmasking at the endpoint of the study. This will either be at the 
Week 3 visit, or earlier if study treatment is discontinued prior to the third week. Participants and their 
referring physicians will be informed of treatment assignment after unmasking. 
 
5. 
Participant Procedures: 
 
Following the informed consent process, each participant will complete assessments conducted by the 
study coordinator and the principal investigator or delegated study staff member.  The specific 
assessments conducted are detailed below.  The participant’s participation will be comprised of 4 visits 
spanning their 3-week study enrollment. The study procedures per visit are outlined in Table 2.  
 
- 
Coronavirus Impact Scale (CIS):  The CIS is a short, 12-item scale that rates the influence of the 
Coronavirus (COVID-19) pandemic on multiple health factors, including employment, access to 
healthcare, and stress.  The CIS was developed by Joel Stoddard, MD MAS, and Joan Kaufman, 
Ph.D. 
 
Clinical Assessments 
 
- 
Pittsburgh Agitation Scale (PAS) (40) (Co-primary outcome): The PAS was developed for both 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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clinical and research settings to monitor symptoms of agitation that may fluctuate during the course of 
a day or week and to assess the response to therapeutic interventions.  The PAS rates the severity of 
agitation in four behavioral domains: Aberrant Vocalization, Motor Agitation, Aggressiveness, and 
Resisting Care, on a scale ranging from 0 to 4. Anchor points guide the rater to assign the highest 
possible score within each behavior group so that the score reflects the most aberrant behavior during 
a period of observation. The PAS takes less than 1 minute to complete. Reliability and validity were 
assessed in an acute-care psychogeriatric unit and a chronic-care nursing facility. The intra-class 
correlation for four nurses using the PAS during their work on the inpatient unit was +0.82 for the PAS 
Total Score.  
- 
Neuropsychiatric Inventory, Clinician Version (NPI-C) (41) (Co-Primary Outcome)The NPI-C is 
an improved version of the Neuropsychiatric Inventory (NPI) (42) that has been expanded to have 
separate subscales for “Agitation” and “Aggression”.  We will use clinically significant NPI-C 
Agitation or Aggression as entry criteria for the study and as co-primary outcomes. There is a training 
DVD available for the NPI-C.  The validation study (41) not only reported good inter-rater reliability 
but better convergent validity than the NPI with other agitation instruments such as the Cohen-
Mansfield Agitation Inventory (CMAI).  We propose to use NPI-C Agitation, Aggression, and the sum 
of Agitation and Aggression as co-primary outcomes. 
- 
Sleep assessment (NPI-C Sleep Subscale):  Sleep is an important outcome in on its own and 
additionally may be associated with Agit-AD.  Sleep will be quantified by using the Sleep Disorders 
subdomain of the NPI-C.  The NPI-C collects information on eight domains of sleep quality and 
behavior.  Information is collected on frequency and severity of sleep problems that patients 
commonly experience.  We will use the NPI-C Sleep Disorders subdomain score as a secondary 
outcome.  
- 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL): a 27-item 
instrument assessing participant’s ability to perform activities of daily living (ADLs) (43).  THC-AD 
staff will assess the ADCS-ADL by chart review and, where necessary, interview clinical staff who 
interact daily with the participant.  The ADCS-ADL has been used to assess ADLs as an outcome 
measure in clinical trials targeting moderate-to-severe dementia (44) 
- 
Cohen-Mansfield Agitation Inventory (CMAI) (45,46)  (Secondary Outcome) CMAI is one of the 
most widely used agitation indicators for dementia-related clinical trials. We will use the 14-item 
CMAI short form, which rates 14 behaviors associated with agitation according to frequency from 1 
‘never’ to 7 ‘several times an hour’. It was developed by directly observing behavioral disturbances 
in dementia patients and examines several agitated behaviors including verbal and physical agitation 
and aggression. Most dementia agitation trials have included CMAI, including CitAD.  
- 
Delirium (Confusion Assessment Method, CAM: {Inouye et al. 1990 (34)}: The CAM was 
developed for both clinical and research settings to accurately and quickly identify delirium in older 
patients. The CAM can be used to diagnose delirium using four key criteria including acute onset and 
fluctuating course, inattention, disorganized thinking, and altered level of consciousness.  The CAM 
has excellent inter-rater reliability and validity confirmed in a recent meta-analysis (47). 
 
Cognitive assessments 
 
The major function of assessing cognition in this proposal is as a safety evaluation, to determine whether 
dronabinol adversely affects cognition.  Alternatively, dronabinol might improve cognition, but the 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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literature and preliminary data do not point in this direction.  We propose to use SIB-8 (targeted for 
advanced dementia) and MMSE (to anchor the assessments in the larger world of dementia research). 
 
- 
SIB-8 (48): The SIB-8 is designed to assess cognition in severely impaired individuals, and consists 
of 8 items chosen from the original SIB (see Preliminary Data above).  We have shown that the SIB-
8 score has a strong correlation with SIB in the proposed patient population at Johns Hopkins, and 
given the short duration of administration is preferable to the full SIB.     
- 
Mini Mental State Exam (MMSE) (49): The MMSE is the most widely used instrument for 
assessment of general cognition, and widely used in dementia research.  It consists of 30 items 
assessing orientation, immediate recall, concentration, delayed recall, repetition, ideomotor praxis, 
reading, writing, and visuoconstructional ability. 
 
Drug effect monitoring  
 
Traditional measures of drug effect and medication side effects are often designed to be administered 
directly to participants.  Given that THC-AD participants will have dementia and in many cases severe 
dementia, we propose to rate the following two questionnaires on the basis of “all evaluable data” 
including participant interview, chart review, and discussion with clinical staff. 
 
- 
Drug Effect Questionnaire (DEQ) (Appendix 2): The subjective ratings of cannabis intoxication 
will be determined using the Drug Effect Questionnaire (DEQ). The individual items of the DEQ 
include ratings of drug effects (e.g. drug effect, pleasant effect, unpleasant effect) and 
behavioral/mood states often associated with cannabis intoxication (e.g. relaxed, paranoid, 
hungry/have munchies). Each item will be rated using a 100mm visual analog scale (VAS) anchored 
with “not at all” at one end and “extremely” at the other end. We have shown this method is sensitive 
to detecting dose effects of cannabis and dronabinol.  There are few data reflecting the validity and 
reliability of the DEQ in persons with cognitive impairment, and most neuropsychiatric measures in 
this field require the use of an informant. Dr. Vandrey, our substance abuse specialist and co-I, has 
developed an informant version of the DEQ (Appendix 2).  The items are similar but worded to be 
administered to an informant. 
- 
Medication Side-Effects Questionnaire: Research staff will interview participants and clinical staff 
and will rate on a 4-point scale (none, mild, moderate, strong) their impression of potential side 
effects of dronabinol.  Based on the list of potential side effects from clinical trials with dronabinol, 
items will include nausea, diarrhea, dry mouth, upset stomach, vomiting, vivid or abnormal dreams, 
anxiety, dizziness, fatigue, confusion, depersonalization, hallucination, paranoia, depression, rapid 
heart rate/palpitations, flushing in the face or body, tinnitus, speech difficulty, blurred vision, 
headache, sweating, runny nose, and coughing.  
 
Safety and Adverse Event (AE) monitoring 
All AEs occurring after randomization and during the 3-week treatment period, regardless of adherence 
to study treatment, will be recorded at all contacts. AEs will be assessed by using all available data to 
determine if new symptoms or medical events have occurred. A list of common side effects of dronabinol 
will be used to monitor for adverse events. At scheduled visits, participants and clinical staff/family 
caregivers will be interviewed about whether the participant experienced any symptoms or side effects on 
the list since the last visit. Adverse events, other than what is listed as common side effects, will still be 
recorded. If adverse events are noted, they will be rated as mild, moderate, or severe based on their 
clinical severity and frequency. Finally, medical transfers to outside general hospitals (McLean) or to a 
medical/surgical unit in the same hospital (Johns Hopkins and Miami Jewish Health) will be monitored. 
The PIs and designated study physicians will be responsible for monitoring the safety of participants. 
They will be responsible for appropriate medical care of participants during the study in connection with 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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study procedures. Safety assessments will include physical exams, vital signs, ECGs, monitoring of 
adverse events, and monitoring and maintenance of concurrent medication records.  AEs will be reported 
to the local IRBs per local policy.  Serious adverse events (SAEs) will be defined per FDA guidelines 
and reported in a timely manner as is standard in clinical trials (with the initial report being next business 
day). In addition, we will add the following DSMB-agreed upon SAEs to the SAE definition: 
 
1) Death (already defined as an SAE per standard FDA guidelines) 
2) Delirium at two consecutive weekly assessments 
3) Seizures 
4) Fall resulting in injury 
 
In accordance to FDA reporting requirements, any serious adverse events (SAEs) that occur at Johns 
Hopkins, Miami Jewish Health, and McLean Hospital will be reported to Johns Hopkins and Dr. Paul 
Rosenberg, M.D., the Sponsor-Investigator. Expected SAEs include delirium, intoxication, sedation, and 
increased appetite. Such reporting will adhere to the following process: 
1) Sponsor-Investigator will be notified of the SAE and will be given a report 
2) Sponsor-Investigator will notify the FDA of the SAE and a report will be submitted to the 
Regulatory Project Manager (RPM)/ FDA reviewing division within 7 calendar days via 
telephone, fax or email 
3) Following the Sponsor-Investigator’s initial receipt of the SAE, any relevant observations from 
animal or epidemiological studies suggesting significant risk to human subjects will be reported 
within 15 calendar days to the FDA in a written Safety Report via MedWatch Form 3500A 
4) Any relevant additional information obtained by the Sponsor-Investigator that pertains to the 
previously submitted Safety Report will be submitted as a Follow-up Safety Report, within 15 
calendar days following the Sponsor-Investigator initially receiving the information 
 
- 
Collection of vital signs 
- 
General medical health rating (GMHR) (50): this is a valid and reliable 4-point global rating of the 
severity of medical co-morbidity in patients with AD that our center has used in previous AD trials 
(51,52)   
- 
Adverse events monitoring: All adverse events occurring after randomization will be recorded. AEs 
will be assessed by using all available data to determine if new symptoms or medical events have 
occurred 
- 
Observation of ECG changes 
- 
Observation of changes in laboratory values.  
- 
Neurological and physical Exams 
 
Rationale for duration:  
 
The average length of inpatient stay in our observational data was ~16 days, and to cover this time period 
3 weeks should be sufficient. Additionally, in CitAD we observed that the placebo response largely 
reached its maximum after 3 weeks. We are proposing a trial of dronabinol for patients with Agit-AD; 
there are practical and ethical limitations on the duration of such a trial given available resources and the 
ongoing stress that families and caregivers are experiencing. If we demonstrate efficacy, there will likely 
be a role for dronabinol as a relatively rapidly acting agent for Agit-AD; for example, the full response to 
citalopram in CitAD was observed after 9 weeks (53). More rapid response should be beneficial for 
reducing family/caregiver stress. Since placebo response is largely complete by 3 weeks, we argue that 3 
weeks will be sufficient to distinguish drug from placebo response and to address whether dronabinol 
achieves a rapid response in that timeframe.  
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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Non-pharmacologic strategies for addressing Agit-AD:  
 
All participants will be provided with evidenced-based standard treatment for individuals with dementia 
complicated by agitation. This is an individualized approach and includes a combination of the following 
elements: 1) evaluation and clinical management of all medical co-morbidities that may be associated 
with behavioral disturbances (e.g., infection, pain, constipation, sensory problems); 2) reduction or 
elimination of all medications with anticholinergic effects that may adversely impact cognitive 
functioning and exacerbate behavioral symptoms; 3) maximization of environmental supports and non-
pharmacological treatments to reduce agitation using the DICE approach (12) including but not limited to 
1:1 staffing for ADL (activities of daily living) care in quiet setting and assessing environmental 
antecedents to behavioral agitation; 4) permission to continue and monitor all concomitant psychotropic 
medications; 5) incorporation of relevant elements of the psychosocial intervention used to address 
agitation in CitAD (33).  
 
Exploratory biomarkers:  
 
 1) We propose to collect DNA specimens at baseline to explore the possibility that cannabinoid receptor 
polymorphisms may affect response to dronabinol.  There has been preliminary work on the association 
between CB1 receptor polymorphisms and addiction (54) but none to date in AD.   
 
 While quantification of cannabinoid receptor density with neurochemical imaging could be very 
enlightening as to potential mechanism, it is neither practical nor ethically advisable to perform such 
imaging in advanced dementia and we do not propose it for this trial. 
 
Inflammatory Markers (Cytokines):   
 
We propose that participants will have blood drawn (approximately 42mL) to collect serum samples at 
Baseline and Week 3 to assay pro-inflammatory cytokines Interleukin-1 beta (IL-1β), tumor necrosis 
factor-alpha (TNF-α, and Interleukin-6 (IL-6) among others. The aforementioned serum samples will be 
collected to examine the association of peripheral markers of inflammation with agitation and response to 
dronabinol.  Serum will be separated within ½ hour following the draw. The sample will stored at -80 
degrees Celsius until ready ice until ready to ship.  The assays will be performed at an outside laboratory.  
 
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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Table 2. Study Procedures by Visit 
Procedure 
Screening 
 Baseline 
Week 1 
Week 2 
Week 3 
Informed Consent Process 
X 
  
  
  
  
Review of inclusion/exclusion criteria  
X 
  
  
  
  
Demographics 
X 
  
  
  
  
Medical History 
X 
  
  
  
  
Other Medications  
X 
  
  
  
  
Randomization 
  
X 
  
  
  
Study medication dispensing  
  
X 
X 
X 
  
Coronavirus Impact Scale (CIS) 
 
X 
 
 
 
Unblinding*  
  
  
  
  
X * 
Clinical Instruments 
  
  
  
  
  
Pittsburgh Agitation Scale (PAS) 
  
X 
X 
X 
X 
Neuropsychiatric Inventory, Clinician 
Version (NPI-C) 
  
X 
X 
X 
X 
Cohen-Mansfield Agitation Inventory 
(CMAI) 
  
X 
X 
X 
X 
Modified Alzheimer's Disease Cooperative 
Study- Clinical Global Impression of 
Change (CGI-C) 
  
X 
X 
X 
X 
Alzheimer's Disease Cooperative Study - 
Activities of Daily Living (ADCS-ADL) 
  
X 
X 
X 
X 
Confusion Assessment Method (CAM) 
  
X 
X 
X 
X 
Sleep Assessment (NPI-C Sleep Subscale) 
  
X 
X 
X 
X 
Cognition 
  
  
  
  
  
SIB-8 
  
X 
  
  
X 
Mini Mental State Exam (MMSE) 
  
X 
  
  
X 
Drug Effect 
  
  
  
  
  
Drug Effect Questionnaire (DEQ) 
  
X 
X 
X 
X 
Medication Side-Effects Questionnaire 
  
X 
X 
X 
X 
Safety and AE monitoring 
  
  
  
  
  
Physical Exam 
X 
  
  
  
  
Neurological Exam 
X 
  
  
  
  
Vital Signs 
  
X 
X 
X 
X 
General Medical Health Rating (GMHR) 
X 
  
  
  
  
Adverse Event Monitoring 
  
X 
X 
X 
X 
ECG 
  
X 
  
  
X 
Blood draw (DNA, Biomarker, CBC, CMP, 
TSH) 
  
X 
  
  
X 
*Only done after all other study procedures are complete  
 
 
 
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
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Protocol Version: 6.0/2July2020 
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6. 
Biostatistical Analysis: 
 
All analyses will be conducted using STATA (55) and R (56) under the supervision of the study 
statistician (Dr. Leoutsakos).  Descriptive analyses will be conducted and measures checked for outliers 
and to ensure that distributional assumptions of the planned analyses are appropriate.  If not, analogous 
non-parametric methods will be used. Analyses will be intent-to-treat.  We expect minimal missing data, 
but if there is a significant amount of missing data, multiple imputation may be used if appropriate (57).  
To investigate sensitivity to missing values, those with and without missing values will be compared by 
background covariates. Tests will be two-sided and p-values <0.05 will be considered significant. 
Multiple test corrections will be applied as appropriate.  All primary analyses will be adjusted for site as 
well as the variables balanced through minimization (use of antidepressants and use of antipsychotics).  
To account for the inclusion of multiple sites, we will include site as a covariate, with individuals being 
seen on an outpatient (largely remote) basis being treated as its own site.  Secondarily, we will fit models 
with site, site x time, and site x treatment x time to determine if there are any effects of site on treatment 
effect over time.  These analyses must be secondary as the study was not powered to detect these 3 way 
interactions.  Importantly, no participants were stopped during their participation and all participants will 
have the same mode of assessment (either in-person or remote) throughout. 
 
Aim 1:  Efficacy will be assessed by fitting a longitudinal linear model with the co-primary outcomes 
(PAS and NPI-C Agitation/Aggression/Sum of Agitation and Aggression) and with time, treatment 
assignment and interaction between time and treatment.  The latter term will be the coefficient of interest 
and will represent the mean difference in change over the 3-week period between the treated and placebo 
groups.  Within-person correlations will be handled via the method of generalized estimating equations 
(58).   
 
Aim 2:  We will model risk of a severe adverse event as a function of treatment assignment using logistic 
regression, and counts of total adverse events using ordinal logistic regression or poisson regression as 
appropriate.  We will also scrutinize counts of each specific type of AE as a function of treatment 
assignment to determine if there are specific adverse events which we should power ourselves to detect in 
future larger-scale trials. Special attention will be paid to new-onset delirium, seizures, and arrhythmias.  
Additionally we will specifically look at the effect of dronabinol on cognition using the SIB-8, and a 
regression model analogous to that in Aim 1.  We will stratify adverse events by site and assess whether 
rates of particular AEs vary by site.  In particular, we will assess whether outpatients differ in their rates 
and types of AEs (either favorably, due to being less acute, or unfavorably, due to a less controlled 
environment where falls might be more likely, for example). 
 
Secondary Analyses:  We will model change in additional outcomes (e.g., CMAI, MMSE, sleep, DEQ) 
using models analogous to that of Aim 1.  We will also look at predictors of dronabinol response, 
including cannabinoid receptor polymorphisms and other patient characteristics.  We will also model 
change in IL1β, TNF α, and IL6 as a function of treatment assignment.  All secondary analyses will be 
conducted with site as a covariate, and additional analyses which include site x treatment and site x 
treatment by time will be performed. 
 
Sample size and Power analysis  
 


Protocol: Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer’s disease (AD) (THC-AD) 
Protocol Number: IRB00052955 
 
Protocol Version: 6.0/2July2020 
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We observed a large effect in our observational study that used PAS as outcome.  PAS is one of the co-
primary outcomes and we will estimate power to detect change in PAS.  There are no pilot data to 
estimate power to detect change in NPI-C which has not been used in prior trials of dronabinol.  The PAS 
declined in our observational study from 9.68 (3.91) pre-treatment to 5.25 (4.17) post-treatment for a 
treatment effect of 1.1 and 45% reduction in PAS score.   
 
     We propose to use a more conservative estimate of 30% reduction in PAS score and calculated 
statistical power using the formulae of Jung and Ahn (59).  A 30% reduction translates to decreasing from 
9.68 PAS points to 7.26 points after 3 weeks, which means a slope of -0.81 points/week.  This translates 
to an effect size of 0.206.   It is essential to account for missing data including those from dropouts.  
Assuming first a missing data pattern that increases monotonically to 15% by week 3, with N= 80, a 
within-person correlation of 0.5 and an exchangeable correlation structure, we will have 80% power to 
detect a treatment effect of size 0.22, which translates to a decrease in PAS from 9.68 to 7.1 over 3 weeks; 
this is a 26.7% decrease. Assuming next a missing data pattern that increases monotonically to 30% by 
week 3, then with 80 people and a within-person correlation of 0.5 and an exchangeable correlation 
structure, we would have 80% power to detect a treatment effect of size 0.24, which translates to a 
decrease in PAS from 9.68 to 6.87 over 3 weeks; this is a 29.1% decrease.  Thus, THC-AD is well-
powered to detect a clinically plausible and conservatively estimate decrease in PAS which is a co-
primary outcome. 
 
We repeated the above power analysis assuming a sample size of 60 in the event that we do not meet our 
original recruitment goals.  With a missing data pattern that increases monotonically to 15% by week 3, 
with N=60, a within-person correlation of .5 and an exchangeable correlation structure we will have 80% 
power to detect a treatment effect of size .25, which translates to a decrease in PAS from 9.68 to 6.75 over 
3 weeks; this is a 30.3% decrease.  With a missing data pattern that increases monotonically to 30% by 
week 3, and identical conditions otherwise, we would have 80% power to detect a treatment effect of size 
.27, which translates to a decrease in PAS from 9.68 to 6.51 over 3 weeks; this is a 33 % decrease.   
 
7. 
Risks and Discomforts: 
 
Study medication side effects: 
 
Based on the list of potential side effects from clinical trials with dronabinol, items will include nausea, 
diarrhea, dry mouth, upset stomach, vomiting, vivid or abnormal dreams, anxiety, dizziness, fatigue, 
confusion, depersonalization, hallucination, paranoia, depression, rapid heart rate/palpitations, flushing in 
the face or body, tinnitus, speech difficulty, blurred vision, headache, sweating, runny nose, and 
coughing. 
 
Potential substance abuse: 
 
Dronabinol is a Schedule III substance indicating moderate abuse liability relative to other drugs.  Given 
the low doses to be administered, close monitoring of participants and medication administration, and 
relatively short duration of exposure proposed in the present study, we believe the risk of participants 
misusing the study medication or becoming dependent on dronabinol to be very low.  Outcomes obtained 
from the DEQ patient-based and informant-based questionnaires will provide outcomes relevant to 
examining the abuse liability of the study doses in this population (e.g. subjective ratings of pleasant drug 
effect) that will be valuable for future studies.  We will also evaluate whether participants or families of 
non-responders to dronabinol request to continue medication after the trial is completed. 


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Risk of Treatment Limitations: 
It is possible that enrolling in this study will limit administration of medications typically used to 
treat agitation in AD. For example, this study allows participants to receive lorazepam up to 0.75 mg 
per day as a rescue medication, but some patients might have received higher dosages if they were 
not enrolled in this study. The study clinician will monitor these circumstances on a case-by-case 
basis and determine the best course of action in his professional judgement. By enrolling in this 
study, participants acknowledge this possible limitation of treatment.  
 
Risks associated with blood draw: 
 
When blood is drawn, some discomfort may be associated with it at the time of the blood draw. Bruising 
and/or bleeding at the needle site may occur. Occasionally a person feels faint. Rarely, an infection may 
develop. If an infection does occur, it can be treated. All McLean, Miami Jewish Health, and Johns 
Hopkins employees who may draw blood for this protocol will be phlebotomy trained and certified. 
 
Risks associated with clinical assessment/rating scales: 
 
Due to the nature of the clinical assessment and rating scales, participants may become distressed or 
frustrated when answering questions and/or recalling periods of their lives or their current mood state. In 
addition, some participants may feel fatigued while completing study assessments, such as the 
neuropsychological testing, due to the length of administration. Study staff will provide opportunities for 
participants to take breaks or, if requested, reschedule testing for another time.  
 
During study participation, study staff may ask participants to answer sensitive and personal questions 
(such as previous substance use and psychiatric history) in order to evaluate study eligibility, 
appropriateness, and monitor for potential safety concerns. Although it is preferred that participants 
answer all questions, they have a right to not answer any questions. 
 
Risks associated with protection of participant confidentiality: 
 
Protected health information will be collected as part of this protocol and study staff take serious measure 
to preserve participant privacy. However, it is possible that confidentiality may be breached, despite the 
precautions.  
 
Confidentiality will be maintained with the assignment of an identification number or code, which will be 
used in place of participant names in all data analyses and reports. All documents that contain confidential 
information that cannot be replaced with an identification code (such as a signature) will be stored in 
locked filing cabinets and offices, separately from the research scales, as an additional protection against 
potential loss of confidentiality. The principal investigator, the research staff, and the study collaborators 
may have access to the data that is collected, in addition to the parties listed on the ICF (i.e., federal or 
state agencies that oversee research, the McLean IRB, the Johns Hopkins IRB, the Miami Jewish Health 
IRB etc.). 
 
Stored confidential information on the computer will be password protected. Keys showing the 
assignment of identification numbers to participant names will be stored with participant files in a room 
under lock and key. All of the data that is collected will be kept for a minimum of seven years once the 
study has been completed per federal guidelines. After the seven years, the research information is 


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destroyed appropriately. We will cease to use identifiable data collected for this protocol once the 
protocol has been closed out with the McLean, Miami Jewish Health, and Johns Hopkins IRBs. 
 
All participants or legally authorized representatives will be required to give informed consent and must 
understand all procedures prior to the participant’s participation in the study A member of the research 
staff will explain the consenting procedure and be available for any questions that arise from the consent 
form.  
 
Participants are informed of their confidentiality and privacy rights in the informed consent form and 
receive information about the Privacy Rule, Partners Privacy/HIPAA policies at screening. To ensure that 
participants’ rights and safety are protected during the conduct of this research study, participants consent 
to the inspection of their medical records by specifically authorized monitors. Such monitoring may be 
performed by the Human Research Protection Program of McLean Hospital, Miami Jewish Health, and 
Johns Hopkins, or by the FDA or other involved federal agency. 
 
Participants are informed that all the information obtained in this study will be used for research 
investigational purposes only. Name of participants will never be publicly disclosed at any time. 
Participants will not be identifiable in any publication that may arise from this research. 
 
Participants will receive a copy of the consent document to keep as well as a copy of the “Partners 
Healthcare Notice for Use and Sharing of Protected Health Information” for McLean Hospital, and the 
“Authorization for Release of Health Information” for Johns Hopkins or Miami Jewish Health. 
Participants will be informed that this research will be conducted and administered in compliance with all 
state and federal laws. 
 
Release of information to the participants:  
 
Participants may request that clinically-relevant information collected through the research study be 
shared with others. In order for staff to comply with such a request, participants must request the sharing 
of research information by completing an “Authorization for Release of Medical Records” form for 
McLean Hospital and an “Authorization for Release of Health Information” form for Johns Hopkins or 
Miami Jewish Health. Information most typically shared from the research study includes blood 
laboratory results, physical examination, and vital signs. Likewise, participants must also complete this 
form to give staff permission to obtain information, on behalf of the participant, from outside sources, 
such as the participant’s psychiatrist.  
 
Unknown risks and discomforts:  
 
In addition to the risks described above, study procedures may have other risks that are not yet recognized 
or delayed. 
 
8. 
Potential Benefits: 
 
Participants may benefit from knowing that the results of this study could improve future care of patients 
with Alzheimer’s disease by contributing to knowledge in the field and potentially providing benefits to 
treatment and management as a result of this increased understanding. This could result in improving the 
quality of life, safety, and possibly daily functioning of patients with Alzheimer’s disease, which could 
allow for a transition to a more independent level of care.  


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The study medication, dronabinol, may also reduce agitation thereby improving the participants’ quality 
of life, safety, and possibly daily functioning. This could allow for the transition to a more independent 
level of care.  
  
9. 
Monitoring and Quality Assurance: 
 
Potential participants are presented with information about possible risks during the consent process. The 
informed consent document contains all the known risks and warnings associated with participating in the 
research study. If any new changes in scientific knowledge alter our understanding of the condition or the 
proposed treatment, the consent form and the study clinician’s instructions will be adjusted accordingly.  
 
Data Safety Monitoring Board (DSMB):   
 
THC-AD will use a three-person DSMB described in detail under “Protection of Human Subjects”.  This 
board will be constituted with one expert in dementia trials, one expert in geriatric medicine, and one 
biostatistician experienced with clinical trial design and management.  The DSMB will meet by 
videoconference prior to the first randomization and every 6 months thereafter, along with the NIA 
program officer.  The DSMB will review unblinded data supplied by the THC-AD statisticians, and will 
make recommendations about whether to alter study procedures based on safety considerations.  The PIs 
of THC-AD will have the final responsibility about implementing such changes and will do so in 
accordance with IRB procedures, NIH policy, and full attention to the need to protect the safety and rights 
of research participants. 
 
Adverse Event reporting:  
 
All adverse events will be systematically recorded and reported to the McLean Hospital, Miami Jewish 
Health, and Johns Hopkins University IRBs, to the DSMB, and to the FDA via the Annual Report per 21 
CFR 312.33. In the event that a participant becomes ill or injured as a direct result of participation in the 
research study, necessary medical care will be made available. The NIH Project Officer will be informed 
of any actions taken by the McLean, Miami Jewish Health, and Johns Hopkins IRBs as a result of such 
adverse events. All possibly related and unexpected adverse effects will be reported per current IRB 
guidelines. Unrelated or expected AEs will be reported at continuing review per current IRB guidelines. 
Serious adverse events will be followed to resolution or stabilization and reported per current reporting 
guidelines.  
 
A participant may be discontinued from the study at any time as a result of adverse event, PI discretion, or 
participant non-compliance with protocol. All the information about participants will be treated 
confidentially. Overall, the principal investigator (AG) will be responsible for the execution of these 
protocol procedures and will monitor adverse events and participant safety throughout the study. The 
principal investigator will be informed of all adverse events that occur in the study. 
 
Minimizing discomforts:  
 
All procedures have been designed to minimize participant discomfort.  
No participant will be asked to engage in research procedures not outlined in the consent form. We will 
follow and adhere to all guidelines as defined and outlined on the IRB websites of McLean Hospital, 
Miami Jewish Health, and Johns Hopkins. 


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Inter-rater reliability:  
 
Prior to any data collection activities, THC-AD will have an in-person Investigator’s Meeting for study 
initiation.  Training will occur for all primary and secondary outcome measures and inter-rater reliability 
will be assessed for the PAS and NPI-C Agitation and Aggression domains by rating videotaped 
interviews and assessments.  To prevent rater drift over time, this training and assessment of inter-rater 
reliability will be performed annually by videoconference with the goal of achieving intra-class 
coefficient (ICC[3,1]) of .75 or greater (60). 
 
Blind maintenance plan: 
 
In any drug study there is the risk that the study team will obtain data that might be interpreted as hinting 
at treatment assignment particularly due to observation of AEs, and that the observation of outcomes will 
become biased due to this awareness.  This is a common issue in AD pharmaceutical industry trials. We 
will adopt the strategy of splitting up the members of the team who assess primary outcomes from those 
who assess AEs. Primary outcomes will be assessed by research assistants and/or coordinators.  
Outcomes that encompass subjective effects of drug exposure and/or AEs will be assessed by study 
physicians and/or nurses.  These two teams will not exchange any information obtained and thus will be 
blinded to each other’s findings.  Combined with the fact that all study/clinical staff are blind to treatment 
assignment, this will ensure that observation of outcomes will remain unbiased. 
 
 
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