A Nursing Home Pragmatic Trial of APPROACHES (Aligning Patient Preferences: a Role Offering Alzheimer's Patients, Caregivers, and Healthcare Providers Educ. and Support)
Phase: NA
Conditions: Alzheimer Disease, Dementia
Sponsor: Indiana University

APPROACHES Protocol Version 1.3 Date: July 15, 2025 
 
APPROACHES: ALIGNING PATIENT PREFERENCES – A ROLE 
OFFERING ALZHEIMER’S PATIENTS, CAREGIVERS, AND 
HEALTHCARE PROVIDERS EDUCATION AND SUPPORT  
 
A Nursing Home Pragmatic Clinical Trial 
 
Principal Investigators: 
Susan Hickman, PhD 
Clinical Geropsychologist & Professor 
Indiana University School of Nursing 
 
Kathleen Unroe, MD, MHA 
Geriatrician & Associate Professor 
Regenstrief Institute 
Indiana University Center for Aging Research 
 
Co-Investigator: 
Wanzhu Tu, PhD 
Biostatistician 
Regenstrief Institute 
Indiana University Center for Aging Research 
 
Supported by: 
The National Institute on Aging 
 1R21AG057463-01 
 
NCT03323502 
 
 

APPROACHES Protocol Version 1.3 Date: July 15, 2025 
 
 
Version 1.3  
July 15, 2025 
 
TABLE OF CONTENTS 
................................................................................................................................................... Page 
TABLE OF CONTENTS .............................................................................................................. i 
PRÉCIS ......................................................................................................................................... iii 
Study Title .................................................................................................................................. iii 
Objectives .................................................................................................................................. iii 
Design and Outcomes ................................................................................................................ iii 
Sample Size and Population....................................................................................................... iii 
STUDY TEAM ROSTER ............................................................................................................ 4 
PARTICIPATING STUDY SITES ............................................................................................. 6 
1 
STUDY OBJECTIVES ......................................................................................................... 7 
1.1 
Primary Objectives .......................................................................................................... 7 
1.2 
Secondary Objective ....................................................................................................... 7 
2 
BACKGROUND AND RATIONALE ................................................................................. 7 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .............................. 7 
2.2 
Study Rationale ............................................................................................................... 7 
3 
STUDY DESIGN ................................................................................................................... 8 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................. 8 
4.1 
Inclusion Criteria ............................................................................................................ 9 
4.2 
Exclusion Criteria ........................................................................................................... 9 
4.3 
Study Enrollment Procedures ......................................................................................... 9 
5 
STUDY INTERVENTIONS ................................................................................................. 9 
5.1 
Interventions, Administration, and Duration .................................................................. 9 
6 
STUDY PROCEDURES ..................................................................................................... 10 
6.1 
Description of Evaluations ............................................................................................ 10 
6.1.1. Enrollment, Baseline, and/or Randomization .............................................................. 10 
7 
SAFETY ASSESSMENTS .................................................................................................. 10 

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7.1 
Adverse Events and Serious Adverse Events ............................................................... 11 
7.2 
Safety Monitoring ......................................................................................................... 12 
8 
INTERVENTION DISCONTINUATION ........................................................................ 14 
9 
STATISTICAL CONSIDERATIONS ............................................................................... 15 
9.1 
General Design Issues ................................................................................................... 15 
9.2 
Sample Size and Randomization .................................................................................. 15 
9.3 Interim analyses and Stopping Rules .................................................................................. 16 
9.4 Outcomes ............................................................................................................................ 16 
9.4.1 
Primary outcome ....................................................................................................... 16 
9.4.2 
Secondary outcomes ................................................................................................. 16 
9.5 Data Analyses ..................................................................................................................... 16 
10 
DATA COLLECTION AND QUALITY ASSURANCE ............................................ 17 
10.1 
Data Management ......................................................................................................... 17 
10.2 
Quality Assurance ......................................................................................................... 17 
10.3.1 Training ...................................................................................................................... 17 
10.3.2 Quality Control Committee ....................................................................................... 17 
10.3.3 Metrics ...................................................................................................................... 17 
10.3.4 Protocol Deviations ................................................................................................... 17 
10.3.5 Monitoring ................................................................................................................ 18 
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY ............................................. 18 
11.1 
Institutional Review Board (IRB) Review .................................................................... 18 
11.2 
Informed Consent Forms .............................................................................................. 18 
11.3 
Participant Confidentiality ............................................................................................ 18 
11.4 
Study Discontinuation ................................................................................................... 19 
12 
ETHICAL CONSIDERATIONS ................................................................................... 19 
13 
COMMITTEES............................................................................................................... 19 
14 
PUBLICATION OF RESEARCH FINDINGS ............................................................ 21 
15 
REFERENCES ................................................................................................................ 23 
 
 
 

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PRÉCIS  
Study Title  
APPROACHES: Aligning Patient Preferences – a Role Offering Alzheimer’s patients, 
Caregivers, and Healthcare providers Education and Support  
 
Objectives  
APPROACHES is a pragmatic cluster randomized control trial testing the impact of a 
structured ACP specialist program on patients with Alzheimer’s and dementia related 
diseases in nursing homes. 
 1.1 Primary Objective R33 Phase (42 months) 
1.1.1  
Aim 1: Compare hospital transfers (admissions and emergency department 
visits) over 12 months between ADRD patients in intervention vs. control 
nursing homes 
1.2.1.1   H1: Transfers will be lower among ADRD patients in intervention 
vs. control nursing homes. 
1.2 Secondary Objective  
1.2.1  
Aim 2: Compare the following secondary outcomes between ADRD 
patients in intervention vs. control nursing homes over 12 months: 1) hospice 
enrollment; and 2) death in hospital. 
1.2.2.1 H1: ADRD patients in the intervention vs. control nursing homes will 
have:  
1.2.2.1.1 i. Greater hospice enrollment;  
1.2.2.1.2 and ii. Lower rates of dying in the hospital.  
 
Design and Outcomes   
In intervention nursing homes, a nursing home provider (e.g. social worker or chaplain) 
will be trained as an ACP Specialist who will work with nursing home leaders to: i. 
Consolidate nursing home ACP procedures; ii. Train and educate staff; and iii. Facilitate 
ACP with patients and their family caregivers. Control nursing homes will apply the 
usual ACP practices. The implementation period will be 18 months. All ADRD patients 
in the nursing homes during the implementation will be followed for 12 months. 
 
Sample Size and Population  
A total of 142 nursing homes will be randomized to either an intervention or control arm 
within each corporation (Signature, N= 109; Miller’s, N= 33).  

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STUDY TEAM ROSTER  
Co-Principal Investigator:        Susan Hickman, PhD 
 
600 Barnhill Drive 
 
Indianapolis, IN 46202 
 
(317) 274-0032 
 
hickman@iu.edu 
 
Main responsibilities/Key roles: Leading the project 
 
Co-Principal Investigator:        Kathleen Unroe, MD, MHA 
 
1101 West 10th Street 
 
Indianapolis, IN 46202 
 
(317) 274-9227 
 
kunroe@iu.edu 
 
Main responsibilities/Key roles: Leading the project 
 
Co-Investigator:  
 
       Wanzhu Tu, PhD 
 
1101 West 10th Street 
 
Indianapolis, IN 46202 
 
(317) 278-6451 
 
wtu@iu.edu 
 
Main responsibilities/Key roles: Data management & analysis 
 
Consultant:  
 
              Susan Mitchell, MD, MPH 
 
1200 Centre Street 
 
Boston, MA 02131 
 
(617) 971-5326 
 
smitchell@hsl.harvard.edu 
 
Main responsibilities/Key roles: Reviewing material, providing 
resources 
 
Consultant:  
 
 
 
 Laura Hanson, MD, MPH 
 
5003 Old Clinic 
 
Chapel Hill, NC  
 
(919) 843-4096 
 
laura_hanson@med.unc.edu 
 
Main responsibilities/Key roles: Consulting, reviewing 
material, providing resources 
 
Project Coordinators/Managers: Laramie Mack (from 2018 to April 2024) 
 
1101 West 10th Street 
 
Indianapolis, IN 46202 
 
(317) 274-9126 
 
lbrewer@regenstrief.org 
 
Main responsibilities/Key roles: Project management 
 
Abigail Evans (from April 2024 to present) 

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1101 West 10th Street 
 
Indianapolis, IN 46202 
 
(317) 274-9059 
 
abievans@regenstrief.org 
 
Main responsibilities/Key roles: Project coordination 
 
 
 

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PARTICIPATING STUDY SITES  
Indiana University School of Nursing 
600 Barnhill Dr.  
Indianapolis, IN 46202 
(317) 274-0032 
hickman@iu.edu 
 
Regenstrief Institute, Inc. 
1101 W. 10th St.  
Indianapolis, IN 46202 
(317) 274-9227 
kunroe@iu.edu 
 
 
Miller’s Health System 
1690 S. County Farm Rd.,  
Warsaw, IN 46508 
Alaina Butiste, Corporate Representative 
abutiste@millershealthsystems.com 
 
 
 
Signature HealthCARE 
12201 Bluegrass Pkwy., 
Louisville, KY 40299 
Katy Wane, Assistant Chief Compliance & Ethics Officer 
Kwane@signaturehealthcarellc.com 
 
 
 

APPROACHES Protocol Version 1.3 Date: July 15, 2025 
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1 
STUDY OBJECTIVES 
1.1 Primary Objectives  
1.1.1  Aim 1: Compare hospital transfers (admissions and emergency department 
visits) over 12 months between ADRD patients in intervention vs. control 
nursing homes.  
1.2.1.1   H1: Transfers will be lower among ADRD patients in intervention vs. 
control nursing homes. 
1.2 Secondary Objective 
1.2.1  Aim 2: Compare the following secondary outcomes between ADRD patients in 
intervention vs. control nursing homes over 12 months: 1) hospice enrollment 
and 2) death in hospital. 
1.2.2.1  H1: ADRD patients in the intervention vs. control nursing homes will have:  
1.2.2.1.1 i. Greater hospice enrollment;  
1.2.2.1.2 and ii. Lower rates of dying in the hospital.  
 
2 
BACKGROUND AND RATIONALE  
2.1 Background on Condition, Disease, or Other Primary Study Focus 
A significant number of patients Alzheimer’s disease or related dementia diagnoses will 
be cared for in nursing homes near the end of life. Unfortunately, many of these patients 
experience unwanted and burdensome medical treatments, such as potentially avoidable 
hospitalizations, that negatively impact quality of life. Advance care planning (ACP) 
discussions with patients and family caregivers are important to explore goals in advance 
of a crisis and support informed, values-based decision-making. The ACP process helps 
to ensure that preferences about treatments such as hospitalization are known, 
documented, and honored. Research indicates that ACP can reduce burdensome 
treatments and increase the likelihood that care will match documented preferences. 
Nursing homes are currently required by regulations to offer ACP to patients and 
families. However, there are no training requirements for nursing home staff and 
approaches to fulfilling this regulatory and ethical responsibility vary widely, resulting in 
inconsistent ACP. The “Aligning Patient Preferences – a Role Offering Alzheimer’s 
patients, Caregivers, and Healthcare providers Education and Support (APPROACHES)” 
trial will test the ACP Specialist Program. Existing nursing home staff members will be 
trained to enhance care and reduce unwanted, burdensome hospitalizations through 
improved ACP procedures, standardized staff education on ACP, and systematic ACP 
facilitation. 
 
2.2 Study Rationale 
The ACP Specialist Training courses will serve as an educational tool to provide training 
to the ACP Specialists at enrolled nursing facilities that engage in ACP conversations. 
This tool will help refine and improve their knowledge of how to best have and record 
these conversations by providing tips, examples, and information on nursing homes. 
 
A majority (72%) of nursing home patients have cognitive impairment1 and about half 
have a documented diagnosis of Alzheimer’s Disease or a related dementia (ADRD).2 As 
a result of the progressive, downward trajectory of ADRD,3 70% of patients live their 
final days in nursing homes.4 These patients often receive burdensome and expensive 

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treatments that may be avoidable and even unwanted.5,6 Hospitalizations are increasingly 
identified as a concern because of high burdens, high costs, and low clinical benefits in 
patients with advanced stages of dementia.7 Advance care planning (ACP) provides 
family caregivers of ADRD patients with education and support in identifying and 
documenting goals of care to align treatments with preferences.8 Documentation 
reflecting preferences for less aggressive treatment is associated with lower rates of 
hospitalization.9,10,11 However, nursing home staff are rarely trained to facilitate ACP or 
provided with strategies to integrate into practice resulting in highly variable practice and 
inaccurate documentation.6,7,12-18 
 
Under the auspices of a Centers for Medicare and Medicaid Services Initiative, our team 
has developed and successfully implemented a multi-component intervention to reduce 
avoidable hospitalizations of long-stay patients in 19 nursing homes across Indiana.19,20 
While the scalability and sustainability of the full intervention model remains untested, 
our experience to date indicates the ACP component is particularly practical, effective, 
and translatable. The proposed ACP Specialist Program will build on this foundation by 
refining the ACP component to target ADRD patients and their family caregivers. This 
intervention will be delivered by existing nursing home staff (e.g., social worker). 
 
The over-riding objective of this proposal is to conduct a pragmatic cluster randomized 
controlled trial (RCT) of “Aligning Patient Preferences – a Role Offering Alzheimer’s 
patients, Caregivers, and Healthcare providers Education and Support (APPROACHES)” 
that aims to improve ACP and goal-directed outcomes in nursing home patients with 
ADRD. In the R33 phase, we will conduct the full pragmatic RCT in partnership with 2 
nursing home corporations (Signature HealthCARE  and Miller’s Health Systems) in a 
combined total of 142 diverse facilities in 8 states. Consistent with the spirit of a 
pragmatic trial, we will use existing data sources including electronic health records 
(EHR), the Minimum Data Set 3.0 (MDS), and Medicare Claims data to characterize the 
cohort and measure outcomes. Hospital transfers over 12 months among ADRD patients 
is the 1o trial outcome. 
 
3 
STUDY DESIGN 
A total of 142 nursing homes will be randomized to either an intervention or control arm 
within each corporation (Signature, N= 109; Miller’s, N= 33). In intervention nursing 
homes, a nursing home provider (e.g. social worker) will be trained as an ACP Specialist 
who will work with nursing home leaders to: i. Consolidate nursing home ACP 
procedures; ii. Train and educate staff; and iii. Facilitate ACP with patients and their 
family caregivers. Control nursing homes will apply the usual ACP practices. The 
implementation period is expected to be 18 months. All ADRD patients in the nursing 
homes during the implementation will be followed for 12 months. 
 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
Facilities will be randomized to either the control arm or the intervention arm. This 
selection will take into account the choice of each organization considering half the 
organizations facilities are included in each arm.   
 

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The focus of the ACP Specialist will be patients with ADRD who reside in the nursing 
homes during the initiative, though other patients residing in the nursing home may 
benefit from it in keeping with the spirit of a pragmatic trial.21 Only patients with ADRD 
will be included in the analysis. ADRD is defined to include cognitive impairment1 or a 
documented diagnosis of dementia in the MDS. Patients will be excluded if they are 
currently enrolled in hospice at the start of the intervention period. 
 
Eligible facilities who agree to participate in the trial will be stratified at two levels: 
corporate ownership (Signature HealthCARE and Miller’s Health Systems) & average 
number of hospital transfers per 1000 person-days alive using 2017 MDS data provided 
by CMS. Facilities will be grouped into low versus high hospitalization rates, using the 
median rate for the nursing home system as the threshold value for dichotomization. 
Facilities will be randomized to the intervention or control within each strata at a 1-to-1 
ratio. Specifically, randomization will occur at the facility level, meaning that all patients 
with ADRD in the intervention buildings are eligible for inclusion in the trial. Following 
random assignment, we will use all available facility and patient-level data to test the 
balance of the intervention and control arms.  
 
Nursing home characteristics will be obtained from nursing home corporate partners and 
the MDS. Potentially eligible nursing homes will be reviewed by the Data Management 
and Analysis Workgroup in preparation for potential inclusion in the pragmatic cluster 
RCT. Problematic or unstable facilities will be removed in consultation with nursing 
home corporate leaders prior to randomization. 
 
4.1 Inclusion Criteria  
• 
Medicare-certified  
• 
All residents with Alzheimer’s disease and related dementias. 
• 
> 50 licensed beds  
• 
>50% of residents are long-stay (>100 days in the facility) 
4.2 Exclusion Criteria 
• 
Patients currently enrolled in hospice at the start of the intervention period 
• 
Problematic or unstable nursing homes  
• 
Defined by corporate leadership prior to randomization 
4.3 Study Enrollment Procedures 
• 
Enrollment is occurring at the facility level; individual patients are not being 
enrolled. 
 
5 
STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
Following randomization, the ACP Specialist program will be rolled out to the 
intervention buildings. All communications will be tailored to fit the corporate branding 
style of Signature HealthCARE and Miller’s Health Systems. Communications about the 
ACP Specialist Program with individual facilities will be delivered by the Corporate 
Implementation Champion and the designated ACP Specialists, with, at minimum, 
monthly meetings with the project team to discuss issues and any unmet needs. At the 
conclusion of the pragmatic cluster RCT, we will merge our data and analyze to measure 

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our primary and secondary outcomes. 
6 
STUDY PROCEDURES 
6.1 Description of Evaluations  
6.1.1. Enrollment, Baseline, and/or Randomization 
Nursing home Eligibility: All Medicare-certified nursing homes are eligible at 
Signature HealthCARE and Miller’s Health Systems. 
 
Nursing home Recruitment & Characteristics:  
The ACP Specialist Program will be rolled out as a corporate initiative and nursing 
home Executive Directors will be requested to participate in the initiative by nursing 
home corporate leadership. It is anticipated all nursing home Executive Directors who 
are approached will agree to participate. 
 
Nursing home corporate partners each provided data about key nursing home 
characteristics. At the time of randomization Signature HealthCARE owns 109 
nursing homes in 8 states, with a total of 8,811 beds; 43% are rural. Miller’s Health 
Systems owns 33 nursing homes, all in Indiana with 3,066 beds; 55% are rural. The 
mix of rural and urban facilities will provide a rich environment for this pragmatic 
trial. Self-reported 30-day hospital readmission rates for 2016 range from 13% for 
Miller’s Health Systems and 17% for Signature HealthCARE nursing homes. 
 
Random Assignment: Nursing homes will be sorted into groups that are comparable 
on hospital transfer rates. Eligible facilities who agree to participate in the trial will be 
stratified at two levels: corporate ownership (Signature HealthCARE and Miller’s 
Health Systems) & average number of hospital transfers per 1000 person-days alive 
using 2017 MDS data. Facilities will be grouped into low versus high hospitalization 
rates, using the median rate for the nursing home system as the threshold value for 
dichotomization. Facilities will be randomized to the intervention or control within 
each strata at a 1-to-1 ratio. Specifically, randomization will occur at the facility level, 
meaning that all patients not currently on hospice at the start of the intervention 
period in the intervention buildings are eligible for inclusion in the trial. The 
intervention focuses on patients with ADRD, but other residents of intervention 
facilities are not excluded. Following random assignment, we will use all available 
facility and patient-level data to test the balance of the intervention and control arms. 
 
7 
SAFETY ASSESSMENTS   
IRB has determined this study to be minimal risk. 
 
Although this study includes a vulnerable population of patients with cognitive 
impairment, it is anticipated that this study will be determined to represent no more than 
minimal risk to patients and family caregivers. All nursing homes are required to offer 
ACP to patients and family caregivers as part of routine care. This requirement is 
inclusive of patients with cognitive impairment or ADRD. Therefore, the ACP Specialist 
Program is consistent with the standard of care and the risk of harm is no greater than 
those ordinarily encountered in the daily life of a nursing home patient or family 
caregiver who may be offered the opportunity to engage in ACP by nursing home staff. 

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According to 45 CFR 46.102 (OHRP 2017),22 research is considered to pose minimal risk 
if the likelihood and degree of harm or discomfort anticipated from the research is no 
greater than that ordinarily encountered during daily life. 
 
7.1 Adverse Events and Serious Adverse Events  
An adverse event (AE) is generally defined as any unfavorable and unintended 
diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or 
disease which either occurs during the study, having been absent at baseline, or if present 
at baseline, appears to worsen.  
 
A serious adverse event (SAE) is generally defined as any untoward medical occurrence 
that results in death, is life threatening, requires inpatient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly.  
 
The potential serious negative reaction (SNR) that could occur during this trial is serious 
patient or family caregiver distress when engaging in ACP with the ACP Specialist. 
Based on our experience and results from other research studies, we anticipate that this 
will be rare. Serious distress could be demonstrated by negative reactions such as anger, 
uncontrolled crying, or early termination of an ACP discussion with the Specialist. The 
nature of these discussions is sensitive and personal, thus expressions of emotion, 
including tears, is expected and would not be considered a SNR. Training of the ACP 
Specialist will include emphasis on the importance of asking permission to begin an ACP 
conversation and respecting patient and family refusals. It will also include provision of 
emotional support and empathic statements during discussions. ACP Specialist training 
will include recognition of SNRs and instruction. In the R33 phase, staff will be 
instructed to report any negative reactions immediately to the Executive Director and the 
nursing home Corporate Implementation Champion. Together, these health care 
providers will evaluate the severity of the event and, if deemed serious, will report the 
SNR to the research team project manager via email or fax within 24 hours of the event. 
The project manager will report the SNR to both co-PIs via email or telephone 
immediately upon becoming aware of the event and will also notify the TBN Data and 
Safety Monitoring Board (DSMB) Chair in writing (email and hard copy) within 48 
hours. The Co-PIs will take ultimate responsibility for ensuring the DSMB chair is 
informed in a timely manner. Follow-up includes checking in with the patient or family 
caregiver within 6 to 24 hours of the initial SNR to assess whether further intervention is 
needed to mitigate the SNR. If necessary, the patient or family caregiver should be 
referred for follow-up (e.g., referring family caregiver to primary care provider or 
community mental health facility). 
 
We do not believe any potential consequences of APPROACHES would be considered 
serious adverse events (SAEs). We do not believe that death should be considered an 
SAE for this trial as: 1) death is often not unexpected in this nursing home population 
with ADRD; 2) death is not an adverse outcome for patients and families with goals of 
comfort or palliation if those goals are met; and 3) it is not known whether or not 

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aggressive care provided at the hospital results in lower mortality compared with 
conservative care in the nursing home.  
 
In this pragmatic trial, we will work closely with the nursing home corporate partners 
deploying the intervention in order to monitor the overall safety of patients in the project, 
minimize any risk associated with the research, and protect confidentiality. After the 
initiation of the R33, the nursing home Corporate Implementation Champions and 
nursing home Corporate Data Experts from each of the 2 nursing home partners will 
participate in monthly meetings to discuss project implementation and address questions, 
problems, or concerns that might arise, including data safety and risk to patients.  
 
Co-PIs Hickman and Unroe will continue to actively monitor for any results of other new 
research studies or regulatory policies that may have an impact on APPROACHES. 
Further, we will request the DSMB members to monitor for any external scientific or 
therapeutic developments that could impact the ethics of the trial or safety of participants 
 
7.2 Safety Monitoring 
The Co-PI Hickman will be responsible for executing the DSMP in her role as the lead 
for the Regulatory and Operations Workgroup. Co-PI Unroe, the project manager, data 
manager, information technology (IT) support person, and the IT representatives for each 
of the two partner institutions will all participate in the Regulatory and Operations 
Workgroup. This workgroup will also be responsible for obtaining appropriate 
agreements for nursing home health system partners, including Memoranda of 
Understanding (MOU) and Data Use Agreements (DUA) prior to any data transfer. This 
workgroup has oversight of submission of CMS data requests, that must include all data 
security precautions, as well as submission of the protocol to the Indiana University 
Indianapolis (IUI) Institutional Review Board (IRB) for review and approval. The 
Regulatory and Operations workgroup will also support the coordination of DSMB. All 
study personnel, including PIs, Co-Is, consultant, project manager, and nursing home 
Corporate Implementation Champions will complete online education in the Protection of 
Human Research Practice and complete Conflict of Interest Forms. Our DSMP will be 
included as part of the research protocol and submitted to the IUI IRB. 
 
Frequency of Data and Safety Monitoring. 
During the intervention phase of the R33 trial, nursing home Corporate Implementation 
Champions will be charged with asking nursing home based ACP Specialists about any 
adverse events and unanticipated problems that may have occurred in the course of their 
role. The nursing home Corporate Implementation Champions will meet at least monthly 
with the project team during the intervention phase. Any adverse events and 
unanticipated problems requiring immediate action will be discussed immediately with 
either of the PIs to determine necessary corrective action. Problems not requiring 
immediate actions will be addressed during monthly research team meeting and at 
quarterly DSMB meetings. Outcome of adverse events and unanticipated problems will 
be periodically reported to the IRB and the NIH. 
 
Content of Data and Safety Monitoring Report 

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A Data and Safety Monitoring Report will be prepared once a year and will include 
status, participant descriptive information, safety information, and fidelity monitoring. 
 
Data and Safety Monitoring Board Membership 
DSMB membership will include experts or representatives of the field with relevant 
clinical expertise, clinical trials methodology, and biostatistics. The members will be 
selected by the National Institute on Aging (NIA) program officer in consultation with 
the Co-PIs. 
 
Conflict of Interests 
Members of the DSMB shall have no direct involvement with the study investigators or 
nursing home corporate partners. Each DSMB member will sign the IU Conflict of 
Interest Statement, which include current affiliations and any other relationships that 
could be perceived as a conflict of interest related to the study. 
 
Protection of Confidentiality 
Data will be presented in a blinded manner with no participant or nursing home 
identifiers. All materials, discussions, and proceedings of the DSMB will be completely 
confidential and DSMB members are expected to maintain confidentiality. 
 
DSMB Responsibilities 
The DSMB will be formed in consultation with the NIA program officer and will include 
2-3 external members. According to NIA guidance, the Chair will be selected by the 
NIA. The DSMB Chair will serve as the safety officer for the project and will be 
responsible for running meetings. The DSMB will be charged with monitoring patient 
safety, data quality and overall performance of the study. Responsibilities will include 
review of the research protocol, with a focus on protecting patient confidentiality and the 
plan for data and safety monitoring. Review of performance will include progress 
towards milestones, evaluation of recruitment, assessment of any serious negative 
reactions, and identification of issues around data storage or quality. The DMSB will also 
advise the NIA on the readiness of the trial to initiate recruitment, progress of the trial, 
and review of study performance including making recommendations and/or assisting in 
the resolution of problems identified by the Co-PIs. The DMSB will report to the NIA on 
the safety and progress of the trial as well as commenting on any problems with study 
conduct, enrollment, sample size, and/or data collection. All adverse events and 
unanticipated problems occurring during the course of the study will be collected, 
documented, and reported to the PIs and the DSMB Chair. These will be reported to NIA 
Project Officer and IRB quarterly. The PIs will meet with the study team staff weekly and 
at least one of the Co-PIs will be available at all times via email or phone. Serious 
adverse events potentially related to the intervention will be reported to both the Chair of 
the DSMB and to the NIA Project Officer within 24 hours of either PI learning of the 
issue. The DSMB Chair will determine if an additional meeting of the DSMB is needed 
and convene. 
 
 

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8 
INTERVENTION DISCONTINUATION  
Adverse Event and Serious Adverse Event Collection and Reporting. 
The potential adverse event (AE) that could occur during this trial is significant distress 
by patients or family members in the intervention NHs. Such events may be the 
manifestation of a very negative emotional reaction during a facilitated ACP discussion 
including uncontrolled crying or complaining to facility leadership. Due to the sensitive 
nature of the material, tearing up, crying, expressions of emotion, or early termination of 
the conversation by the proxy can be expected during advance care planning and are not 
deemed to be adverse events. The risk of potential distress caused by exposure to the 
ACP Specialist Program is no greater than the risk of distress from experiencing these 
conversations in routine clinical care. 
Training of the ACP Specialist will include emphasis on the importance of asking 
permission to begin an ACP conversation and respecting patient and family refusals. It 
will also include provision of emotional support and empathic statements during 
discussions. ACP Specialist training will include recognition of AEs and instructions. In 
the R33 phase, staff will be instructed to report any negative reactions immediately to the 
Executive Director and the nursing home Corporate Implementation Champion. 
Instructions are provided to the ACP Specialists and Corporate Implementation 
Champions about what constitutes an adverse event. In the event of an AE, ACP 
Specialists will report the event to his/her immediate supervisor, who will report it to the 
Corporate Implementation Specialist. Together, these professionals will determine the 
severity of the event and if it is a true AE related to the ACP Specialist Program. If 
deemed necessary, the Corporate Implementation Champion will notify the research 
project staff within 48 hours of the event.   
The project manager will report the AE to both co-PIs via email or telephone 
immediately upon becoming aware of the event and will also notify the TBN Data and 
Safety Monitoring Board (DSMB) Chair in writing (email and hard copy) within 48 
hours. The Co-PIs will take ultimate responsibility for ensuring the DSMB chair is 
informed in a timely manner. Follow-up includes checking in with the patient or family 
caregiver within 6 to 24 hours of the initial AE to assess whether further intervention is 
needed to mitigate the AE. If necessary, the patient or family caregiver should be referred 
for follow-up (e.g., referring family caregiver to primary care provider or community 
mental health facility). A summary of any AEs will be reported quarterly to the NIA 
program officer and the IRB.  
 
We do not believe any potential consequences of APPROACHES would be considered 
serious adverse events (SAEs). We do not believe that death should be considered an 
SAE for this trial as: 1) death is often not unexpected in this nursing home population 
with ADRD; 2) death is not an adverse outcome for patients and families with goals of 
comfort or palliation if those goals are met; and 3) it is not known whether or not 
aggressive care provided at the hospital results in lower mortality compared with 
conservative care in the nursing home. 
 

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In this pragmatic trial, we will work closely with the nursing home corporate partners 
deploying the intervention in order to monitor the overall safety of patients in the project, 
minimize any risk associated with the research, and protect confidentiality. After the 
initiation of the R33, the nursing home Corporate Implementation Champions and 
nursing home Corporate Data Experts from each of the 2 nursing home partners will 
participate in monthly meetings to discuss project implementation and address questions, 
problems, or concerns that might arise, including data safety and risk to patients.  
 
Co-PIs Hickman and Unroe will continue to actively monitor for any results of other new 
research studies or regulatory policies that may have an impact on APPROACHES. 
Further, we will request the DSMB members to monitor for any external scientific or 
therapeutic developments that could impact the ethics of the trial or safety of participants. 
 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
The over-riding objective of this proposal is to conduct a pragmatic cluster-randomized 
controlled trial (RCT) of “Aligning Patient Preferences – a Role Offering Alzheimer’s 
patients, Caregivers, and Healthcare providers Education and Support (APPROACHES)” 
that aims to improve ACP and goal-directed outcomes in nursing home patients with 
ADRD. In the R33 phase, we will conduct the full pragmatic RCT in partnership with 2 
nursing home corporations (Signature HealthCARE and Miller’s Health Systems) who 
operate a combined total of 142 diverse facilities in 8 states. Consistent with the spirit of 
a pragmatic trial, we will use existing data sources including electronic health records 
(EHR), the Minimum Data Set 3.0 (MDS), and Medicare Claims data to characterize the 
cohort and measure outcomes. Hospital transfers over 12 months among ADRD patients 
is the 1o trial outcome. 
 
9.2 Sample Size and Randomization 
Power Calculations.  
The implementational advantages of cluster RCT are gained at the expense of reduced 
analytical power, as compared to a simple RCT.23 Reduction of power is proportional to 
the intracluster correlation (ICC) coefficient 𝜌𝜌, which represents the strength of 
correlation among subjects within the same cluster. The within-cluster correlation has a 
correlate – the between cluster variation, which is commonly expressed as the coefficient 
of variation (CV).24   Larger ICC or CV values will lead to bigger variance inflation and 
more power loss.  
 
A power analysis was conducted using preliminary data from the Minimum Data Set 
(MDS) provided by CMS. We estimated that the between-cluster CV would be less than 
0.5. Assuming that the two treatment arms have similar CV values of a similar 
magnitude, we calculated the power for detecting 20% reduction in rate of hospital 
admission by the proposed intervention. Our analysis showed that with 120 facilities (60 
per arm) and an average of 50 residents per facility, we will have 81% power to detect a 
20% difference in the rate of hospitalization (1.0 per resident year in the control group vs 
0.8 per resident year in the intervention group), by using a Poisson regression analysis 

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with 0.05 level of significance. We note that the power estimate is likely to be 
conservative because in the actual analysis, we plan to control for the effects of the 
covariates; the reduced variability explained by the covariates will increase the power.  
   
 
9.3 Interim analyses and Stopping Rules 
We will not be conducting an interim analysis or developing rules for stopping the trial 
early for several reasons. The planned intervention of a trained ACP Specialist who will 
augment usual care is unlikely to cause harm. The IRB has determined that this study is 
minimal risk. Particularly given the delay in obtaining Medicare claims for determining 
the primary outcome, hospitalization or emergency department visits, it will not be 
feasible to determine the differences in this outcome between the intervention and control 
groups until the end of the 12 month outcome observation period.   
 
9.4 Outcomes  
9.4.1 Primary outcome   
9.4.1.1 Hospital transfers over 12 months among ADRD patients 
9.4.2 Secondary outcomes   
9.4.2.1 Hospice enrollment over 12 months among ADRD patients 
9.4.2.2 Death in hospital over 12 months among ADRD patients 
 
9.5 Data Analyses 
Design consideration. The R33 phase of the study has two aims: (Aim 1 – Primary) To 
compare hospital transfers (admissions and emergency department visits) over 12 months 
between ADRD patients in the intervention and control facilities; and (Aim 2 - 
Secondary) assess the interventional effect of the ACP Specialist Program on hospice 
enrollment and place of death. Towards these ends, we employ a cluster RCT design. 
With this design, randomization will be carried out at the nursing home level, stratified 
by nursing home corporate ownership and baseline hospitalization transfer rates (low 
versus high). All patients at a given nursing home will have the same intervention 
assignment. The trial outcomes will be analyzed at the individual patient level and 
reported at the facility level. The cluster RCT with nursing home randomization is chosen 
because of its ability to simultaneously maximize the implementational feasibility and 
minimize the contamination risk.25,26 Counts of hospital transfers and emergency 
department visits incurred by individual ADRD patients during the follow-up period will 
be considered as the primary outcome. We designed the trial to ensure adequate power 
for the hypothesis concerning the primary outcome. Average age and proportion of 
female patients is similar across our nursing home partner facilities and the U.S. The % 
of Black patients ranges from 6-17% across the population of our partner nursing homes. 
About half of nursing home patients have a dementia diagnosis. This is similar for our 
partner facilities.  
 
Analysis will be carried out in an intention-to-treat (ITT) framework, which gives a 
pragmatic estimate of the interventional benefit.27 The ITT analysis will use data from all 
eligible patients in randomized facilities, regardless of the level of facilities’ adherence to 
the study protocol and patient attrition. ITT is a preferred approach for pragmatic trials 

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because the analysis generates estimates of treatment effectiveness in a more realistic 
way. In fact, clinical effectiveness can be severely overestimated if ITT analysis is not 
performed.28 Within the ITT framework, we propose to analyze the trial data using 
appropriate generalized linear models. Specifically, we plan to compare the rates of 
hospital admissions in patients residing in the intervention vs control facilities. In line 
with intention-to-treat principles and our cluster randomized design, hospitalizations will 
be analyzed at the facility level, including for residents who moved across intervention 
and control buildings during the study period. Group assignment will be based on the 
facility each resident was first admitted to during the intervention period. Thus, some 
residents may have a documented ACP encounter in intervention facilities but also spent 
some time in control facilities. The analysis will be carried out using an appropriate count 
data regression model, length of observation will be adjusted as an offset parameter. We 
will test the levels of extra-Poisson variation to determine if a Poisson regression model 
is sufficient for the analysis. If the level of variation is beyond what can be 
accommodated by the Poisson model, we will consider using negative binomial 
regression. Similarly, we will test the presence of extra zeros that beyond the Poisson or 
negative binomial models. If necessary we will consider the use of zero-inflated Poisson 
or negative binomial regression analysis. Correlations among outcomes measured from 
residents in the same facility will be accounted for by adding random facility effects into 
the regression models. This analytical approach handles missing data (early dropout due 
to death or transfer to hospice) more easily because of the inclusion of offsetting 
parameters in the model. 
 
10 
DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Management  
The proposed study will combine multiple sources of patient data to measure impact on 
the quality of care near the end-of-life.  
 
10.2 Quality Assurance  
10.3.1 Training 
ACP Specialists will complete standardized training via modules created for the study 
and available in their learning management systems. Corporate representatives and 
corporate implementation champions will complete a corresponding training adapted 
for key leaders via modules created for the study and available in their learning 
management systems. 
10.3.2 Quality Control Committee  
Not applicable. 
10.3.3 Metrics 
Provide quality control metrics for outcome measures. 
10.3.4 Protocol Deviations 
Protocol deviations will be assessed in monthly meetings with the corporate 
implementation champions. Since this is a pragmatic trial, we anticipate and have 
built-in flexibility in implementation of the ACP specialist program that would not be 
considered a protocol deviation. 

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10.3.5 Monitoring 
Monitoring will occur via review of the monthly data transfer and through monthly 
meetings with the corporate implementation champions.   
 
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
The proposed study has been reviewed by the Indiana University Institutional Review 
Board (IRB), which will serve as the centralized, single IRB for the trial in accordance 
with National Institutes of Health policy. This trial is registered at clinicaltrials.gov 
(NCT03323502). A Data Safety and Management Plan is described in this protocol. 
 
11.2 Informed Consent Forms 
A wavier of informed consent was sought from the IRB. This pragmatic clinical trial 
meets the criteria for a waiver of informed consent as described in 45 CRF 46:116. 
Specifically: 1) this research represents no more than minimal risk; 2) a waiver does not 
adversely affect the rights and welfare of participants; 3) the research could not be 
practicably carried out without the waiver; and 4) information will be provided to the 
nursing home partners after the trial to share with interested patients and family 
caregivers.29 Patient and family caregiver refusals to participate in ACP discussion will 
be honored.  
11.3 Participant Confidentiality  
Data provided by nursing home corporate partners (MDS, EHR) will be transferred using 
HIPAA compliant, encrypted processes. CMS (Claims, MDS) and EHR data files will be 
securely stored using processes developed to meet CMS data requirements as part of a 
prior CMS data request. Specifically, data will be stored on a virtual server administered 
by Indiana University’s Clinical Affairs IT Service (CAITS) team. The virtual server is 
located on Indiana University’s Intelligent Infrastructure on hardware that is physically 
located in two enterprise-class machine rooms in separate physical locations. The server 
rooms require biometric authentication in addition to a chip-based access card and are 
staffed 24x7x365 and feature video security. Network firewall rules are used to restrict 
server access to only necessary subnets. Only IU domain workstations with security 
controls (auto logoff, centralized threat management, host-based firewall, and more) will 
be permitted to connect to the virtual server. Each study team member with access to the 
CMS data must use a passphrase. Protocols are in place dictating that passphrases must 
be at least 15 characters in length with at least 4 unique characters (letters, numbers, and 
symbols) and use at least 4 words separated by spaces or other non-letters. Password 
reuse is restricted, not allowing the previous 2 passwords to be reused. Sessions on 
workstations and servers, whether local or remote, are locked after being idle for 15 
minutes and terminated after 24 hours of non-use. 
 
The systems used to store and analyze the data will be subjected to a documented NIST-
based risk management process prior to receipt and use of the requested data. The process 
is briefly outlined below: 
 
a) Inventory assets—hardware, software, personnel. 

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b) Document controls—identify every existing and appropriate NIST 800-53 control for 
the system. NIST 800-53 (an industry and government standard) is a comprehensive 
catalog of 926 security controls. NIST 800-66 (a mapping of the HIPAA security rule to 
NIST 800-53) is used to identify appropriate controls for electronic Personal Health 
Information. 
c) Assess risk—identify risks that existing control address and residual risk from missing 
controls. 
d) Respond to risk-how each residual risk is addressed (mitigated, transferred or 
accepted), explanation/justification, and timelines for mitigation, if any. 
e) Establish ongoing risk management—semi-annual reviews and documentation 
updates, external assessments. 
f) Training-two annual HIPAA training courses (University general course and an IT-
specific course). 
 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NIA, the OHRP, the FDA, or 
other government agencies as part of their duties to ensure that research participants are 
protected.  
 
12 
ETHICAL CONSIDERATIONS 
Protections against Risk 
Informed consent will not be sought from patients or family caregivers for this pragmatic 
cluster randomized control trial.30 Strategies to minimize risk to participants are based on 
the experiences of the study PI and Co-Is in conducting research on ACP and in the 
nursing home setting. Additionally, Dr. Hickman has expertise in ethical issues in 
research with these populations to inform both study design and strategies to protect 
against risk. Dr. Hickman has previously conducted research on ethical issues in 
conducting long-term care research31,32 and NIH-funded research on ethical issues in end-
of-life research.33 
 
13 
COMMITTEES 
Executive Committee: The Executive Committee will oversee all aspects of project 
development, implementation, and analysis including human resources, communications 
with the National Institutes of Health, and budgetary decisions.  
 
Steering Committee: The Steering Committee will include the Co-PIs Hickman and 
Unroe, Co-I Tu, Consultants Mitchell and Hanson, and representatives from each nursing 
home corporate partner. This group will be responsible for overseeing the project 
direction, ensuring close collaboration between APPROACHES and nursing home 
partners, coordinating workgroup tasks, and meeting project milestones. This includes 
transition to the R33 phase. The Steering Committee will also be responsible for 
reviewing EHRs to ensure existing fields adequately capture relevant ACP data to guide 
clinical care (e.g., allow for documentation of specific POLST form orders and not just 
code status) with the goal of standardization of documentation across sites and the 
creation of clinically useful dashboards. 
 

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Regulatory and Operations Workgroup: This workgroup will be led by Co-PI Hickman, 
with Co-PI Unroe, the project manager, data manager, information technology (IT) 
support, and nursing home Corporate Data Experts. This Workgroup will be responsible 
for obtaining signed Memoranda of Understanding as well as a signed Data Use 
Agreements (DUA) from each corporate nursing home partner and ensuring data are 
transferred safely. This Workgroup will prepare and submit the CMS data request 
outlining all data security precautions along with related institutional policies. Because of 
the close link between data security and issues related to patient and family caregiver 
confidentiality, this workgroup will be responsible for oversight of the human subjects’ 
protections. This included submitting an application to the Indiana University 
Institutional Review Board (IU IRB), which will serve as the IRB of record, and 
requesting a waiver of informed consent for patients and family caregivers. Finally, this 
group will oversee the implementation of the Data Safety and Monitoring plan, which 
includes developing the Data Safety and Monitoring Board (DSMB) charter, convening 
the DSMB, and supporting its work (see Section F). 
 
APPROACHES Intervention Protocol Workgroup: This group will be responsible for 
implementation in the R33 phase. It will be led by Co-PI Hickman with Co-PI Unroe, 
Consultant Hanson, the Project Manager, and representatives from the partner 
organizations.  
 
The ACP Specialist Program is based on the successful OPTIMISTIC nurse role but 
adapted for use by internal nursing home staff. The ACP Specialist Program will be 
implemented as a new nursing home initiative. Corporate policies regarding ACP 
practices will be reviewed and potentially modified or developed in collaboration with 
our nursing home partners to support roll out of this new initiative. Signature 
HealthCARE and Miller’s Health Systems corporate leadership have expressed 
willingness to make policy or procedure modifications necessary to support the ACP 
Specialist Program. Similar to OPTIMISTIC, a process will be developed to ensure the 
staff member designated as the ACP Specialist is assigned a group of 10 ADRD patients 
each month to approach about ACP with accountability for reporting to local nursing 
home leadership. The intervention will be refined in collaboration with nursing home 
partners and current OPTIMISTIC nurses. Any modifications will be based on consensus, 
and rely on national standards and existing evidence from research. Meetings will first be 
held separately with Signature HealthCARE and Miller’s Health Systems corporate 
leadership to identify opportunities and potential barriers within each system. The 
program will be refined based on this feedback followed by a smaller, combined meeting 
with representatives from each organization to review and finalize. 
 
The ACP Specialist Program includes a brief online training for Executive Directors, 
Medical Directors, and Directors of Nursing (approximately 1 hour for each). The 
materials have been tailored to each nursing home corporation electronic learning 
platform and brand standards. The goals of this training are: a review of ACP and its 
importance, particularly for patients with ADRD and their families; an understanding of 
the ACP Specialist Program and role; and to convey the importance of support for the 
ACP Specialist dedicated role as a key nursing home staff position. Nursing home 

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21 
leadership will be expected to offset the ACP Specialist’s new responsibilities by 
permanently shifting work to other staff. 
 
The nursing home staff member designated as the ACP Specialist will complete a longer 
training (approximately 7 hours) and will receive a hard-copy manual including sample, 
educational handouts and access to videos for patients, families, and other nursing home 
staff, documentation instructions, tracking tools, and tips for navigating common barriers. 
Due to the COVID-19 pandemic and its significant impact on NHs, an Introductory 
Launch Course was created for ACP Specialists to complete prior to implementation at 
their facility with the understanding that all additional training modules would then be 
completed. The training will include specific information about decision-making for 
patients with dementia. Training materials are anticipated to include OPTIMISTIC 
educational tools created by Dr. Hickman and materials developed by Dr. Hanson. Core 
expectations include review and modification of ACP procedures as needed, education 
provided to other nursing home staff, and dedicated time to coordinate and facilitate ACP 
discussions with ADRD patients and/or family caregivers using the target assignment list. 
Based on experience with OPTIMISTIC, the ACP Specialist will require a minimum of 1 
day per week (20% FTE) initially, with a reduction over time after the initial start-up 
work. Dedicated time and schedule flexibility are critical to the success of the ACP 
Specialist to reach family caregivers and facilitate conversations. 
 
Consistent with the principles of a pragmatic trial, instructions about how to implement 
the protocol role will be highly flexible.34 For example, some facilities may decide to 
train more than one ACP Specialist within the building to share responsibilities. There is 
also flexibility in level of expertise required by practitioners delivering the intervention 
so the ACP Specialist may be any staff person deemed qualified by the nursing home 
Executive Director to fulfill the role, though it is anticipated it will likely be a social 
worker or a nurse. It is expected that there will be adaptations to the ACP tools and 
educational materials as needed. 
 
Data Management and Analysis Workgroup: This group will be led by Co-PI Unroe with 
Co-I Tu, Co-PI Hickman, Co-I Mitchell, biostatistician, data manager, and IT Support. 
This group is responsible for the data management required to link data sources in 
preparation for analysis as well as the analysis itself. In order to assess our outcome 
measures to both justify the adequacy of these measures and finalize these variables, a 
subset of MDS and Claims file records will be compared to the nursing home EHR in 
collaboration with our clinical partners to determine whether the process of merging was 
accurate. For example, validity checks will be performed to see if all hospital transfers 
are captured.  
 
14 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures 
developed by the Steering Committee. Any presentation, abstract, or manuscript will be 
made available for review by the sponsor and the NIA prior to submission. Publication 
authorship will be based on the relative scientific contributions of the PIs, key personnel, 
and nursing home corporate partners (e.g., nursing home Corporate Implementation 

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Champion). 
 
 
 

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15 
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