Over 5 million Americans have Alzheimer's disease or a related dementia, a progressive and irreversible neurodegenerative condition, affecting also close to 15 million family caregivers (CG). A hallmark of the disease and one of the most significant challenges in dementia care is neuropsychiatric symptoms (NPS) of which agitation is the most disabling and frequently occurring. It is associated with increased health care costs, reduced life quality, heightened caregiver burden, disease acceleration and nursing home placement. Treatment typically involves pharmacologic agents; however, these are at best modestly effective, carry serious risks including mortality, and may not reduce family distress. Recently issued position statements from medical organizations suggest nonpharmacologic strategies as first-line treatment. Nevertheless, nonpharmacological strategies for agitation remain understudied. We propose a Phase III efficacy trial to test a novel 8-session patient-centric intervention, the Tailored Activity Program. We will test the program using a randomized two-group parallel design of 250 people with dementia (PwD) and their CGs (dyads) who will be randomly assigned to received a program of tailored activities or a control intervention of equivalent in-home attention and social contact. The trial assesses PwDs' preserved capabilities, deficits, previous roles, habits, interests and home environment from which activities are developed to match PwD profiles. Families are trained to implement activities and modify them for future decline. Our primary study aim evaluates the effect of tailored activities at 3 months on agitation (Hypothesis: PwD in the tailored activity program will have less frequent agitation compared to the control intervention condition. Three secondary aims evaluate: 1) 6-month effects of tailored activities on agitation and quality of life in PwD (Hypothesis: PwD receiving tailored activities will manifest lower severity scores at 6 months and better quality of life compared to PwD in the control intervention); 2) Immediate effects of tailored activities at 3 and 6 months on CG wellbeing, and time spent providing care (Hypothesis: CGs receiving training in tailoring activities will report enhanced wellbeing and less time caregiving compared to the control intervention (3 and 6 months); and 3) Cost effectiveness of the Tailored Activity Program expressed as an incremental cost outcome achieved in the form of CG burden reductions and willingness to pay for burden reductions (3 and 6 months; Hypothesis: Tailoring activities will be cost effective compared to the control intervention at each test occasion). Exploratory aims will evaluate treatment effects on psychotropic medication use and other troublesome behaviors, if effects differ by cognitive status, if CGs receiving the tailored activity program will use activities at 6 months and with what frequency, how time gained is spent, and if frequency/duration of treatment and activity use affects outcomes. If proven efficacious and cost effective, the Tailored Activity Program has potential to transform clinical practice by offering a proven nonpharmacologic treatment for agitation of PwDs at home. This trial addresses a critical clinical need and public health priority identified by recent legislative activity.

Over 5 million Americans have Alzheimer's disease or a related dementia, a progressive and irreversible neurodegenerative condition, affecting also close to 15 million family caregivers (CG). A hallmark of the disease and one of the most significant challenges in dementia care is neuropsychiatric symptoms (NPS) of which agitation is the most disabling and frequently occurring. It is associated with increased health care costs, reduced life quality, heightened caregiver burden, disease acceleration and nursing home placement. Treatment typically involves pharmacologic agents; however, these are at best modestly effective, carry serious risks including mortality, and may not reduce family distress. Recently issued position statements from medical organizations suggest nonpharmacologic strategies as first-line treatment. Nevertheless, nonpharmacological strategies for agitation remain understudied. We propose a Phase III efficacy trial to test a novel 8-session patient-centric intervention, the Customized Activity Program (CAP). We will test CAP using a randomized two-group parallel design of 250 people with dementia (PwD) and their CGs (dyads) who will be randomly assigned to CAP or a control intervention of equivalent in-home attention and social contact. CAP assesses PwDs' preserved capabilities, deficits, previous roles, habits, interests and home environment from which activities are developed to match PwD profiles. Families are trained to implement activities and modify them for future decline. A pilot phase with 60 dyads showed clinically meaningful and statistically significant reductions in agitation, with no adverse effects. Our primary study aim evaluates the effect of CAP at 3 months on agitation (Hypothesis: PwD in TAP will have lower caregiver rated agitation compared to the control intervention condition. Three secondary aims evaluate: 1) 6-month effects of TAP on agitation and quality of life in PwD (Hypothesis: PwD in CAP will manifest lower caregiver rated subscale frequency and severity scores at 6 months and better quality of life compared to PwD in the control intervention); 2) Immediate effects of CAP at 3 and 6 months on CG wellbeing, and time spent providing care (Hypothesis: CGs receiving CAP will report enhanced wellbeing and less time caregiving compared to the control intervention (3 and 6 months); and 3) Cost effectiveness of CAP expressed as an incremental cost outcome achieved in the form of CG burden reductions and willingness to pay for burden reductions (3 and 6 months; Hypothesis: CAP will be cost effective compared to the control intervention at each test occasion). Five exploratory aims will evaluate treatment effects on psychotropic medication use and other troublesome behaviors, if effects differ by cognitive status, if CGs receiving CAP use activities at 6 months and with what frequency, how time gained is spent, and if frequency/duration of treatment and activity use affects outcomes. If proven efficacious and cost effective, CAP has potential to transform clinical practice by offering a proven nonpharmacologic treatment for agitation of PwDs at home. This trial addresses a critical clinical need and public health priority identified by recent legislative activity.

Objectives

Our primary study aim evaluates the immediate effect of CAP on agitation at 3 months. Our hypothesis is that PwD receiving CAP will manifest a lower caregiver rated frequency and severity score on the Neuropsychiatric Inventory-(NPI) subscales of agitation+aggression (21 items), compared to those in the control intervention.

Three secondary aims are to evaluate: 1) effects of CAP at 6 months on agitation and quality of life in patients. Hypothesis: Patients receiving CAP will manifest lower caregiver rated frequency and severity scores on the NPI-C agitation + aggression subscales and better quality of life in comparison to patients receiving the control intervention from baseline to 6 months; 2) effects of CAP at 3 and 6 months on CG wellbeing, (burden, skill acquisition, efficacy using activities), and time spent providing care. Hypothesis: Caregivers receiving CAP will report enhanced wellbeing and less time caregiving compared to those in the control intervention at 3 and at 6 months; and 3) cost effectiveness of CAP expressed as an incremental cost outcome achieved in the form of CG burden reductions and willingness to pay for burden reductions at 3 and 6 months. Hypothesis: CAP will be cost effective compared to the control intervention at each test occasion.

To further understand treatment effects and enhance translation, we propose exploratory aims to evaluate: 1) Impact of CAP on psychotropic medication use in treatment and control conditions at 3 and 6 months by comparing proportion of PwD who require dose increases or incident use of psychotropic medications (negative outcome) and proportion of PwD who reduce or eliminate medication use because agitation improved (positive outcome); 2) Whether treatment effect on agitation differs at 3 and 6 months by cognitive status; 3) Whether CAP reduces total NPI scores as rated by CGs at 3 and 6 months, 4) If at 6-months CGs receiving CAP are using prescribed activities and with what frequency; and how CGs use any personal time gained; and 5) Extent to which treatment receipt and enactment (frequency/duration of sessions and use of activities) affects NPI-C scores. If proven efficacious and cost effective, CAP has potential to transform the current paradigm of dementia care that relies primarily on the pharmacologic management of agitation. It will offer clinicians and families a proven nonpharmacologic approach to enhance quality of life that can be replicated, has reimbursement potential, and resonates with medical treatment guidelines and health care reform efforts aimed at reducing pharmacologic use and helping older adults be cared for at home.

Background

This proposed trial specifically builds upon and extends the pilot phase testing of the proposed intervention with 60 dyads (NIMH R21 grant # R21 MH069425). This pilot phase evaluated program acceptability, identified behaviors most responsive, and evaluated magnitude of change for NPS and CG burden. Dyads were interviewed at baseline, randomized to intervention or wait-list control, and then reassessed at 4-months. After 4-months, the wait-list control group received the intervention and was reevaluated at 8 months (within group comparison 4 to 8 months). Main outcomes: At 4-months, a statistically significant treatment effect was found for frequency of NPS overall (p=.010; Cohen's d=.72) using the 16-item Agitated Behavior Inventory for dementia. Specifically, 77% of CGs in treatment reported improvements in NPS compared to 40% in the wait-list group; 23% in treatment reported worsening of NPS compared to 60% in wait-lists. As untreated agitation worsens over time in a significant proportion of patients, our pilot data suggests that worsened agitation was less common in the intervention group; the intervention also appeared to help reduce likelihood of worsening in patients whose agitation was destined to worsen without treatment. It appears unlikely that the intervention caused an adverse effect of worsening. However, as this is a possibility, it is listed in the consent form as a possible risk. Reductions for intervention group also occurred for specific behaviors reflecting agitation and behaviors of most concern to this CG sample; shadowing (p=.003, Cohen's d=3.10), and repetitive questioning (p=.023, Cohen's d=1.22), with slight increases (worsening) found for the control group. As shown in Figure 2, we also found a statistically significant reduction in prevalence of caregivers reporting agitation (p=.014, Cohen's d=.75); 14.8% in treatment vs. 44.8% in control reported PwD agitation at 4 months. A similar pattern was found for argumentation (p=.010, Cohen's d=.77). Also, CG in treatment reported that PwD demonstrated better engagement (p=.029, Cohen's d=.61), more pleasure (p=.045, Cohen's d=.690), and improved ability to keep positively busy (p=.017, Cohen's d=.71). Equally significant were reductions in CG objective burden as measured by NIH REACH vigilance items hours "doing things" for PwD (p=.005, Cohen's d=1.14); and hours "on duty" (p=.001, Cohen's d=1.01) with those in intervention reporting 5 hours less and those in control reporting spending 3 hours more on duty. Control group participants demonstrated similar benefits from 4 to 8 months. Medication Use: Of 60 PwD, 78.3% were on an anti-dementia medication (cholinesterase inhibitor or memantine), 32% were on psychotropic medication for NPS, and 45% were on antidepressants at study entry. Use of medications did not impact the primary outcome (e.g., frequency of behavioral symptoms). In separate regression analyses, we entered baseline use/non-use of 3 medication-types (e.g., anti-depressant, other psychotropic medication, and anti-dementia medications) as a predictor and found no impact on treatment outcome or effect size. This shows that medications are common, yet NPS persist. It also suggests the importance of assuring that PwD are on a stabilized dose prior to entering a trial so that treatment effects are not confounded by medication use. Cognitive Status: We found no difference in treatment effect by cognitive status: both high (>10) and low (< 10) MMSE groups benefited similarly with regard to the reduction of behavioral frequency. However, the high MMSE group also showed a reduction in the number of behaviors occurring at 4 months (p=.028). Cost: We also calculated preliminary incremental cost-effectiveness ratios (ICER), expressed as cost to bring about one additional unit of benefit measured by CG hours per day "doing things" and hours per day "being on duty" and decision tree and Monte Carlo analyses tested robustness of economic models. Average intervention cost was $941.63 per dyad. ICER showed that CGs in treatment saved one extra hour per day "doing things" at a cost of $2.37 per day; and one extra hour per day "being on duty" at a cost of $1.10 per day. Monte Carlo showed that the intervention was cost-effective 79.2% of the time for "doing things" and 79.6% of the time for "being on duty." Varying cost assumptions did not change cost-effectiveness. In summary, this pilot phase demonstrated proof of concept; high acceptability by PwD and CGs, preliminary positive outcomes, preliminary cost effectiveness, and that benefits were for PwD agitation and no adverse events. It also provides guidance for trial design considerations including importance of assuring dyads on medications have a stabilized dose prior to study enrollment and evaluating relationship of cognitive status to outcomes. Our proposed trial advances this pilot phase by: a) testing efficacy with a larger, diverse sample that will be well characterized as to diagnosis, disease severity, and behaviors using standard clinical assessments, b) comparing CAP to a control intervention condition receiving equivalent attention and social contact, controlling for unknown effects of empathy, validation and attention provided in CAP; c) examining cost effectiveness prospectively from a societal perspective, and d) evaluating a broad range of other outcomes and moderators (dose, intensity, activity use) to support future translational efforts.

Inclusion Criteria: Inclusion criteria pertain to both the person with dementia (PwD) and the caregiver (CG) such that if either is eligible but the other is not, the dyad is not enrolled.

• PwD and caregiver are English speaking
• Diagnosed with probable dementia
• PwD is able to participate in at least 2 activities of daily living (bathing, dressing, grooming, toileting, transferring from bed to chair)
• Person with dementia exhibits agitated or aggressive behaviors
• If PwD is on a psychotropic medication he/she must be on a stable dose for at least 60 days
• CG is at least 21 years old
• CG lives with or within 5 miles of the person with dementia
• CG is accessible by telephone to schedule interviews and sessions
• CG is planning to live in the area for at least 6 months
• If the CG is on a psychotropic medication he/she must be on a stable dose for at least 60 days

Exclusion Criteria:Exclusion criteria pertain to both the person with dementia and the caregiver such that if either is eligible but the other is not, the dyad is not enrolled.

• PwD has a history of schizophrenia or bipolar disorder
• Dementia is secondary to probable head trauma
• PwD is not responsive to environment (e.g., unable to understand short commands or recognize a person coming in/out of the room).
• the CG is currently involved in another clinical trial of psychosocial or educational interventions
• the CG is planning to place PwD in a nursing home within 6 months.
• dyads will be excluded if either CG or PwD: 1) has a terminal illness with life expectancy < 6 months, 2) is in active treatment for cancer, or 3) has had > 3 acute medical hospitalizations in past year.