A Dyadic Approach for a Remote Physical Activity Intervention in Adults With AD and Their Caregivers
Phase: NA
Conditions: Alzheimer Disease
Sponsor: University of Kansas

 
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Study Protocol and Statistical Analysis Plan   
A Dyadic Approach for a Remote Physical Activity Intervention in Adults with AD and their Caregivers 
 
NCT04102514 
 
May 9th, 2022 
 
 
 
 

 
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Principal Investigator: Lauren T. Ptomey 
Study Title: A Dyadic Approach for a Remote Physical Activity Intervention in Adults with AD and their 
Caregivers 
Co- Investigator(s): Joseph E Donnelly, Richard Washburn, Amanda Szabo, Eric Vidoni, Anna Gorczyca.  
 
 
I. 
Purpose, Background and Rationale 
A. Aim and Hypotheses  
Approximately 5.3 million adults age 65+ in the U.S. have Alzheimer’s dementia (AD), a number that 
is projected to increase to 13.8 million by 2050. Most adults with AD live in the community and 
receive support from a caregiver. Participation in moderate intensity physical activity (MPA) 
improves activities of daily living and mobility, and may improve general cognition and balance in 
adults with AD, as well as reducing the risk of AD, improving depression, sleep, sense of burden and 
level of fatigue in caregivers. However, MPA in community dwelling adults with AD and their 
caregiver is lower than in healthy older adults and non-caregivers, respectively. Usual care 
strategies for increasing MPA have shown minimal effectiveness in this population. For example, our 
group completed an 8-wk. trial in 21 adults with AD designed to increase their daily steps.  
Participants were given a pedometer to wear daily and asked to double number of steps taken. 
Baseline step counts were low (27,059 steps/wk.) and only increased by 5% (1,284 steps/wk.) 
across the 8-wk trial. Trials evaluating innovative, scalable strategies for increasing and maintaining 
MPA in community dwelling dyads of adults with AD and their caregivers are currently unavailable.  
Our group recently completed a single arm pilot trial in 9 adults with AD/caregiver dyads which 
demonstrated the feasibility of delivering group-based MPA via video conferencing (Zoom® software) 
on a tablet computer (iPad®) to participants in their homes. A health coach delivered three, 30 min 
interactive exercise sessions/wk. to 4-6 dyads over 12 wks. Each session included a warm-up (5 
min), aerobic and resistance exercise (20 min), and cool down (5 min).  Session attendance was 
~77% for adults with AD and ~79% for their caregiver. Total PA assessed by (Fitbit) increased by 60 
min/wk. with an increase in MPA of 24 min/wk. (49%) in adults with AD and 35 mins/wk. with an 
increase in MPA of 23 min/wk. (13%) in caregivers across 12 wks. This approach may be effective 
for increasing MPA in adults with AD and their caregiver as it allows participants to engage in group-
based activity in their home, thus eliminating the need to travel to an exercise facility, provides an 
opportunity for interaction and social support from both the health coach and their peers, and 
decreases caregiver burden associated with caregiver directed exercise, e.g., finding time, providing 
adequate support, motivation. Although the group video approach appears promising, the 
effectiveness of this approach to increase and maintain MPA over a longer time frame in adults with 
AD and their caregiver is unknown. Thus, we propose to compare the effectiveness of two delivery 
strategies for increasing MPA, real-time group video conferencing (RGV) vs. usual care enhanced 
with caregiver support and participation (EUC), in 100 community dwelling adults with mild to 
moderate AD and their caregiver (dyads) over 18 mos. (6 mos. active, 6 mos. maintenance, 6 mos. 
no contact). All participants will be provided with an iPad® for intervention delivery, Fitbit for self-
monitoring MPA, and will be asked to complete 150 min of MPA/wk. Dyads in the RGV arm will be 
asked to complete three 45 min sessions that will include aerobic, resistance, and 
balance/coordination exercises delivered by a trained health coach via Zoom® software on an iPad® 
during mos. 0-6, and 1 session/wk. during mos. 7-12 to groups of 5-8 dyads in their home. Dyads in 
the EUC arm, will be provided with structured exercise plan to complete on their own. Dyads in both 
arms will be provided with written materials regarding exercise and physical activity from the 
National Institute on Aging and will be asked to complete brief (15-20 min) FaceTime® meetings (0-6 
mos.= 2/mo.; 7-12 mos.= 1/mo.) with the heath coach to discuss progress, provide support and 
receive additional guidance on how to increase MPA. Our primary outcome, MPA, will be assessed 
by accelerometer across the 6-mo. active intervention and total 18 mo. trial. 

 
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Primary aim. To compare total MPA (min/wk.) across the 6-mo. active intervention in adults with AD 
and their caregiver randomized to RGV and EUC. We expect greater MPA in the RGV compared to 
EUC arm.  
Secondary aims: To compare the following across 18 mos. between RGV and EUC. Adults with 
AD:  MPA (min/wk.), sedentary time (min/wk.), percentage meeting 150 min/wk. goal, functional 
fitness, activities of daily living (basic/instrumental), quality of life, residential transitions, 
neuropsychiatric symptoms, cognitive function. Caregivers: Total MPA (min/wk.), sedentary time 
(min/wk.), functional fitness, quality of life, caregiver burden. We expect more favorable changes for 
all secondary outcomes for both adults with AD and caregivers in the RGV compared with the EUC 
arm. 
Exploratory aim. To evaluate the influence of process variables/ characteristics on MPA in adults 
with AD and their caregiver across 18 mos.: age, sex, BMI, attendance (exercise/support sessions), 
use of recorded sessions, PA self-monitoring, peer interactions during group sessions, caregiver 
support, level of dementia.   
 
B. Background and Significance 
Alzheimer’s Dementia. Approximately 5.3 million adults in the U.S. age 65+ (3.3 million women, 2 
million men) have Alzheimer’s dementia (AD). AD is a progressive, irreversible brain disease that is 
characterized by amyloid plaques and neurofibrillary tangles in the brain which are associated with 
the deterioration of brain function resulting in cognitive decline, behavioral and psychiatric symptoms 
and reductions in functional status including the ability to complete activities of daily living (ADL) and 
self-care (1). A series of recently published systematic reviews concluded there is insufficient 
evidence for interventions employing physical activity (2), pharmacologic treatments (3), over the 
counter supplements (4) or cognitive training (5) for the prevention of cognitive decline or dementia 
in healthy older adults. Aging is the prominent risk factor for the development of AD. Thus, the 
prevalence of AD is expected to increase to 13.8 million by 2050 as the number of adults age 65 and 
over increases (6). Individuals who survive with AD will eventually become completely dependent on 
others for assistance with basic ADLs, including eating (1).  The long duration of illness spent in a 
state of disability and dependence prior to death contributes to the public health impact of AD.  
Between 1990 and 2010 the burden of AD, measured by disability-adjusted life years, has increased 
from 25th to 10th, more than any other disease or condition (7). Adults with AD and their family 
members, who provide the majority of unpaid care for adults with AD living in the community, suffer 
significant emotional, financial and physical stress (8). In addition, caring for adults with AD burdens 
both the health and long-term care systems as the rates of hospitalization in this group are 2 to 3 
times that of same age adults without AD, and ~70% of residents of assisted living facilities have 
some form of cognitive impairment (9, 10). Thus, interventions targeting both the prevention of 
residential transitions to long-term care systems in adults with AD and improvements in the quality of 
life and level of burden of caregivers are warranted.  
 
Role of physical activity in AD. Drugs approved for the treatment of AD may temporarily improve 
disease symptoms; however, none of these drugs modify the underlying neuropathology of the 
disease or its progression, and are associated with side effects that may limit long-term use (11, 12).  
Physical activity may provide an accessible, practical and economical non-pharmacologic approach 
for the management of AD. Participation in moderate intensity physical activity (MPA) may allow 
patients with AD to maintain cognitive and physical function and quality of life to the extent possible 
as the disease progresses, without the side effects associated with currently available medications.  
Physical activity in adults with dementia, assessed by both accelerometer (13-16) and questionnaire 
(17, 18) is lower than healthy older adults. For example Van Alpen et al (14) reported  that physical 
activity assessed by accelerometer over 6 consecutive days was ~22% lower and sedentary time 
was ~9% greater in community dwelling adults with dementia (n = 37, age = 77 yrs.) compared with 
community dwelling healthy older adults (n = 26, age=79 yrs.). A recent Lancet Commission report 

 
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on prevention, intervention and care for dementia concluded that exercise programs for adults with 
mild-to-moderate dementia are feasible and well tolerated, and offer small positive effects on 
physical function; however, the impact on cognition is unclear (12). Martin-Ginis et al (19) recently 
developed an evidence based public health messaging statement for the use of physical activity for 
the prevention of AD and the management of symptoms and complications of AD based on a 
systematic review of 20 systematic reviews (121 unique studies) on this topic. Management 
outcomes considered included cognition, depression/mood, challenging behaviors (aggression, 
restlessness, wandering, rummaging), physical performance/function (cardiovascular fitness, gait 
speed, lower extremity strength, mobility) balance and fall prevention, ADLs, and quality of life. The 
messaging statement resulting from this review reads “Regular participation in physical activity is 
associated with a reduced risk of developing Alzheimer’s disease. Among older adults with 
Alzheimer’s disease and other dementias, regular physical activity can improve performance of 
activities of daily living and mobility, and may improve general cognition and balance” (19).  
Insufficient or inadequate evidence was available to address the other management outcomes.  
Physical activity in adults with dementia has been associated with low risk of adverse events (20) 
with no evidence of increased physical activity being associated with disease progression (19). 
Thus, increased physical activity may play an important role in the management of AD; however, 
effective, cost-efficient, scalable strategies for increasing physical activity in community dwelling 
adults with AD are not currently available.   
 
Caregivers. Over 15 million people in the U.S. provide unpaid care for adults with AD or other 
dementias (1). Approximately 80% of adults with AD in the U.S. live in the community (21); 66% of 
caregivers live with the care recipient (22).  More than 90% of those with AD living in the community 
rely on family or unpaid caregivers for their care (22). Caregiving typically includes assistance with 
ADLs, including bathing and dressing, and with instrumental activities of daily living including (IADL) 
such as bill paying, transportation and shopping. Approximately 50% of caregivers for individuals 
with dementia are in a high-burden situation based on the Burden of Care Index which is a 
composite of the number of hours of care provided, and the number of ADLs and IADLs performed 
(21). Care for dementia patients tends to be of longer duration than care for other conditions. More 
than half (57%) of family caregivers for adults with AD or other dementias living in the community 
provide care for 4 or more yrs. (1). High burden of care over an extended time frame places 
significant mental and physical strain on caregivers, and may have a negative impact on caregiver 
health (21, 23). Thirty-five percent of dementia caregivers report declines in their health status as a 
result of caregiving responsibilities compared with 20% of caregivers of non-dementia adults (21). 
Caregivers of adults with AD have reduced health related quality of life (24, 25), are often socially 
isolated (8, 26) and are at  increased risk for depression and anxiety (8, 27), musculoskeletal 
discomfort (28), and stroke (29), and show elevated biomarkers for cardiovascular disease (30, 31). 
Caregiving has also been associated with reduced physical activity (32-36). Caregiver health 
problems are frequently superseded by those of the care recipient although poor caregiver health 
may negatively impact the quality of care provided and hasten nursing home placement for the adult 
with AD. Data from a limited number of home-based physical activity interventions directed to family 
members providing care for adults with dementia have shown reduced stress, caregiver burden, 
depression, and improved sleep quality and positive affect (37-43). 
 
Promotion of MPA. As previously described, increased MPA in both adults with AD and their 
caregiver is associated with important health and functional benefits. Usual care strategies to 
promote MPA typically include providing recommendations for MPA, handouts on how to achieve 
this recommendations, and provision of a pedometer for self-monitoring. However, usual care 
strategies have shown minimal improvements in MPA. For example, members of our research team 
completed an 8-wk. trial  designed to evaluate a usual care approach to increase the number of 
steps/wk., assessed by a Fitbit, in a sample of 21 adults with cognitive impairment (age=72 yrs., 
43% female)(44). Participants were provided written recommendations to increase their steps by 

 
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20% each wk. over the first 5 wks. and to maintain this level for the remainder of the 8- week 
trial. Health coaches made individual phone calls to each participant (2 calls/mo.) to encourage 
exercise, problem-solve barriers to exercise, and provide technical support. Health coaches also 
monitored participants daily step data obtained from the Fitbit and made additional phone calls to 
remind participants to wear or upload Fitbit data if no activity was recorded for 3 consecutive days. 
Baseline steps were low, 27,058 ± 21,661 steps/wk., and increased by 1,284 ±12,976 steps/wk. 
(4.7%) across the 8-wk intervention (44). Caregiver support, which was not included in this trial, may 
have improved the effectiveness of this minimal intervention. 
 
Intervention delivery. Usual care strategies have not been shown to provide significant 
improvement in MPA in adults with AD across time and there are no trials designed specifically to 
evaluate alternative strategies to increase long-term (≥12 mos.) daily MPA in this group. Most trials 
in community dwelling adults with AD and/or caregivers have been designed primarily to assess the 
impact of exercise on cognitive and physical function, neuropsychiatric symptoms, quality of life etc., 
and did not include assessments of changes in daily MPA.  Participants in these trials were 
generally required to travel to a medical clinic or community site for supervised exercise (45-50); 
however, home visits by exercise specialists, (43, 46, 51-53), and  trained  caregivers have also 
been used to deliver exercise interventions (54, 55). The significant barriers associated with these 
approaches, including the time and cost associated with travel to clinic or community site, expense 
associated with individual home visits and additional burden associated with caregiver directed 
exercise greatly reduce the potential of these approaches to result in sustained improvements in 
MPA. Limited information is available regarding alternative strategies to increase MPA in community 
dwelling adults/caregivers that eliminate or reduced barriers including telephone (37, 39) ,and 
telehealth  (56). For example, Farran et al (39) completed a 12 mo. telephone delivered behavioral 
intervention designed to increase MPA (goal ≥ 150 min/wk., assessed by self-report) in  family 
caregivers (n=211, age= 61 yrs.) for adults with dementia living in the community. Brief intervention 
calls (15-20 min) using social cognitive approaches were conducted with participants weekly over 
the first 2 mos., bi-weekly during mos. 3-4, and monthly during mos. 5-12. Control participants 
completed a 12-mo. skill building intervention, delivered by phone on the same schedule as the MPA 
intervention. The skill building intervention was designed to provide information and support for 
caregivers but did not include any information or discussion regarding physical activity.  At 12 mos., 
MPA (min/wk.) doubled in the intervention group and decreased by 5% in controls. From mos. 3-12, 
63% of the intervention compared with 37% of controls achieved the 150 min/wk. goal (p<0.0001). 
The assessment of MPA by self-report and high and differential drop-out between groups 
(intervention = 37%, control = 16%, p=0.001) limit the validity of these findings. A small (n=2 
patient/caregiver dyads), short-term (4 wk.) pilot trial demonstrated the feasibility of telehealth (video 
link) delivery of an exercise intervention; however, this approach does not remove the transportation 
burden as participants need to travel to a telehealth site which are limited and often located some 
distance from participants (56).  
 
Potential for video conferencing. An intervention delivered via video conferencing to adults with 
AD and their caregivers in their homes, represents a potentially effective approach for increasing 
MPA in this group. This approach requires no travel, since the need for transportation to a medical 
clinic or other community facility is eliminated, and offers the potential for peer support and 
socialization, which may be important for initiation and maintenance of MPA. To assess the 
feasibility of the video conferencing approach, we recently completed a 12-wk. single arm pilot trial 
in 9 adults with AD (age = 74 ± 16 yrs., 56% female) and their family caregiver (dyads) (age = 67 ± 
13 yrs., 67% female) funded by the University of Kansas Alzheimer’s Disease Center (KU-ADC). 
Three, 30-min.  group exercise sessions/wk. were delivered by trained health coaches via video 
conferencing (Zoom® software) on a tablet computer (iPad®) to 4-6 dyads in their homes. Each 
session included a warm-up (5 min), aerobic (10-15 mins) and resistance exercise (5-10 mins), and 
cool down (5 min). Participants wore a Fitbit activity tracker over the 12 wk. intervention to assess 

 
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the duration and intensity of the physical activity sessions and total weekly MPA (min./wk.). 
Participants received brief monthly phone calls (<5 min) from the health coach to provide strategies 
for encouraging and supporting MPA, and as a reminder of the upcoming video session.  Session 
attendance was ~77% for adults with AD and ~79% for caregivers.  MPA per group session 
averaged 20.4 ± 8.5 (at ~ 57% of estimated HRmax) and 27.0 ± 8.2 min/session (at ~61% of 
estimated HRmax) in adults with AD, and their caregiver, respectively. Attendance at the monthly 
individual support session was 87% for both the adults with AD and the caregivers. At baseline, total 
weekly MPA was 53.9 ± 34.5 min/wk.in adults with AD and 166.4 ± 54.7 min/wk. in caregivers, and 
increased by 24 min/wk (45%) and 49 min./wk. (30%), in adults with AD and caregivers, 
respectively.  Compliance with the Fitbit protocol was acceptable as adults with AD and caregivers 
wore the Fitbit on 82.5 ± 27.7% and 79.9 ± 25.7% of the total study days, respectively.  Exit surveys 
indicated that participants generally enjoyed the program, preferred a home-based program vs. 
traveling to an exercise facility, preferred group over individual exercise sessions, and were 
interested in participating in longer sessions.   
 
C. Rationale 
Adults with AD and their caregivers represent a sizeable and underserved segment of the population 
with low levels of MPA and diminished physical, functional, and psychological outcomes. Available 
evidence suggests that regular MPA can improve performance of ADLs, IADLs, and mobility, and 
may improve general cognition and balance in adults with AD, as well as reduce the risk of 
development of AD and improve health and well-being in caregivers. However, the options for 
increased MPA in community dwelling adults and their caregivers are limited, e.g., medical clinics, 
community sites, home visits, caregiver delivered, and are associated with significant barriers 
including the time and cost associated with travel to clinic or community site, expense associated 
with individual home visits and additional burden for caregiver directed exercise that greatly reduces 
the potential of these approaches to result in sustained improvements in MPA. Trials specifically 
designed to evaluate strategies to increase long-term daily MPA in adults with AD and their 
caregivers are currently unavailable. Results from our single arm, short-term (12-wk.) pilot trial 
suggest the feasibility and potential effectiveness of video conferencing to deliver an intervention to 
increase MPA in this group. Video conferencing allows participants to engage in group-based 
activity, led by a health coach, in their home, and provides an opportunity for interaction and social 
support from both the health coach and their peers. However, the effectiveness of the group video 
approach to increase and maintain MPA over a longer time frame (12-18 mos.) in adults with AD 
and their caregiver is unknown. Thus, we propose to compare 2 strategies for the delivery of an 
intervention to increase MPA in adults with AD and their caregiver; real-time group video 
conferencing (RGV) vs. enhanced usual care (EUC). If effective, RGV may provide a scalable and 
sustainable format, which could be used by community agencies, or others to efficiently deliver MPA 
to adults with AD and caregivers in their homes. 
 
A. Study Objectives 
We will compare 2 strategies for the delivery of an intervention to increase MPA in community 
dwelling adults with AD and their caregiver (dyads); real-time group video conferencing (RGV) vs. 
enhanced usual care (EUC- caregiver participation plus support).  
 
B. Study Type and Design:  
We will study older adults (age ≥ 55 yrs.) with mild to moderate AD (n=100) and their caregiver 
(n=100) randomized (1:1) to one of two intervention delivery strategies for increasing MPA; real-
time group video conferencing (RGV) vs. enhanced usual care (EUC). All participants will be 
provided with an iPad® for intervention delivery, Fitbit for self-monitoring MPA, and will be asked to 
complete 150 min of MPA/wk. Dyads in the RGV arm will be asked to complete three 45 min 
sessions that include aerobic, resistance, and balance/coordination exercises delivered by a trained 

 
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health coach via Zoom® software on an iPad® during mos. 0-6, and 1 session/wk. during mos. 7-12 
to groups of 5-8 dyads in their home. Dyads in the EUC arm, will be given an exercise plan to do 
own their own. Dyads in both arms will be provided with written materials regarding exercise and 
physical activity from the National Institute on Aging and will be asked to complete brief (15-20 min) 
FaceTimeTM meetings (0-6 mos.= 2/mo.; 7-12 mos.= 1/mo.) with the heath coach to discuss 
progress, provide support and receive additional guidance on how to increase MPA. Our primary 
outcome, MPA, will be assessed by accelerometer across the 6 mo. active intervention and total 18 
mo. study (secondary outcome). 
 
C. Sample size, statistical methods, and power calculation 
We will recruit 100 adults with AD and their caregiver (100 dyads) at baseline to achieve adequate 
power to test both short-term (0-6 mos.) and long-term (0-18 mos.) effects of the intervention. Our 
power calculation, based on 21 measurements of MPA, 35 measurements of secondary and 
exploratory outcomes, a previously observed correlation of 0.22 between repeated measures, and a 
high attrition rate of ~20%, indicated that this sample size (≥42/arm after attrition) would produce 
≥80% power to detect an anticipated difference of 10-min/d in MPA (SD=30 min/d; f=0.17) between 
adults with AD randomized to RGV and EUC during the active intervention (0-6 mos.). This sample 
size would also yield ≥81% power to test a between-arm difference as small as f=0.15, e.g., 6 ± 30 
min/d in MPA, during maintenance (7-12 mos.) and no contact (13-18 mos.). 
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable):  
Primary care physician (PCP) clearance will be required of participants with AD and their caregiver. 
To enhance generalizability, individuals taking AD or other medications, or receiving treatment for 
other chronic diseases, or with risk factors such as hypertension, tobacco use, lipid abnormalities, 
T2DM, etc., will be allowed to participate with PCP clearance. Inclusion criteria (Adults with AD): 
Inclusion: 1) Very mild to moderate dementia (MMSE or STMS > 11; Telephone Interview for 
Cognitive Status (TICS) ≥ 6). 2) Age ≥ 55 yrs. 3) Low-risk of falls, assessed by PCP consent 4) 
Ability to participate in MPA, e.g., walk including with an assistive device, as verified PCP clearance. 
5) Ability to communicate verbally. 6) Vision and hearing sufficient to safely comply with the 
intervention program as verified by PCP clearance. 7) Reside at home and receive support from a 
caregiver. 8) Internet access in the home. Exclusion criteria (Adults with AD):1) Current exercise, 
i.e., > 3, 30-min bouts of planned exercise/wk. 2) Clinically significant psychiatric disorder; systemic 
illness or infection likely to affect safety; clinically-evident stroke; myocardial infarction or coronary 
artery disease in the last 2 yrs.; cancer in the last 5 yrs.; or significant pain or musculoskeletal 
symptoms that would prohibit exercise. 4) Unwilling to be randomized. Inclusion criteria (caregivers): 
1) Age ≥18 yrs. 2) Spends at least 20 hrs./wk. with the adult with AD. Exclusion criteria (Caregiver): 
1) Unable to participate in MPA, i.e., brisk walking. 2) Unwilling to be randomized. 3) Serious 
medical risk, such as cancer within the last 5 yrs. or cardiac event, i.e., heart attack, stroke, 
angioplasty within the last 2 yrs.  
 
E.  Specific methods and techniques used throughout the study  
 
Randomization. Cohorts of ~20 dyads will be stratified by sex and computer randomized by the 
study statistician with equal allocation to the RGV or EUC arms. Intervention assignments will be 
concealed in envelopes and delivered to the study coordinator. Assignments will be revealed to 
adult/caregiver dyads at the orientation session described below.  
 
Consumer advisory panel. Prior to initiating the intervention, we will convene a group of 4-5 adults 
with AD and their caregivers, who will not participate in this trial, and representatives from 4-5 
community agencies providing services to adults with AD. This group will review the intervention 
protocols, materials, etc., and offer suggestions for modification, and will reconvene annually to 
offer input on issues that may arise during the intervention, discuss results, and provide insight 

 
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regarding logical next steps. If our intervention is successful, community agencies will be provided 
with information and guidance on implementing the intervention within their agency and individuals 
they serve, if desired. 
 
Intervention components common to both arms 
Orientation. One week prior to initiating the intervention, health coaches will conduct a home visit (~ 
60 min) with each adult with AD/caregiver dyad in both intervention arms. Health coaches will 
deliver all necessary equipment and orient participants to the use of all equipment/software, answer 
questions regarding the general requirements of the trial, and demonstrate/practice the basic 
aerobic and resistance exercises with participants. Each dyad will be provided with the following: 
iPad®, iPod® touch, 2- Fitbit Versa Lites ® and resistance bands (TheraBand, Akron, OH). The iPad® 
will be used to deliver either the real time exercise sessions (RGV only), individual support 
sessions, and for syncing the Fitbit of adults with AD. The iPod® will be used to sync the Fitbit of 
caregivers, as the iPad® is capable of syncing only one Fitbit. The iPod® will also allow for 
communication between the caregiver and the health coach via iMessage. Dyads in the RGV arm 
will be provided with an iPad®/HDMI adaptor, which allows video conference sessions to be 
displayed on a larger TV screen, if desired. All software/apps appropriate for each intervention arm 
will be loaded on the iPad®/ iPod®, i.e., Zoom®, Dropbox® (to provide access to recorded videos and 
written materials) and Fitbit app. Reminders regarding upcoming group video and/or health 
educator/dyad support sessions will be programed using the iCalendar app on the iPad®. Access to 
non-study related materials, e.g., web browsing, app store etc. will be blocked on all iPads®/ iPods® 
until completion of the maintenance intervention (12 mos.). Individual support sessions. Dyads will 
be asked to attend 15-20-min education/support sessions (2 sessions/mo. during the active 
intervention (0-6 mos.) and 1 session/mo. during maintenance (7-12 mos.) delivered remotely on 
the iPad® using FaceTime®. No individual support sessions will be scheduled during the no-contact 
period (13-18 mos.). Sessions will be designed to educate and support the adult with AD and 
caregivers with meeting their 150 min/wk. goal for MPA. Each session will include a review of 
physical activity self-monitoring data, goal setting, strategies to increase and support MPA, and 
discussion of a topic relevant to MPA. During the active intervention (0-6 mos.) topics will include 
the importance of MPA for health and function, how to include MPA in the daily schedule, reduce 
barriers to physical activity, appropriate types of activity, creating a safe environment for physical 
activity, alternative activities for inclement weather, importance of hydration, etc. During 
maintenance (7-12 mos.) the discussion will focus on strategies to ensure continued participation in 
MPA, opportunities for physical activity in the community, and continued encouragement of dyadic 
activity. Topic outlines and information relative to support sessions will be pre-loaded on the iPad® 
where they can be assessed at any time across the 18-mo. trial.  Self-monitoring-physical activity. 
Adults with AD and caregivers in both arms will be asked to wear a Fitbit Versa Lite activity tracker 
on their non-dominant wrist over the duration of the 18-mo. trial. This request may appear onerous; 
however, wearing the Fitbit is akin to wearing a wristwatch. Real-time data from the Fitbit is 
automatically transferred, via the web, to cloud storage (Fitabase, Small Steps Labs LLC, San 
Diego, CA), thus, participant burden is minimal. Fitbit data is available to both participants and the 
health coach via the Fitbit app. Immediate participant feedback of daily steps, minutes of sedentary 
time, and time spent in light, moderate and vigorous physical activity will be available via a graphic 
display on the device and the Fitbit app. The health coach will log into each participant account 
once per week to verify they are wearing and charging the device and to monitor participant activity 
solely for use in providing motivation and feedback during the individual support sessions. Outcome 
data for MPA and sedentary time will be assessed by accelerometer as described subsequently. 
Dyads will be reminded to wear and charge the Fitbit during group exercise (RGV only) and 
individual support sessions, and will receive automatic reminder messages every 3 days via the 
iPad® using the iCal app. We successfully used the Fitbit and these reminder procedures in our 
pilot trails in adults with AD (44) and similar procedures have been used by others (60).  
 
RGV arm  

 
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Schedule. Group exercise sessions will be scheduled on 3 non-consecutive days/wk.(M,W,F) 
during the active intervention (0 to 6 mos.) and 1 day/wk. during maintenance (mos. 7-12). Group 
sessions will not be scheduled during the no-contact period (13-18 mos.). During orientation 
sessions, dyads will be asked to provide times of the day, between 10 a.m. and 7 p.m., that would 
be most convenient to complete the group sessions. Based on this information we will offer dyads 
in each cohort the choice between 2 potential session times each day. Prompts reminding adults 
with AD/caregivers of upcoming sessions will be sent using iMessage on the iPad® (adult with 
AD)/iPod® (caregiver) and iCalendar. Session delivery. Real-time exercise sessions will be 
delivered to adults with AD/caregiver dyads in their home by a trained health coach experienced in 
working with adults with AD using Zoom® video conferencing software. This software allows 
multiple users to see and interact with each other and the health coach via the iPad®. The health 
coach will conduct exercise sessions from our remote-delivery exercise studio (see facilities) which 
we used for remote delivery of exercise in our AD pilot (61) and in trials with adolescents with 
intellectual and developmental disabilities (IDD) (62), and adults with Down Syndrome (63). 
Tutorials describing trouble shooting for common technical problems with the Zoom® software, e.g., 
internet connectivity etc., will be loaded on the iPad®. Dyads with technical issues during the 
intervention may also contact research staff by phone or email.  An alternative caregiver (other 
family member, staff etc.) may participate in the event that the caregiver enrolled in the trial is 
unable to attend an exercise session. These procedures were used in our AD pilot trial where 
alternative caregivers attended 8% of sessions (61). MPA session content. Dr. Vidoni, a physical 
therapist, will develop the exercise program for this trial. He developed the exercise content for our 
pilot trial in adults with AD and has been involved in other exercise trials for adults with AD 
(R01AG034614, R01AG033673) (64-66). Each session will include a warm-up (~5 min), moderate 
intensity aerobic activity (3-5 METs) (~30 min), resistance and balance/coordination exercise (~5 
min.), and cool-down/stretching (~5 min.). The MPA portion will ramp from 10 min/session at wk. 1 
to the goal of 30 min/session at wk. 8. Each session will include aerobic activity, e.g., 
walking/jogging standing in place or sitting in a chair, sit to stand, dance movements); resistance 
exercise, e.g., TheraBand®-arm curls, leg extensions, side leg raises, and seated rows; and 
balance exercise, e.g. heel to toe walks, balance walk, and standing on one foot with/without 
support of a chair). Dr. Vidoni will provide modifications for participants having difficulty with any 
specific exercises. Health coaches will encourage interactions between participants during group 
sessions and ensure interactions between participants do not focus on dementia (67), but rather on 
issues relative to supporting their peer’s efforts to increase MPA. Additionally, the Zoom app used 
for the sessions allows for messaging between participants during and after the group exercise 
sessions. Caregivers will be allowed to message the research staff and other caregivers for help 
and support both during the sessions and outside of the group sessions. We will keep copies of the 
messages sent to research staff on the KUMC P-Drive. Outside session MPA. Group exercise 
sessions will provide the potential to accumulate 90 min/wk. (3 sessions x 30 min/session) during 
the active intervention (0-6 mos.) and 30 min/wk. (1 session) during maintenance (7-12 mos.). 
Thus, MPA in addition to that accumulated in group sessions will be required to meet the MPA goal 
of 150 min/wk. To provide a transition from a sedentary to a more physically active lifestyle we will 
recommend goal of 45 min of MPA/wk. at wk. 1 and increase the goal by 15 min/wk.to reach the 
150 min/wk. goal at wk. 8. We successfully used this MPA progression in previous trials in adults 
with AD (57). At the completion of each group session health coaches will provide a “weekly 
challenge” for participants to try a new activity or create and perform a new exercise routine etc. in 
order to reach the 150 min./wk. goal. Additionally, the NIA pamphlet “Exercise and Physical Activity: 
Your Everyday Guide” will be loaded on the iPad to assist participants in meeting the 150 min./wk. 
goal. Video recordings. Video recordings of all group exercise sessions will be uploaded to 
Dropbox® . Participants/caregivers will be encouraged to access video recordings using their 
iPads®/iPods® to assist with meeting the 150 min./wk. goal.  Frequency and duration of 
participant/caregiver video access will be tracked using Dropbox® analytics. No contact follow up 
(13-18 mos.). Group video and individual support sessions will be discontinued. Participants will be 

 
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asked to continue to obtain 150 min/wk. of MPA and self-monitor their MPA via Fitbit. Access to the 
video recorded sessions will be maintained; however, new content will not be added.  
 
EUC arm  
Intervention. Individuals with AD and caregivers will be provided information regarding increasing 
MPA, available from the “Exercise and Physical Activity: Your Everyday Guide from the National 
Institute on Aging (NIA)”, provided with a Fitbit for self-monitoring, and encouraged to achieve 150 
min/wk. of MPA. The NIA guide reviews the importance of endurance, strength, balance and 
flexibility exercise, provides suggestions for incorporating physical activity into daily life, describes 
how to properly perform different types of exercises, and includes examples of daily exercise 
schedules. Protocols for individual support sessions and self-monitoring have been described 
previously (see Intervention components common to both arms). Caregivers will be allowed to 
message research staff through the Zoom app for additional support or questions as needed. No 
contact follow up (13-18 mos.). Individual support sessions will be discontinued. Participants will be 
asked to continue to obtain 150 min/wk. of MPA and self-monitor their MPA via Fitbit. To provide a 
transition from a sedentary to a more physically active lifestyle we will recommend goal of 45 min of 
MPA/wk. at wk. 1 and increase the goal by 15 min/wk.to reach the 150 min/wk. goal at wk. 8.  
 
Health coach training/blinding/fidelity. Training. We currently have 3 health coaches with 
experience in delivering group exercise using video conferencing to adults with AD. If needed, new 
health coaches will be trained by Drs. Vidoni and Ptomey, and will shadow an experienced health 
coach for a minimum of 3 mos. prior to delivering the intervention on their own. Dr. Vidoni will train 
health coaches on how to perform each exercise, the order of presentation of the exercises, and 
provide guidance on how to recognize and correct common mistakes in performing specific 
exercises. Dr. Ptomey will provide training regarding strategies for effective communication with 
adults with AD, i.e., speaking clearly and slowly, providing/repeating simple specific instructions 
(68), focusing on reassurance and empathy for each participant (69), and fostering interaction 
between participants with strategies to ensure the focus of the interactions is not on dementia (67). 
Blinding. The nature of this trial precludes blinding of the health coaches; however, investigators, 
data analysts and research assistants will be blinded to condition. Intervention fidelity. Recordings 
from all group exercise sessions (RGV only) and individual support sessions will be reviewed.  Dr. 
Gorczyca will compare recordings of both group exercise and support sessions with a check list of 
exercises/topics scheduled to be included in each session. Health educators covering <80% of 
scheduled content, or failing to deliver physical activity as prescribed, will receive additional training 
from Dr. Ptomey, and will be dismissed if the problem recurs. 
 
 
ASSESSMENTS  
MPA. Primary outcome (Baseline (0 mos.)- 6 mos.)/Secondary outcomes (0-18 mos.) 
Schedule. MPA in adults with AD and their caregiver will be assessed at baseline (1 wk. prior to 
starting the intervention), 3, 6, 12, and 18 mos. Equipment. MPA/sedentary time will be assessed 
using an ActiGraph model wGT3x-BT tri-axial accelerometer (3.3 x 4.6 x 3.5 cm, wt. = 19 g., 
dynamic range ± 8 g). The ActiGraph provides valid and reliable assessments of MPA/sedentary 
time in adults (70-73). Our group has used the ActiGraph in several trials in a variety of populations 
including adolescents (74) and adults with IDD (75), and in typically developing children (76, 77) 
and adults (78, 79). Protocol. There is a lack of consensus on the best protocols to collect, process, 
and score ActiGraph data (80-82). Thus, our decisions regarding ActiGraph location, monitoring 
period, data processing etc. were based on current practice, as described below. Participants will 
be asked to wear the ActiGraph on a belt over the non-dominant hip at the anterior axillary line 
during waking hours for 7 consecutive days, except for bathing and swimming. A 7-day monitoring 
period provides a reliable estimate of MPA (81, 83-85). The hip, rather than the wrist location, will 
be used due to the lack of comparable data and established protocols for assessment of MPA using 
wrist-worn ActiGraphs (86-88). ActiGraph distribution/reminders. Research staff will distribute and 

 
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demonstrate proper placement of the ActiGraphs at home visits scheduled at 0, 6, 12 and 18 mos. 
ActiGraphs will be distributed by mail for the 3-mo. assessment. Daily reminders to comply with the 
ActiGraph protocol will be sent to participant’s iPad® each morning during the 7-day monitoring 
period. We have employed similar distribution and reminder protocols in previous trials (74 , 75-77, 
79). Our current supply of ActiGraphs, plus the additional units requested in this proposal, will allow 
physical activity assessments to be completed on all participants in the proposed timeframe. Data 
collection. ActiGraphs will be initialized and downloaded using ActiLife Software version 6.13.3 or 
higher (ActiGraph Corp, Pensacola, FL) and set to collect in the raw data mode from all 3 axes at 
60 Hz. Although the wGT3x-BT collects raw data from 3 axes, the widely used cut-points for 
determining activity intensity in adults proposed for this trial use acceleration data from the 
ActiGraph vertical axis (89). However, raw data from all 3 axes will be downloaded and stored, and 
will be available should algorithms for processing this data become available during this trial. Data 
processing Accelerometer data will be processed using the protocol for adults used in the 2003-
2004 and 2005-2006 cycles of NHANES (89, 90). Data will be aggregated over 60-sec epochs. The 
following intensity cut-points will be used: sedentary (< 1.0 MET; ≤ 100 counts/min), light (1.1-2.99 
METs; 101-2019 counts/min.), moderate (3.0-5.99 METs; 2020-5988 counts/min) and vigorous ≥ 6 
METs; ≥ 5999 counts/min) (89, 90). Non-wear time will be defined as at least 60 consecutive 
minutes of zero counts, with allowance for 1-2 min of counts between 0 and 100. Counts ≥ 
20,000/min will be considered spurious (91). All accelerometer data processing will be completed 
using custom SAS/-R programs developed by Drs. Little and Lee, the project statisticians, in 
collaboration with our research group. Missing accelerometer data. Recent advances in both 
statistical methods and computing power have made it possible to impute missing data with large 
data sets, such as will be collected in the proposed trial, i.e., 7 wk.-long assessments across 18 
mos. A detailed description of the methods and procedures for handling missing ActiGraph data 
(non-wear and device malfunction time) is included in the analysis plan. MPA data for both adults 
with AD and caregivers will be analyzed including and excluding video conference exercise 
sessions (RGV arm).  
 
Secondary outcomes. Secondary/exploratory outcomes will be assessed at baseline (1-2 wks. 
before starting the intervention), 6, 12 and 18 mos. in the adult with AD or caregiver’s home. Our 
experience with similar trials suggests these assessments, which will be completed by trained staff 
blinded to condition, will require ~75 min to complete. Staff will receive refresher training and 
complete reliability assessments for all physical measures 2-3 times/yr.  
 
Secondary outcomes-Adult with AD. Sedentary time will be assessed using data collected from 
the ActiGraph as described above. Functional fitness will be measured using Functional Fitness 
Test (FFT) previously called the Senior Fitness Test (92). The individual fitness test items involve 
common activities such as getting up from a chair, walking, lifting, bending, and stretching. 
Reliability of the FFT in older adults with cognitive impairment is high in all of the test items 
(ICC ≥ 0.93) (93). Activities of daily living will be assessed using the Disabilities Assessment for 
Dementia (DAD)(94). The DAD includes 40 items: 17 related to basic self-care and 23 to 
instrumental activities of daily living. DAD demonstrated a high degree of internal consistency 
(Cronbach's alpha = .96) and excellent inter-rater (n = 31, ICC = .95) and test-retest (n = 45, ICC = 
.96) reliability. In addition, it has been shown to have no gender bias. Quality of life will be assessed 
using the QOL-AD(95), a brief, 13-item self-report and 15-item caregiver-report. The QOL-AD has 
shown acceptable validity and reliability when completed by adults with AD or a caregiver proxy 
(ICC= .76 and .92 respectively) (95). Residential transitions, i.e., from home to institutional care, will 
be tracked by health coaches. We will also assess caregiver desire to institutionalize the adult with 
AD using the 6-item Morycz’s Desire-to-Institutionalize Scale (96). This scale demonstrated 
moderate reliability with KR-20 alpha of .694 for Whites, .742 for African Americans, and .767 for 
Hispanics (97). Neuropsychiatric symptoms will be assessed using the Neuropsychiatric Inventory 
(NPI) (98). The NPI evaluates 12 neuropsychiatric disturbances common in dementia and the 
amount of caregiver distress engendered by each of the neuropsychiatric disorders. Validity 

 
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(ICC=0.53-0.97) and reliability (inter-rater agreement=94-100%) of the NPI are acceptable (99). 
Cognitive function will be assessed using the Symbol Digit Modalities Test (SDMT) (100) which has 
previously been used in adults with AD (101, 102). Test-retest correlations for the SDMT, as well as 
the correlation between its written and oral administrations, are both 0.80 (103, 104). Quality of the 
dyadic relationship will be assessed using the dyadic relationship scale (DRS) which measures 
negative and positive dyadic interactions from the perspective of both the patient and the caregiver. 
The DRS has acceptable construct, discriminant, and concurrent validity, as well as reliability for 
both patients and family caregivers (105) 
 
Secondary outcomes-Caregiver. Sedentary time will be assessed using data collected from the 
ActiGraph as described above. Functional fitness will be measured using the FFT described above. 
Reliability of the FFT for community-dwelling older adults without cognitive impairment is 
acceptable (ICC = 0.80–0.98)(92). Quality of Life will be assessed using the SF-36(106) which has 
acceptable reliability and validity in the general population (107). Caregiver Burden will be assessed 
using the Zarit Burden Interview-short version, a 12-item self-report questionnaire in which the 
caregiver is asked to answer using a 5-point scale. The short version (108) has shown acceptable 
correlations (0.92 to 0.97) with the full 22-item version in caregivers of adults with AD.(109). Quality 
of the dyadic relationship will be assessed using the dyadic relationship scale (DRS) described 
above.  
 
Exploratory outcomes 
BMI. Weight will be measured in duplicate in light clothing on a calibrated scale (Model #PS6600, 
Belfour, Saukville, WI) to the nearest 0.1 kg. Standing height will be measured in duplicate with a 
portable stadiometer (Model #IP0955, Invicta Plastics Limited, Leicester, UK). BMI will be 
calculated as weight (kg)/height (m2). Session attendance for group exercise (RGV only) and 
support sessions will be obtained from records maintained by the health coach, and expressed as 
the percent of possible sessions from 0-6 mos. and 7-12 mos. Attendance for adults with AD, 
enrolled caregivers, and alternative caregivers will be recorded separately. Use of recorded videos 
(frequency and duration of access, RGV only) will be assessed using Dropbox® analytics. Self-
monitoring of physical activity will be assessed as the percentage of days with Fitbit data over a 
minimum of 8 hrs., between 6 am and midnight (0-6, 7-12, 13-18 mos.). Peer interactions (RGV 
only). Staff will review video recordings of a random sample of 33% of group exercise sessions to 
identify and classify both peer to peer, and health coach to participant interactions. Interactions will 
be quantified and coded as verbal/non-verbal (waving, pointing, shaking head in 
agreement/disagreement), and as positive, neutral or negative, relative to support, using a 
modification of a checklist we previously developed for a group video exercise intervention for 
adolescents with IDD (62).Caregiver support will be assessed using the percentage of group 
exercise sessions (RGV) and/ or individual support sessions completed by both the person with AD 
and their caregiver. Quality of the dyadic relationship will be assessed at baseline, 6, 12, and 18 
mos. using the dyadic relationship scale (DRS) which measures negative and positive dyadic 
interactions from the perspective of both the patient and the caregiver. The DRS has acceptable 
construct, discriminant, and concurrent validity, as well as reliability for both patients and 
caregivers(105). We will evaluate the impact of the DRS on our primary and secondary outcomes 
as well as examine changes across time in both groups. Type of dyadic relationship. We will 
document the type of caregiver, e.g., spouse, adults child, paid staff, and evaluate the impact of 
caregiver on our primary and secondary outcomes. Number of caregivers. We will document the 
number of different caregivers for adults with AD and evaluate the impact of the number of 
caregivers on our primary and secondary outcomes. Level of dementia will be assessed at baseline 
using the CDR(110) which has shown acceptable validity(111) and reliability(112). Energy 
Expenditure of Remote Sessions Energy expenditure of the remote sessions will be assessed in a 
volunteer sample of both patient and caregiver using a previously validated portable, open-circuit 
indirect calorimeter (Cosmed, Italy) which measures breath-by-breath ventilation, expired oxygen, 
and carbon dioxide. Study staff will schedule the assessment with participants which will involve an 

 
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additional visit to participants’ homes in which study staff will administer the assessment. The flow 
turbine will be calibrated using a 3.0-L syringe. The lightweight (~1.5 kg) portable system will be 
attached by a harness around the waist and shoulders of the participant before each assessment. 
The device will be programmed utilizing study ID numbers, with no other identifying information. 
During exercise sessions, participants will breathe into a facemask that directs air into the unit 
housing the O2 and CO2 analyzers. Data will be retrieved for analysis via a serial port interface and 
downloaded to a university monitored, HIPPA compliant computer once staff returns to campus. 
Software provided with the calorimeter will be used to analyze data by aggregating over 20-second 
epochs for the calculation of 1-min averages. MET levels will be age corrected using the Schofield 
equation (117) as recommended by McMurray et al (118). Participants will be asked to wear both 
hip and wrist ActiGraphs during the assessment for comparison of physical activity levels between 
devices.  
 
Exit interview. We will conduct structured interviews by phone with a 20% random sample of 
adults with AD and caregivers from both intervention arms to gather information that might be 
useful for improving the intervention and/or implementing the intervention in settings serving adults 
with AD. Topics will include preference for the RGV or EUC interventions, reasons for missing 
scheduled sessions for both the adult with AD and caregiver, enjoyment of the live video sessions, 
intervention length, difficulties with compliance, suggestions for improvements and overall 
satisfaction with the intervention, caregivers enjoyment of the exercise and educational sessions, 
performance of health coaches, physical activity recommendations etc. Qualitative content analysis 
(Atlas, ti 6.2) will be conducted to search for broad themes across interviews (113).  
) 
 
F. Risk/benefit assessment:  
 
Potential Risks. Risks to the individual with AD and caregiver in this study are minimal. There have 
been no serious adverse events with PA interventions in any of our completed trials, including trials 
with older adults and individuals with AD. Increased PA may be associated with minor injuries such 
as strains and sprains, and the potential for muscle soreness, particularly in the early stages of the 
PA protocol, may exist.  These risks will be minimized by gradually increasing the MVPA 
recommendation and providing instruction on proper exercise technique.  
 
Protection Against Risk. Risks for injury related to participation in PA will be minimized by 
discussions with health coaches and the individual with AD and caregiver regarding gradual 
progression of PA, warm up, cool down, etc. and modification of activities, if necessary, by Dr. 
Vidoni. There are some potential health risks for individuals who are using medications during 
exercise interventions; however, we have appropriate inclusion/exclusion criteria and physician 
consent will be necessary for participation. We also have over 30 years’ experience with physical 
activity studies that provide services to individuals with a wide variety of health risks without any 
serious adverse events or deaths. We will use a data safety and monitoring plan to assure 
participant safety during the intervention.  Participant’s data will be identified only by an assigned 
study ID number. Participant’s identifiable information will not be shared unless required by law or 
with written permission. All iPads will be set up by the IT team at KUMC and additional security 
software, Casper, will be installed. On top of encrypting all data on the iPad, Casper will prevent 
participants from downloading and using non-study related apps. Additionally, if the iPad is lost or 
stolen Casper will allow the IT team to wipe it clean remotely.  Individual accounts for all apps 
(Fitbit, Zoom, Dropbox) will be created by the study team and will contain no identifiable 
information. While the videos that will be distributed by cloud-storage (Dropbox) will have 
identifiable information (videos of participants) we will use a HIPPA compliant cloud storage 
program (Dropbox business) to ensure the safety of these video recordings. 
 

 
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Removal from the Study. If the study present greater then minimal risk to a participant they will be 
censored from the study and referred to the University of Kansas Alzheimer’s Disease Center for 
recommendations for other resources for PA. All participants and caregivers will be informed that 
they may be censored from the study due to safety risk during the consent procedure. We believe 
the following scenarios would present a greater than minimal risk to participants.  Lack of caregiver.  
A caregiver will be asked to participate in the intervention with the adult with AD. Many caregivers 
will be older adults and it is possible some may become deceased, become ill or hospitalized and 
unable to provide care to the AD individual. If this happens, the adult with AD will be asked to 
identify another individual to serve as the official study caregiver. if an alternative caregiver cannot 
be identified the individual with AD will be censored from the study from that time forward. 
Transition to a residential facility. Some adults with AD may be placed in a residential care facility 
during the 18-mo. intervention. If this occurs the adult with AD will be censored from the study. 
Change in severity of AD. If dementia progresses to the point that either the caregiver or research 
staff feel the intervention is no longer safe for the individual, they will be censored from the study.  If 
an individual with AD is removed from the study for one of the aforementioned reasons (transition to 
residential facility or change in severity of AD), decides to no longer participate in the intervention, 
or dies during the intervention, the caregiver will be allowed to continue in the intervention, if they 
choose. If a caregiver stays enrolled in the intervention without the person with AD we will no longer 
collect outcomes regarding Caregiver Burden or Quality of the dyadic relationship. 
 
Potential Benefits of the Proposed Research to the Subjects and Others. The benefits to the 
participants are the well-established benefits of PA including improvements in activities of daily 
living and mobility and may improve general cognition and balance in adults with AD. Additionally, 
caregivers may benefit from reduced caregiver burden and increased quality of life. Individuals with 
AD and caregivers may benefit from an increased understanding regarding how to develop PA 
routines, the benefits of regular PA, and ways to encourage PA in the household. The information 
obtained from this study will increase our understanding regarding strategies for the delivery of PA 
interventions to individuals with AD and caregivers. The risks to participants in this study are 
minimal while the benefits to individuals with AD and caregivers in need of increased MVPA are 
potentially large.   
 
Importance of the Knowledge to be Gained. Individuals with AD and caregivers have low rates of 
PA and may benefit greatly from participation in a PA program. The development of an effective 
strategy for increasing PA would be important for improving physical function, mobility, and quality 
of life in adults with AD and their caregivers, resulting in allowing individuals with AD to stay in their 
homes longer and reducing caregiver burden. Thus, we believe adults with AD and their caregivers 
deserve to be included in the development of state-of–the-art interventions to improve their mobility 
and quality of life and believe this proposal offers a potentially viable strategy for increasing MVPA 
in this population. 
 
G. Assessment of Subject Safety and Development of a Data and Safety Monitoring Plan 
 
Adverse Event and Serious Adverse Event Collection and Reporting. Staff involved in 
performance of the protocol are expected continually monitor participants for adverse events 
throughout all outcome’s assessment, exercise sessions, and individual education session. 
Expected side effects of exercise such as mild soreness that resolve in a reasonable short amount 
of time (less than 48 hours) will not be considered an AE.  
 
Adverse Event Grading. This study uses the definition of adverse events (AE) from the “NIA 
Adverse Event and Serious Adverse Event Guidelines, Version 3 December 2013”. AE are defined 
as any untoward or unfavorable medical occurrence in a human subject participant, including any 

 
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abnormal sign, symptom, or disease, temporally associated with the participants’ involvement in the 
research, whether or not considered related to participation in the research. 
The MPIs will determine the severity and relatedness of the AE to the intervention and be 
responsible for reporting to the National Institute on Aging (NIA), and Safety Officer (SO) in the 
appropriate time frames. Severity of the adverse event will be determined using the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0. The intervention 
and measurement protocols proposed for this study pose minimal risk to participants. Because of 
this low risk status, the data safety monitoring plan (DSMP) for this trial focuses on close monitoring 
by the multiple principal investigators (MPI) and the safety officer along with prompt reporting of 
excessive or serious adverse events to the NIH and to the Human Subjects Committee (HSC) at 
The University of Kansas Medical Center.  
  
 
Adverse Event Reporting The MPIs will review and evaluate adverse events within 72 hours.  All 
adverse events, regardless of their seriousness, severity or relatedness to the intervention are 
reportable to NIA PO and the Safety Officer (SO) semi-annually. A summary of these reports is 
provided to the IRB on an annual basis. Deaths and SAEs are handled in an expedited fashion as 
follows:  
• 
Deaths: All deaths will be reported within 24 hours to the NIA Program Officer, SO, and the 
IRB.   
• 
Unanticipated SAEs: When SAEs occur that are unanticipated and related to the 
intervention, they will be reported to the NIA Program Officer, ISO, and the IRB within 48 
hours of study team’s knowledge of the SAE. 
• 
Other SAEs: The summary of all other SAEs will be reported to the NIA Program Officer and 
SO quarterly. 
 All potential Adverse Events will be collected on an Adverse Event Form. If study staff, tester, 
participant, or other individual interacting with the participant during the testing visits, group 
exercise session, or individual education sessions reports adverse events or complaints, relevant 
information will be collected and documented using REDCap.  
 
Stopping Rules. We believe this trial conveys minimal risk. Both intervention groups in this trial will 
have the potential to increase their level of physical activity, a desirable behavior change that 
conveys health benefits when contrasted with sedentary behavior. We expect greater physical 
activity in the RGV compared with the EUC arm; however, the magnitude of this difference is 
irrelevant in regards to decisions to stop the trial. Physical activity in participants in both groups will 
likely be increased.  Even if this is not the case there will be no increase in health risk above 
baseline in either intervention group.  The most likely scenario indicating the need to stop the 
investigation would be a failure to recruit or deliver the intervention as planned.  
 
Data and Safety Monitoring  
The Principal Investigators (MPIs) and co-investigators will be responsible for ensuring study staff 
are appropriately trained in good clinical research practice and human subjects protections to 
minimize risk and maximize the value of the participants’ contributions. The PI and co-investigators 
will be responsible for ensuring the collection of all the information necessary for SO to evaluate the 
quality and safety of the study. The MPIs will be responsive to the questions, inquiries, and 
concerns of the SO, IRB, and NIA regarding these data and procedures. 
 
Frequency of Data and Safety Monitoring. The frequency of data review for this study differs 
according to the type of data, the availability of data collected, and the perceived level of risk. 
Safety reports are sent to the SO at least twice a year and will include a detailed analysis of study 
progress, data and safety issues. 
 
Data type 
Frequency of review 

 
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Subject accrual (adherence to protocol 
regarding demographics, inclusion/exclusion) 
Quarterly  
Adverse events (injuries/illness) 
As they occur 
Compliance to treatment 
Monthly 
Out of range laboratory data  
Semi-annually 
 
Data Analysis and Coordination. Data will be checked for outliers and normalcy at logical time 
points but at least at 4-month intervals. Questionable data (e.g., >3 SD from the mean) will be re-
checked and re-entered, if necessary.  
 
Measurement and Reporting of Subject Accrual, Adherence to Inclusion/Exclusion Criteria. 
The study statisticians Dr. Lee and Little will review of the rate of subject accrual and adherence to 
inclusion/exclusion criteria will occur quarterly to assure that participants meet eligibility criteria and 
ethnic diversity goals outlined in the grant proposal.  
 
Measurement and Reporting of Participant Compliance to the Treatment Protocol. 
Compliance to the intervention will be reported monthly by the study statisticians. To monitor 
compliance, they will report the group attendance at group exercise sessions (RGV) and/or 
individual health education sessions (EUC).  Compliance to the intervention protocol will be 
reviewed monthly by the MPIs. We are using an intent-to-treat design; thus, participants will not be 
dismissed for non-compliance, but will be counseled on strategies to improve compliance during 
scheduled FTF or RD sessions. 
 
Safety Officer. The safety officer for this trial will be Ryan Townley, MD. Dr. Townley is a 
Neurologist at the University of Kansas Alzheimer’s Disease Center and is not affiliated with the 
study in any other fashion and is not in the MPI’s chain of command.  zhe will review the reports 
sent by the study coordinator semi-annually and adverse events as they occur and will use the 
checklists attached to this document to determine whether there is any action, such as an ad hoc 
review or stopping rule violation that should be communicated to the study investigators, The 
University of Kansas Human Subjects Committee, or NIH. In addition, the safety officer may 
comment on whether the study investigator needs to report any specific out of range laboratory 
data to the participant, and/or their physician.  
 
II. 
Subject Participation 
 
A. Recruitment: The KU-ADC will contact individuals in their database who appear to be eligible 
based on patient records by phone and by a letter sent to their homes. Names and contact 
information of interested patients will be forwarded to the study, who will contact the 
patient/caregiver to describe the study, answer questions and to assess initial patient and 
caregiver eligibility. Additionally, we will recruit individuals in the community through flyers that 
will be distributed though  social media advertisement, the city bus system, and email. Flyers will 
have a link to our study website (www.ebl.ku.edu/m2g) which contains a  link to the eligibility 
questionnaire that can be filled out by individuals who are interested in the study. Participants 
who fill out the eligibility questionnaire and appear to qualify will be contacted by a member of 
the  study team who will describe the study, answer questions and complete the dementia 
screening questionnaire.  Informed consent will be obtained from each subject prior to entry into 
the study. Visits, video conference calls (Zoom® software), or phone calls will be scheduled with 
individuals deemed to be initially eligible to describe the project in detail, answer questions, verify 
eligibility, and to obtain subject consent. Prior to the consenting session, the participant will be 
sent the consent form and cover letter through Kansas University Medical Center’s (KUMC) 
secure email system. Each participant will be given the option to consent with staff in-person, 
remotely using video conferencing (Zoom® software) or telephone, or online through REDCap. 

 
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For participants choosing to consent remotely, the signed and dated consent form will be sent to 
the project staff’s secure KUMC email or submitted online through REDCap. Separate informed 
consent will be obtained for the patient and caregiver. If the patient with AD is not their own legal 
guardian, we will obtain consent from their legal guardian and assent from the patient. Project 
staff will fax/email a form to the primary care provider of both the patient and caregiver, which 
describes the eligibility criteria, study requirements, and requests clearance for participation. 
Those found to be ineligible will be provided with written materials describing available resources 
for increasing their MPA.  
B. Alternatives to Participation: Participants may join other physical activity programs. 
C. How new information will be conveyed to the study subject and how it will be 
documented: New information will be told to the subjects during their health educator visits as 
well as by emails sent to all participants and their legal guardians.  
D. Payment, including a prorated plan for payment:  Gift cards valued at $50 for both adults with 
AD and caregivers will be provided for data collection at baseline, 6,12, and 18 mos. to 
compensate for time required to complete testing. Adults with AD and caregivers will receive $50 
gift cards to compensate for time and travel associated with completing the consent process and 
the CDR at KU-ADC at baseline, and $25 gift cards for the assessment of MPA via ActiGraph at 3 
mos. As an additional incentive, adults with AD and caregivers will be allowed to keep the 
iPad®/iPod® and the Fitbit on completion of the active intervention (12 mos.).  
IV. 
Data Collection and Protection 
Data will be entered into a KUMC Redcap database. Only de-identified data will available to study 
personnel, e.g., statisticians. Data will be checked for outliers and normalcy at logical time points. 
Questionable data (e.g., >3 SD from the mean) will be re-checked and re-entered, if necessary. 
Checked data will be archived weekly. Data entry will be completed by research assistants blinded to 
group assignment. All personnel have current Human Subjects/HIPAA certificates. Study materials, 
and copies of the group exercise videos will be stored on our secure sever through KU-L. 
 
iPads will be set up by KUMC’s IT department. All iPads will be set up with a study iCloud account, 
and all Zoom accounts, Fitbit accounts, and Dropbox accounts will be created by the study team, and 
will not have identifiable information on them.  
 
V.Data Analysis and Reporting 
A. Statistical and Data Analysis:   
Statistical design. Baseline equivalence. The distributional properties of baseline demographic 
characteristics (MPA, BMI, age, sex, race/ethnicity, etc.) and dyadic relationship between adults 
with AD and their caregiver (quality, type, number of caregivers) will be inspected within the sample 
and between the RGV and EUC arms. Variables that demonstrate a significant nonequivalence 
between RGV and EUC arms will be statistically controlled in the hypothesis testing to improve 
accuracy of our inferences on intervention effects. Additionally, variables that significantly differ 
between dyads that dropped out and those that did not will be controlled to minimize any systematic 
bias stemming from attrition. 
 
Primary aim: To compare MPA (min/wk.) across the 6-mo. active intervention in adults with AD 
randomized to RGV and EUC. Our analysis will account for/evaluate the clustering of observations 
(repeated measurements; level 1) within participants (level 2) and dyads (level 3; if multiple 
caregivers) by estimating intra-class correlations and variances/covariances of regression 

 
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coefficients at, and across, different levels in random-effects multilevel models (mixed models). To 
address the aim, models will examine overall between-arm difference in MPV across time (group 
effect), linear/non-linear change in MPV over time (time effect), and, if appropriate, between-arm 
difference in this change (group-by-time interaction), while controlling for (i) the number of contacts 
with research staff and (ii) the baseline characteristics imbalances between participant subgroups 
(RGV vs. EUC, dropouts vs. completers). For example, a significant interaction would indicate that 
adults with AD in the RGV arm achieve more minutes of MPA compared to those in the EUC arm 
and this difference becomes greater as intervention participation increases, i.e., in the later mos. 
 
Secondary aim: To compare adults with AD and their caregivers randomized to RGV or ECU on the 
following outcomes across 18 mos. Adults with AD: MPA (min/wk.), sedentary time (min/wk.), 
percentage meeting 150 min/wk. goal, functional fitness, activities of daily living 
(basic/instrumental), quality of life, residential transitions, neuropsychiatric symptoms, and cognitive 
function. Caregivers: MPA (min/wk.), sedentary time (min/wk.), functional fitness, quality of life, and 
caregiver burden. Similar mixed models will be fitted separately for these outcome variables to 
examine group effect, time effect, and group-by-time interaction while controlling for the number of 
contacts with research staff and the baseline characteristics imbalanced between participant 
subgroups. 
 
Exploratory aim: To evaluate the influence of process variables/participant characteristics on MPA 
in adults with AD and their caregiver across 18 mos.: age, sex, BMI, attendance (exercise/support 
sessions), use of recorded sessions, PA self-monitoring, peer interactions during group sessions, 
caregiver support, type and quality of the dyadic relationship, number of caregivers, and level of 
dementia. If MPA is not significantly different between RGV and EUC across 18 mos., i.e., no 
significant group effect or group-by-time interaction, we will combine the two arms and examine 
associations of the process variables/characteristics with MPA in mixed modeling. However, if a 
significant between-arm difference in MPA is identified, we will determine whether the process 
variables/characteristics enhance or attenuate the treatment effects, i.e., moderation, by testing a 2-
way interaction with the group effect and/or a 3-way interaction with the group-by-time interaction 
term. In addition, we will examine how caregiver MPA influences the MPA of adults with AD over 
the 6-mo. active intervention, 6 mos. maintenance, and 6 mos. no contact. Some variables will be 
measured only at baseline, some will be summarized across the trial, while others will be assessed 
at specific time points. Thus, we will carefully design our models to assure the appropriateness of 
the analysis.  
 
Missing data. Missing data is anticipated due to either attrition, e.g., participant dropout, or 
nonresponse, e.g., ActiGraph non-wear or malfunction. Our intent-to-treat approach will employ full 
information maximum likelihood (FIML) estimation in the modeling, which does not discard 
participants who dropped out but utilizes all available data from their partial measurements, thereby 
producing unbiased parameter estimates and smallest possible standard errors. Missing 
observations due to nonresponse will be handled by Monte Carlo Markov Chain (MCMC) multiple 
imputation (MI) (114). A sufficient number of imputed datasets will be created to ensure accurate 
recovery of missing data and analysis results from each imputed dataset will be combined to make 
valid statistical inferences. Our imputation process will incorporate a number of auxiliary variables, 
thereby satisfying the missing at random (MAR) assumption (115). The state-of-the-science on 
missing data indicates that FIML and MI are extremely robust and leads to unbiased generalizability 
(116).  
 
V. 
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