Palliative Care for Persons With Late-stage Alzheimer's and Related Dementias and Their Caregivers
Phase: NA
Conditions: Dementia, Dementia, Vascular, Dementia With Lewy Bodies, Dementia Frontal, Dementia, Mixed, Dementia Alzheimers, Alzheimer Disease, Dementia Severe
Sponsor: University of North Carolina, Chapel Hill

 
 
Palliative Care for Persons with Late-stage 
Alzheimer’s and Related Dementias and their 
Caregivers: A Randomized Clinical Trial 
PROTOCOL 
 
National Clinical Trial (NCT) Identified Number:  NCT04948866 
Principal Investigator: Laura C. Hanson, MD, MPH 
Sponsor: University of North Carolina at Chapel Hill 
Grant Brief Title: ADRD-PC Study 
Grant Number: R01AG065394 
Funded by: National Institute on Aging 
Version Number:  v.2.0 
20 March 2023 
 
 
STATEMENT OF CONFIDENTIALITY 
 
This document is confidential communication. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be published or 
disclosed without prior approval of the Principal Investigator or other participating study leadership 
and as consistent with the NIH terms of award

NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 

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Table of Contents 
STATEMENT OF CONFIDENTIALITY .................................................................................................................... a 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
Schema 
5 
1.2 
Schedule of Activities .......................................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background........................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 9 
3 
OBJECTIVES AND ENDPOINT / OutcomeS ............................................................................................. 9 
4 
STUDY DESIGN ........................................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design.............................................................................................. 11 
4.3 
Justification for Intervention ............................................................................................................. 11 
4.4 
End-of-Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 11 
5.1 
Inclusion Criteria ................................................................................................................................ 11 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Strategies for Recruitment and Retention ...................................................................................... 12 
6 
STUDY INTERVENTION and Control Conditions ................................................................................... 13 
6.1 
Study Intervention .............................................................................................................................. 13 
6.1.1 
Administration and/or Dosing ....................................................................................... 15 
6.2 
Fidelity ................................................................................................................................................. 15 
6.2.1 
Interventionist Training and Tracking .......................................................................... 15 
6.3 
Measures to Minimize Bias: Randomization and MASKing ........................................................ 16 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 16 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 16 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 16 
7.3 
Lost to Follow-Up ............................................................................................................................... 16 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 16 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 17 
8.2 
Safety Assessments .......................................................................................................................... 17 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 18 
8.3.1 
Definition of Adverse Events ........................................................................................ 18 
8.3.2 
Definition of Serious Adverse Events .......................................................................... 18 
8.3.3 
Classification of an Adverse Event .............................................................................. 18 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 19 
8.3.5 
Adverse Event Reporting .............................................................................................. 19 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 20 
8.4 
Unanticipated Problems .................................................................................................................... 20 

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8.4.1 
Definition of Unanticipated Problems .......................................................................... 20 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 21 
9.1 
Statistical Hypotheses ....................................................................................................................... 21 
9.2 
Sample Size Determination .............................................................................................................. 21 
9.3 
Populations for Analyses .................................................................................................................. 22 
9.4 
Statistical Analyses............................................................................................................................ 22 
9.4.1 
General Approach .......................................................................................................... 22 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 23 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 23 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 25 
10.1 
Regulatory, Ethical, and Study Oversight Consideration ............................................................. 25 
10.1.1 
Informed Consent Process ........................................................................................... 26 
10.1.2 
Study Discontinuation and Closure ............................................................................. 26 
10.1.3 
Confidentiality and Privacy ........................................................................................... 27 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 27 
10.1.5 
Key Roles and Study Governance .............................................................................. 28 
10.1.6 
Safety Oversight ............................................................................................................. 28 
10.1.7 
Quality Assurance and Quality Control ....................................................................... 28 
10.1.8 
Data Handling and Record Keeping ............................................................................ 29 
10.1.9 
Protocol Deviations ........................................................................................................ 30 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 30 
10.1.11 
Conflict of Interest Policy .............................................................................................. 30 
10.2 
Abbreviations and Special Terms ................................................................................................... 31 
10.3 
Protocol Amendment History ........................................................................................................... 32 
11 
REFERENCES ............................................................................................................................................. 34 
 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary 
assurances that this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines, as described in the 
Statement of Compliance above. 
 
Principal Investigator: 
Signed: 
 
Date: 
20 March 2023 
 
Name: Laura C. Hanson, MD, MPH 
 
Title: 
Professor of Medicine 
 
Investigator Contact Information 
Affiliation:  University of North Carolina School of Medicine 
Address: Chapel Hill NC 27759 
Telephone: 919-843-4096 
Email: lhanson@med.unc.edu 
 
Site Principal Investigator: 
Signed: 
 
Date: 
 
 
Name:  
 
Title: 
 
 
Affiliation: 
 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
 
Title: 
Palliative Care for Persons with Late-stage Alzheimer’s and 
Related Dementias and their Caregivers: A Randomized Clinical 
Trial 
Grant Number: 
R01AG065394 
 
Study Description: 
 
This study is a multi-site RCT of the ADRD-PC program of 
dementia-specific palliative and transitional care for people with 
late-stage ADRD and their caregivers. 
 
Objectives: 
 
Aim 1: To conduct a multi-site RCT of the ADRD-PC program 
(intervention arm) vs publicly available educational material for 
dementia caregivers (control arm) to compare 60-day hospital 
transfers (hospitalization and emergency room visits) for persons 
with late-stage ADRD (primary outcome).  
 
Aim 2: To compare patient-centered secondary outcomes 
between intervention and control arms: a) symptom treatment; b) 
symptom control; c) post-acute use of community palliative care 
or hospice; and d) new nursing home transitions. 
 
Aim 3: To compare caregiver-centered secondary outcomes 
between intervention and control arms:  a) communication about 
prognosis and goals of care; b) shared decision-making; and c) 
caregiver distress.  
 
Endpoint/ Outcomes: 
60-day hospital transfers (Aim 1, primary outcome).   
Patient-centered secondary outcomes (Aim 2); a) symptom 
treatment (Palliative Care Domain index); b) symptom control 
(Symptom Management at the End of Life in Dementia scale, 
Neuropsychiatric Inventory Questionnaire); c) post-acute use of 
community palliative care or hospice; and d) new nursing home 
transitions. 
Caregiver-centered secondary outcomes (Aim 3); a) 
communication about prognosis and goals of care; b) shared 
decision-making; and c) caregiver distress  
(Family Distress in Advanced Dementia scale, Zarit Burden short 
form). 
 
Study Population: 
424 dyads of hospitalized patients with late-stage ADRD and their 
family caregivers and 50 dyads of hospitalized patients with late-
stage ADRD and their family caregivers who identify as 
Hispanic/Latino  
 
Phase or Stage: 
NIA Behavioral Intervention Efficacy trial (Stage II)  
 

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Description of 
Sites/Facilities 
Enrolling Participants: 
5 medical centers with interdisciplinary specialty palliative care 
teams - University of North Carolina (UNC), University of Indiana 
(IU), University of Colorado (UC), Massachusetts General 
Hospital (MGH), Emory University (EU) 
 
Description of Study 
Intervention: 
The ADRD-PC program includes 3 main components: dementia-
specific palliative care consultation, standardized caregiver 
education, elements of evidence-based transitional care.  
 
Study Duration: 
60 months 
Participant Duration: 
60 days post hospitalization 
 
 
 
 
 
 
 

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SCHEMA  
Flow Diagram 
 
Pre-Screening 
 
  
During 
Hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
During  
Hospitalization  
 
 
 
 
 
72 hours after  
discharge  
 
 
2 weeks after 
discharge 
 
 
 
30 days after  
discharge 
 
 
 
60 days after 
discharge 
 
Total N: 424  
Pre-screen potential participants by inclusion and exclusion criteria 
Conduct informed consent. Perform enrollment assessments 
PC team member call to family 
caregiver 
Intervention  
N = 212 
Dementia-specific palliative care 
(PC) consultation + educational 
booklet + elements of transitional 
Randomize 
PC team member call to family 
caregiver 
CRC conducts 30-day follow-up interview 
CRC conducts 60-day follow-up interview 
CRC conducts post-60 EHR review 
Educational material on ADRD 
caregiving 
Control 
N = 212 

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1.2 SCHEDULE OF ACTIVITIES  
 
 
 
Visit 1: During 
Hospitalization 
Visit 2: During 
Hospitalization 
(Intervention) 
Visit 3: PC Call 72 
hours after discharge 
(Intervention) 
 
Visit 4: PC Call 2 
weeks after discharge 
(Intervention) 
 
Visit 5 CRC interview 
30 days post 
Hospitalization 
 
Visit 6 CRC interview 
60 days post 
hospitalization 
 
CRC EHR Review 
post-60-day 
Hospitalization 
STUDY ENROLLMENT 
ACTIVITIES 
 
 
 
 
 
 
 
EHR Eligibility Screen 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Enrollment Baseline 
Assessment 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Control arm  
X 
 
 
X 
X 
X 
ADRD-PC intervention arm 
X 
X 
X 
X 
X 
X 
X 
DATA COLLECTION 
ACTIVITIES 
 
 
 
 
 
 
 
Hospital / ED transfers 
 
 
 
 
X 
X 
X 
Palliative Care Domain Index 
 
 
 
 
 
 
X 
Symptom Management at 
the End of Life in Dementia 
(SM-EOLD) 
 
 
 
 
X 
X 
 
Neuropsychiatric Inventory 
Questionnaire (NPI-Q) 
 
 
 
 
X 
X 
 
Post-acute use of palliative 
care, hospice 
 
 
 
 
X 
X 
 
New NH transition 
 
 
 
 
 
 
X 
Documented discussion of 
dementia prognosis 
 
 
 
 
 
 
X 
Documented decision-
making for goals of care 
 
 
 
 
 
 
X 
Shared decision-making 
about hospitalization & 
burdensome treatments 
 
 
 
X 
X 
 
Family Distress in Advanced 
Dementia scale 
 
 
 
 
X 
X 
 
Zarit Burden scale 
 
 
 
 
X 
X 
 

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2 
 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
Alzheimer’s disease and related dementias (ADRD) are progressive and incurable.  ADRD 
affects 5.6 million Americans at an annual cost of $157 billion. Approximately 3 million 
Americans are living with late-stage, or moderately severe to advanced dementia. They suffer 
with progressive dependency, loss of awareness of self and family, and escalating physical and 
neuropsychiatric symptoms. ADRD also adversely affects families; caregivers for late-stage 
ADRD experience marked physical, emotional, and financial strain.  
Hospitalizations present a unique opportunity for dementia-specific palliative care, since 72% of 
hospitals have interdisciplinary palliative care teams.  Palliative care improves symptom control 
and quality of life in serious illnesses, but has never been adapted and tested for the unique 
needs of late-stage ADRD. 
We have therefore designed the ADRD Palliative Care (ADRD-PC) program of dementia-
specific palliative and transitional care, and demonstrated its feasibility and potential efficacy.  
We now propose a rigorous multi-site efficacy clinical trial of ADRD-PC. 
2.2 BACKGROUND  
Alzheimer’s disease and related dementias (ADRD) have unprecedented public health impact. 
ADRD affects 5.6 million Americans and their family caregivers; 3 million live with late-stage 
ADRD. The prevalence and incidence of ADRD is increased for under-represented minority 
populations, who are in turn a growing proportion of the US population. Annual dementia care 
costs exceed $157 billion. ADRD contributes to 1 in 3 deaths over age 65, and is the only major 
cause of death with no clinically relevant treatment to prevent, cure or slow disease progression. 
Current care demonstrates unmet needs for palliative care.  People with late-stage ADRD suffer 
progressive dependency and distressing symptoms, and their family caregivers experience 
physical, emotional, and financial strain. Healthcare disparities magnify symptoms and suffering 
associated with late-stage ADRD, and Hispanic / Latino families provide more intensive 
caregiving compared to White Americans. Clinical care is highly fragmented, with frequent 
transitions between home, emergency department, hospital, and nursing facilities. Persons with 
late-stage ADRD become “healthcare nomads,” experiencing frequent burdensome transitions 
between hospitals and home or facility care.   Acute illness hospitalizations for infections, 
injurious falls, or dehydration worsen physical and neuropsychiatric symptoms, and trigger 
decisions about goals of care and intensive treatments. Acute illness hospitalizations are 
burdensome, yet 23-47% are potentially avoidable.  
Palliative care is rare for ADRD, and no major RCT tests dementia-specific palliative care.  
Persons with ADRD and their caregivers have unique palliative care needs that do not match 
standard models of palliative care. Culturally adapted ADRD care is needed, but interventions 
are rarely designed or adapted. Palliative care clinicians lack training in dementia-specific skills, 
and rarely see persons with ADRD.  Our research team completed two pilot trials demonstrating 
feasibility and potential efficacy of the ADRD-PC program. Thus, the necessary next step to 
advance the science of dementia-specific palliative care is an adequately powered efficacy RCT 
of the ADRD-PC program to improve patient and caregiver outcomes. Research responds to the 
National Alzheimer’s Project Act, Alzheimer’s Association guidelines, and NIA priorities for 

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geriatric palliative care (PA-18-502) and research to improve quality of care and quality of life for 
persons with ADRD (PAS-18-030). 
2.3 RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
There are minimal risks associated with participation in this study. All components of the ADRD-
PC program – palliative care consultation, transitional care procedures – have been previously 
established as evidence-based clinical interventions that improve outcomes for other serious 
illness populations. This risk is no greater than a similar risk encountered in all current 
healthcare involving hospital care for persons with late-stage ADRD and the varied treatment 
choices confronting their family caregivers.   
The primary risk to people with ADRD is potential loss of confidentiality, as personal protected 
health information (PHI) will be collected.   
To protect against this risk, all collected data, including PHI, will be defined by the 
research protocol, and limited to research purposes. We will protect confidential medical 
information from EHR reviews by abstracting data directly into a secure database or onto 
coded paper forms separated from personal identifiers. Data will be entered in a password 
protected secure database, and all paper documentation will be maintained in locked files. 
The Sheps Information Technology group enables standard operating procedures required 
to secure the network and databases, including operational and technical controls. All 
servers are located within a hardened data center. Modes of communication between the 
study coordinating center at the University of North Carolina, and between Site-CRC, Site-
PI and hospital attending physicians will be restricted to encrypted e-mail, secure text 
messages, or secure verbal communication to protect confidential health information. 
The primary risk for family caregivers is potential emotional distress related to learning more 
about dementia prognosis and participation in goals of care decisions.  Participation in the 
study, particularly in the intervention group, may draw family members’ attention to ADRD 
as a serious and progressive illness, and ask them to consider the pros and cons of 
different treatment options. This risk is no greater than a similar risk encountered in all 
current healthcare involving hospital care for persons with late-stage ADRD and the varied 
treatment choices confronting their family caregivers. However, given the vulnerable 
characteristics of persons with ADRD and the level of strain documented for ADRD 
caregivers, training of site-based research staff and investigators will explicitly address this 
potential risk. 
To protect against emotional distress for the family caregiver, we will inform them of their 
right to skip interview items, pause during participation, or withdraw from the study at any 
time. During the course of data collection, the CRC may identify clinical concerns or 
extreme emotional distress expressed by the family caregivers. The Principal 
Investigator, Site-PI or other senior investigator will be available to provide timely 
guidance for response to these concerns.  
All CRCs will be trained to notify Site-PIs for any caregiver who expresses extreme 
emotional distress in response to study participation activities such as consent or 
interview items, or scores > 4.1 points average / 37 points summed score (one standard 
deviation above the mean) on the Emotional Distress Subscale of the Family Distress in 
Advanced Dementia scale. The instrument has construct validity established with 
correlation to depression scoring instruments. CRCs will follow-up with caregivers with a 
script asking about their access to current emotional support, and desire for additional 
access to mental health resources. If the caregiver expresses need for additional mental 

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health resources, the CRC will contact the Site-PI, who will assist the CRC in exploring 
level of need and identification of appropriate referral resources, which may include the 
family caregiver’s primary care provider, the current hospital attending physician and 
social worker, or local mental health services.  
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Potential individual benefits:  Study participants in the intervention arm may benefit from the 
palliative care and transitional care services provided in ADRD-PC. Participants in both arms 
will report on their lived experience during study interviews and will receive high quality 
educational material on dementia caregiving.  Thus, all participants may benefit from the 
increased opportunity to communicate about the experience of family caregiving for people with 
late-stage ADRD, and from educational materials provided.  
Potential societal benefits: This study is the first RCT of a hospital-based dementia-specific 
palliative and transitional care intervention.  For people with late-stage ADRD and their 
caregivers, there is an urgent need to improve outcomes of burdensome hospital transfers, 
symptom distress, shared decision-making, and caregiver distress.  The study is responsive to 
the National Alzheimer’s Project Act call for enhancements in quality of care for people with 
ADRD and their caregivers, and to NIA / NIH research priorities.  Thus, potential benefits 
include enhanced understanding of interventions to improve the quality of palliative care and 
outcomes for people with late-stage dementia and their caregivers.  If efficacious, ADRD-PC 
has potential to reduce suffering for millions of people living with ADRD and their caregivers.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The benefit to risk ratio is highly favorable in this study.  First, the ADRD-PC intervention has 
low risk of harms, as it is composed of evidence-based and minimal-risk interventions which are 
shown to improve outcomes for other serious illness populations. Second, there are significant 
potential benefits to participants in both study arms.   
 
3 
OBJECTIVES AND ENDPOINT / OUTCOMES  
  
OBJECTIVES 
ENDPOINT / OUTCOMES 
JUSTIFICATION  
Primary 
 
 
To conduct a multi-site RCT 
of the ADRD Palliative Care 
(ADRD-PC) program of 
dementia-specific palliative 
and transitional care 
(intervention arm) vs publicly 
available educational 
material for dementia 
caregivers (control arm) to 
compare 60-day hospital 
transfers (hospitalization and 
Number of emergency room 
visits + hospital admissions 
within 60 days after discharge 
from index hospitalization  
 
Hospital transfers are common for 
persons with late-stage ADRD, and are 
burdensome and stressful for the 
person and their family caregivers.  
Evidence shows that some hospital 
transfers are avoidable because acute 
illness can be treated in lower intensity 
settings, OR because goals of care are 
more comfort-focused. 
 

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4 
STUDY DESIGN 
 
4.1 OVERALL DESIGN 
Study design is an RCT conforming to SPIRIT and CONSORT statements for trial methods and 
protocol.  Our approach uses NIA standards for a multi-site efficacy trial (Stage II) of a 
protocolized behavioral intervention, while incorporating pragmatic features to support 
sustainability and future dissemination. We will use 1:1 randomization of patient-caregiver dyads 
with concealed allocation until study assignment.  Research will occur at 5 geographically 
diverse sites of the Palliative Care Research Cooperative (PCRC) network, with study 
leadership and centralized IRB at UNC. Sites will enroll N=424 dyads of hospitalized patients 
with late-stage ADRD (GDS 6-7 or GDS 5 with significant co-morbidity) with their family 
caregivers. Sites will additionally enroll N=50 dyads that identify as Hispanic/Latino. Intervention 
dyads will receive the ADRD-PC program of i) dementia-specific palliative care, ii) standardized 
caregiver education, and iii) transitional care. Control dyads will receive publicly available 
educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) 
and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as 
visits to an emergency department or hospitalization (Aim 1). Secondary patient-centered 
outcomes will be symptom treatment, symptom control, use of community palliative care or 
hospice, and new nursing home transitions (Aim 2). Secondary caregiver-centered outcomes 
will be communication about prognosis and goals of care, shared decision-making about 
hospitalization and other treatments, and caregiver distress (Aim 3). The Principal Investigator 
OBJECTIVES 
ENDPOINT / OUTCOMES 
JUSTIFICATION  
emergency room visits) for 
persons with late-stage ADRD 
(primary outcome). 
Secondary 
 
 
To compare patient-centered 
secondary outcomes 
between intervention and 
control arms 
a) Palliative Care Domain Index  
b)  Symptom Management at 
End of Life in Dementia 
c) Neuropsychiatric Inventory 
Questionnaire 
d)  Post-acute use of palliative 
care, hospice 
e) NH transitions 
 
Physical and neuropsychiatric symptom 
distress is common in late-stage ADRD, 
and worsens toward death.  Post-acute 
access to palliative services can 
improve outcomes, while new nursing 
home transitions may be avoidable 
with added community-based services 
and supports. 
To compare caregiver-
centered secondary 
outcomes between 
intervention and control 
arms 
 
a) documented communication 
about prognosis  
 and goal of care 
b) shared-decision making about 
hospitalization and other major 
treatment decisions  
c)  Family Distress in Advanced 
Dementia scale 
d) Zarit Burden scale 
Family caregivers serve as surrogate 
decision-makers in late-stage ADRD.  
They experience poor quality 
communication in usual care.  In 
addition, caregivers experience 
significant emotional strain relative to 
caregiving role.   

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and outcome assessors will be masked; as in most behavioral interventions clinicians and 
participants cannot be masked to study arm.  Analyses will use intention-to-treat, and pre-
specified exploratory analyses will examine effects of sex as a biologic variable, race / ethnicity, 
and GDS stage.   
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We conducted a pilot RCT, randomizing 62 dyads of hospitalized patients with GDS 5-7 ADRD 
and their family caregivers to the ADRD-PC program vs usual care with publicly available 
education material. While underpowered to show a difference in 60-day hospital transfers, we 
found marked differences in intermediate outcomes. Intervention dyads were more likely to have 
an active POLST advance directive (79% vs 30%, p<0.001) and to make a decision to avoid 
future hospitalization (13% vs 0%, p=0.033). With ADRD-PC, persons with late-stage ADRD 
had more palliative care domains addressed in their treatment plan (Palliative Care Domain 
index score 7.6 vs 2.7, p<0.001, range 0-10), and symptom management for dyspnea (77% vs 
34%, p<0.001), constipation (93% vs 25%, p<0.001), depression (83% vs 25%, p<0.001) and 
delirium (80% vs 19%, p<0.001). Caregivers were more likely to discuss prognosis (90% vs 3%, 
p<0.001) and goals of care (90% vs 25%, p<0.001).  Intervention dyads also increased use of 
post-discharge palliative care (21% vs 7%, p=0.124) and hospice (25% vs 3%, p<0.019). 
Results indicate the potential for ADRD-PC to improve patient and caregiver-centered 
outcomes, including hospital transfers. 
4.3 JUSTIFICATION FOR INTERVENTION 
 
Our preliminary studies justify the proposed RCT. First, we have created novel and effective 
methods to find and recruit dyads in hospital.  Second, ADRD-PC is feasible and acceptable to 
people with ADRD, caregivers and clinicians. Third, palliative care clinicians deliver the ADRD-
PC program with high fidelity, ranging from 77% (two follow-up calls) to 93% (dementia-specific 
palliative care, standardized education).  Fourth, we used best practices to optimize enrollment 
and retention. Fifth, pilot data support relevance of ADRD-PC to persons with GDS 5-7, as in 
our pilot trial all stages enrolled equally, had similar death rate, and all 60-day hospital transfers 
affected GDS 5-6. Sixth, results show ADRD-PC improves intermediate outcomes strongly 
linked to hospital transfers. Thus, the necessary next step to advance the science of dementia-
specific palliative care is an adequately powered RCT of the ADRD-PC program to test efficacy 
to improve patient and caregiver centered outcomes. 
4.4 END-OF-STUDY DEFINITION 
 
The end of the study is defined as completion of the 60-day EHR chart review for all dyads.  
5 
STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Target enrollment is N=424 dyads of people with late-stage dementia and their family caregiver, 
and N=50 dyads that identify as Hispanic/Latino. 
People with ADRD will be eligible if they are: (1) aged 55 or older, (2) hospitalized, (3) have a 
physician-confirmed diagnosis of ADRD, and (4) staged GDS 6 or 7; or GDS 5 with additional 

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co-morbidity defined by Charlson Comorbidity Index scored 5 or higher.  As in the pilot, ADRD 
stage will be confirmed by the attending physician and caregiver. 
Caregivers will be eligible if they are: (1) the adult (aged 18 or older) legally authorized 
representative (LAR) for healthcare and have capacity to serve in this role, (2) support the 
person with ADRD, and (3) can complete interviews in English or Spanish.  As in our prior 
ADRD research, other family caregivers may be present per primary caregiver request, but only 
the primary caregiver is a participant. 
5.2 
EXCLUSION CRITERIA 
Dyads will be excluded if (1) the LAR is not a family caregiver, (2) the patient currently receives 
palliative care or hospice, (3) patient or caregiver would be unduly stressed, or (4) dyad is not 
successfully randomized.   
5.3 STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment and retention of seriously ill patients with stressed caregivers is challenging, and 
can threaten validity. We will train all sites in the Palliative Care Research Collaborative best 
practices to assure compliance with research ethics standards, complete and timely case-
finding, compassionate approach and messaging, and flexibility to accommodate caregivers. 
Participant screening: Site-CRCs will use an EHR algorithm for rapid case-finding.  This 
method, developed during the pilot research, generates daily automated EHR lists of 
newly hospitalized patients with ADRD. Site-CRCs will conduct brief chart reviews under a 
HIPAA waiver to confirm eligibility criteria and forward patients with probable late-stage 
ADRD to the Site-PI for review. After brief EHR reviews by Site-CRCs and Site-PIs to 
confirm eligibility, Site-PIs will contact the inpatient attending physicians.  They will confirm 
GDS stage as 5 ,6 or 7, and seek permission to approach caregivers.  
Recruitment and informed consent:  Recruitment will utilize diverse communication 
approaches with family caregivers; these approaches are identical to clinical 
communication used with family caregivers for people with dementia who lack decisional 
capacity. Since family caregivers may be present in hospital, or may be barred from 
visitation due to COVID-19 restrictions and safety concerns, or may live at a great distance 
from the hospital, recruitment and enrollment procedures will include both in-person and 
telephone / virtual communication methods. Further, flexibility of communication is essential 
for the enrollment of the project number of participants, because study enrollment and 
participation in the ADRD-PC intervention must both occur during acute illness 
hospitalization. 
Site-CRCs will introduce the study to eligible family caregivers using scripted telephone 
calls or in-person visits. When the Site-CRC conducts recruitment and enrollment via 
telephone, the Site-CRC will ask if the individual is in a private location, and feels 
comfortable talking about the study at that time; they will schedule an alternative time if 
necessary. The Site-CRC will explain the study over the phone using a telephone script. 
Spanish-speaking CRCs will introduce and explain the study to any Spanish-speaking 
participants using translated recruitment scripts and study materials.  
If the family caregiver is interested and wants to participate, the Site-CRC will conduct the 
informed consent with them verbally in person or over the phone. If the family caregiver 
agrees to consent, study informational materials and the informed consent form will be 
sent to them by mail or secure e-mail.  

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Due to the low risk of study participation and the restrictions on immediate written 
consent described above, verbal consent will be accepted for participation in the 
enrollment caregiver interview, and for randomization with initiation of the ADRD-PC or 
control conditions.  
Site-CRCs will introduce the study in scripted introductory phone calls or in-person visits. 
After informed consent, the caregiver will complete the enrollment interview.  
Retention:  Retention is supported first and foremost by respectful, flexible, and compassionate 
interpersonal encounters with site-based research staff which will be consistently emphasized in 
training and coaching communication.  Secondly, retention is supported by setting appointments 
for follow-up interviews with recognizable Site-CRC names and contact information. Third, 
retention is supported by obtaining multiple contact information for family caregivers.  And 
fourth, retention is promoted by small payments for completion of study visits.  Family 
caregivers will receive a $25 gift card for completing each of the three interviews (enrollment, 
30-day, and 60-day follow-up), for a total of $75.  
6 
STUDY INTERVENTION AND CONTROL CONDITIONS 
 
6.1 
STUDY INTERVENTION 
Intervention Condition: Patient-caregiver dyads randomized to the intervention will receive the 
ADRD-PC program, described below and in Table 1.  
 
Delivering the ADRD-PC Program  
Elements 
Content 
Method of Delivery 
Dementia-specific 
Palliative Care 
1) Prognosis – exploration and 
communication of stage, trajectory and 
prognostic awareness 
2) Symptoms – assessment and 
treatment for physical and 
neuropsychiatric symptoms 
3) Shared decision-making – exploration 
of values and goals of care; discussion 
of treatment decisions 
4) Transitional care – assessment of 
needs, care planning and 
recommendation for support services 
* Interdisciplinary 
palliative care clinicians 
meet with the person 
with ADRD and family 
caregiver. 
* ADRD-PC Note 
Template used to record 
encounters addressing 
these 4 domains 
Standardized 
Caregiver Education 
1) Dementia and its stages 
2) Determining the primary goal of care 
3) Approach to decision-making 
4) Approach to eating problems 
5) Approach to decisions about 
hospitalization 
6) Approach to decisions for infections 
7) How dementia affects the family 
8) What is hospice and palliative care? 
* Clinicians share 
booklet Advanced 
Dementia:  A Guide for 
Families and 
individualize content 
during counseling for 
prognostic awareness 
and decision-making 
Transitional Care 
1) Palliative Care Plan – written summary 
of dementia stage and prognosis, 
recommendations for symptom 
* Palliative Care Plan 
addressing 4 domains 
provided to the 

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treatment, goals of care and treatment 
decisions, and for support services. 
2) New referrals to support services – 
examples include community palliative 
care, hospice, home health, geriatric 
clinic, dementia clinic, caregiver 
support group, adult day care, support 
group. 
3) Contact information for the palliative 
care team 
outpatient clinician AND 
caregiver 
* Referrals to 
community support 
services 
* Post-discharge 
supportive calls at 72 
hours and 2 weeks 
  
1) Dementia-specific palliative care will be delivered by hospital-based specialty 
interdisciplinary palliative care teams. Encounters will include a physician or advanced 
practice provider and at least one additional discipline (nurse, social worker, chaplain). Visits 
will continue until hospital discharge, and will be documented in the EHR with the ADRD-PC 
Note Template.Palliative care clinicians will address four domains. First, the palliative care 
team will promote caregivers’ prognostic understanding of dementia stage and its 
trajectory, contextualizing the acute illness with information about ADRD.  Second, the 
palliative care team will conduct ADRD-specific symptom management of pain, other 
physical and neuropsychiatric symptoms, and recommend treatment consistent with best 
practices for ADRD.  Third, the palliative care team will facilitate shared decision-making 
with the caregiver.  Discussions may include exploration of overall goals of care, and 
decision-making about potentially burdensome treatments of resuscitation, ventilator use, 
feeding tubes, antibiotics, or future hospitalizations.  When clinically appropriate, 
consultation will also include completion of new advance directives such as a Physician 
Orders for Life Sustaining Treatment (POLST) or comparable portable order set to 
document decisions for current care plans. POLST or similar documentation is in all study 
states and enhances treatment matched to patient preferences across healthcare 
transitions. Fourth, the palliative care team will assess transitional care needs for 
community support services.  They will support dyads with post-discharge follow-up calls 
and referral to community services. (see Transitional care).    
 
2) Standardized caregiver education will be provided by the palliative care team. Clinicians will 
share and discuss the booklet Advanced Dementia:  A Guide for Families, which addresses 
common concerns and treatment decisions. Clinicians will individualize its content, 
highlighting key content and providing counseling about its relevance for current or future 
caregiving and treatment decision-making. 
 
3) Transitional care will be provided by the palliative care team. Pre-discharge, the palliative 
care team will explore adequacy of patient and caregiver support for practical, 
emotional and spiritual needs.  Based on needs, they will recommend community-based 
support services.  Examples could include community palliative care, hospice, home 
health, specialty geriatric or dementia clinics, adult day care or Alzheimer caregiver support 
groups.  Near discharge, a member of the palliative care team will create a templated 
Palliative Care Plan and provide copies to the primary or post-acute care provider (PACP)  
AND the family caregiver. This document will summarize recommendations in the four 
domains and provide contact information for the palliative care team for follow-up questions. 
Post-discharge, a designated palliative care team member – usually a social worker or nurse 
coordinator – will call the family caregiver within 72 hours and again within 2 weeks after 
discharge. These calls may also be facilitated by a site CRC. The purpose of these calls will 
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supportive services. Calls will also be used to solicit concerns, offer emotional support, and 
make recommendations to help the caregiver overcome barriers to services. 
 
Control condition: Patient-family caregiver dyads randomized to the control arm will receive 
educational materials from the Alzheimer’s Association, specifically designed for late-stage 
ADRD caregivers. The patient will receive usual hospital and post-acute care. 
6.1.1 ADMINISTRATION AND/OR DOSING 
N/A 
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
Ensuring fidelity to the ADRD-PC will be the responsibility of all site-based investigators.  Our 
approach is based on NIH Behavior Change Consortium standards, with elements relevant to 
study design, interventionist training and standard operating procedures, and tools to support 
delivery of the ADRD-PC intervention. 
Types of 
Fidelity 
Procedures to Ensure Fidelity 
Fidelity Monitoring  
Study 
Design 
• 
Intervention based on a well-
defined protocol 
• 
Standardized tools and templates  
• 
Protocol review and version 
control supported by Palliative 
Care Research Cooperative group 
Standardized 
Training and 
Delivery 
• 
Training of Site-PIs on study 
protocol and SOPs 
• 
Training of Site-CRCs on study 
protocol and SOPs 
• 
Training of PC clinicians to deliver 
ADRD-PC 
• 
Audio-recorded training modules 
for consistent re-training or for new 
personnel 
• 
ADRD-tools and templates 
• 
Training material review by 
Palliative Care Research 
Cooperative group 
• 
Completed training  
• 
Post-training evaluation for PC 
clinicians (threshold score 80%)  
• 
Delivery of tools and templates to 
all study sites 
ADRD-PC 
Intervention 
Enactment  
• 
Monthly conference calls (led by 
Dr. Hanson) with site PC clinicians 
• 
Monthly conference calls (led by 
UNC Project Manager) with site 
CRCs and site PIs=Utilization of 
ADRD-PC Program with 
standardized content areas 
• 
Documentation of clinical 
encounters in site medical record  
• 
Site-CRC tracking of completion 
of 4 ADRD-PC components:  a) 
PC encounter, b) caregiver 
education, c) delivery of PC Plan 
to caregiver and primary or post-
acute care provider (PACP) , and 
d) completion of 2 transitional 
care calls. 
• 
Threshold score 80% of dyads 
with completion of 4 ADRD-PC 
components. 
• 
Site specific feedback when 
fidelity drops below threshold. 
• 
Review 10% random of 
deidentified ADRD-PC encounter 
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scored for quality of content 
across 4 clinical domains  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND MASKING 
Randomization will occur following the enrollment interview, with the dyad as the unit of 
randomization and analysis. Allocation will be concealed prior to randomization.  Randomization 
will be generated within REDCap software, and transmitted by the Site-CRC to the PC team to 
initiate ADRD-PC (intervention) or to deliver dementia caregiver educational material (control).   
 
CRCs who collect outcome data will be masked to study arm in family caregiver interviews. 
Since the EHR will have ADRD-PC palliative care encounters, Site-CRCs will complete follow-
up EHR reviews only after 60-day follow-up interviews. Dr. Hanson (PI) will remain masked to 
study arm assignments to minimize bias in study procedures and analysis.    
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
Due to the low risk of harm to study participants anticipated for this intervention, no interim 
analyses for efficacy or a priori stopping rules are planned.  During the first DSMB meeting, in 
coordination with the NIA Program Official, the DSMB members will be asked to consider and 
recommend possible a priori stopping rules, if any, based on adverse event reporting. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Significant study intervention non-adherence  
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of 
follow-up study data would not be in the best interest of the participant  
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and are randomized 
but do not initiate either the intervention or control procedures may be replaced.   
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to be reached for follow-up 
surveys and study staff are unable to contact the participant after at least 5 attempts.  
8 
STUDY ASSESSMENTS AND PROCEDURES 

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8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
Data collection will be identical for both arms. Data will be obtained from caregiver 
enrollment interviews and 30- and 60-day interviews post-discharge, and from electronic 
health record (EHR) reviews encompassing the 60-day period post-hospitalization.  Based 
on the pilot RCT, we estimate 10% of persons with late-stage ADRD will die during follow-
up; caregiver interview data collection will proceed using a Bereavement Interview 
adaptation. Outcome measures will focus on 60-day interviews; 30-day interim interviews 
are necessary to support retention, ensure data capture for persons with ADRD who die, 
and for valid recall of hospital transfers (primary outcome) and secondary outcomes.  
Family Caregiver Interviews: 
1. Emergency room visits + hospital admissions after discharge from index hospitalization  
2. Use of hospice or community palliative care services 
3. Patient symptom distress 
a. Instrument: Symptom Management at the End of Life in Dementia (SM-EOLD) 
b. Instrument: Neuropsychiatric Inventory Questionnaire (NPI-Q) 
4. Shared decision-making about hospitalization 
5. Shared decision-making about other burdensome treatments 
6. Caregiver distress 
a. Instrument: Family Distress in Advanced Dementia Scale 
b. Zarit Burden scale, short form 
 
Electronic Health Record Review: 
1. Symptom assessment and management plans during hospitalization- 
a. Palliative Care Domain Index Items  
2. Documented discussion of dementia prognosis 
3. Documented discussion decision-making for goals of care  
4. New nursing home transfers 
5. Return to acute care – ED or Hospital readmissions within 60 days and up to 3 reasons 
for return 
 
 
8.2 
SAFETY ASSESSMENTS 
The Principal Investigator and research team will comply with the University of North Carolina 
Office of Human Research Ethics (OHRE) requirements and consistent with DHHS 45 CFR part 
46 and NIA guidelines for defining, collecting and reporting any unanticipated problems, adverse 
events or serious adverse events during the conduct of research. 
This study uses a single IRB (University of North Carolina-Chapel Hill) to conduct ethical review 
required for the protection of human subjects.  The study is a multi-site clinical trial, and the 
participating sites will utilize a single protocol and have agreed to the single IRB oversight 
structure. 
All study procedures, informed consent forms, and recruitment procedures will undergo review 
by the Institutional Review Board at the University of North Carolina-Chapel Hill prior to initiating 
research, and will be subject to annual and other required reviews. Enrolled participants will be 
dyads of persons with late-stage ADRD and their family caregivers; caregivers will provide 
written informed consent for dyad participation.  Investigators will work with NIA to convene a 

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Data Safety and Monitoring Board to oversee the human subjects’ safety and adverse event 
reporting for this multi-site clinical trial. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
Adverse events (AE) are defined as 
• 
Any untoward or unfavorable medical occurrence in a human study participant, including 
any abnormal sign (e.g. abnormal exam or laboratory finding), symptom or disease 
temporally associated with the participants’ involvement in the research, whether or not 
considered related to participation in the research. 
• 
In the ADRD-PC study tracked AEs will include major emotional distress for family 
caregivers, and confidentiality risk events for the person with ADRD. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
Serious adverse events (SAE) are defined as 
• 
Death 
• 
Life-threatening health events 
• 
Acute illness causing hospitalization 
• 
Health event causing persistent new disability or incapacity, or 
• 
Similar significant hazardous events 
• 
In the ADRD-PC study these events will be tracked for all participants.  These events are 
expected health outcomes for people with ADRD and may also occur for family 
caregivers.  SAEs will be included in study data collection but will not be included in AE 
reporting; see explanation below. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs), the following guidelines will be used to describe severity.  
 
• 
Mild – limited in intensity and duration, without sustained effect on participant 
• 
Moderate – limited in intensity or in duration, with some sustained effect on participant 
• 
Severe – significant intensity and duration of event, with significant sustained effect on 
participant 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All adverse events (AEs) will have their relationship to study procedures, including the 
intervention, assessed by an appropriately-trained clinician based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below.  
 

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• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study procedures 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study procedures should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study procedures, 
is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of study procedures). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study procedures administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study procedures) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study procedures administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.] 
8.3.3.3 EXPECTEDNESS  
An investigator team member with expertise in advanced dementia and palliative care will be 
responsible for determining whether an adverse event (AE) is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study procedures. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. Any medical or psychiatric condition that is 
present at the time that the participant is enrolled will be considered as baseline and not 
reported as an AE.  
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case 
report form (CRF). All AEs occurring while on study will be documented appropriately regardless 
of relationship. At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 
8.3.5 ADVERSE EVENT REPORTING  
Adverse event reporting will be refined with input from the DSMB during its initial meeting, to 
address any specific concerns related to this study protocol. 

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Site-based PIs will report any Unanticipated Problem Involving Risk to Subjects or Others 
(UPIRSO)s or AEs to the overall PI and Project Manager in a timely manner.   
When a UPIRSO or AE is present, the overall PI and Project Manager will submit a report to the 
UNC IRB within 3 working days of receipt of this information.  Generally, the report should 
contain the following: 
• 
Detailed information about the event or issue, including relevant dates. The report 
should identify the affected subjects by their study codes and not by their names or other 
personal identifiers.  
• 
An assessment of whether any subjects or others were placed at risk or suffered any 
harm (e.g., physical, social, financial, legal or psychological) as a result of the event.  
• 
If the event involves noncompliance, describe the result of the root cause analysis.  
• 
Any corrective and preventative actions, planned or already taken.  
• 
Any other information requested by OHRE, if applicable.  
• 
If the report cannot be completed in its entirety within the required time period, the report 
should describe what information is still needed and when the investigator anticipates 
that a follow-up report will be submitted. 
 
Information previously unknown to the IRB that suggests new or increased risk to subjects or 
others (hereinafter referred to as New Safety Information) is promptly reportable to OHRE within 
7 calendar days of the investigator becoming aware of the information.  
• 
Information for which the sponsor requires reporting to the IRB, may be summarized and 
submitted to the IRB at continuing review.  
• 
Protocol deviations that did not harm subject(s) or others or place subject(s) or others at 
increased risk must be summarized and reported to the IRB at continuing review.  
• 
Researchers may consult with the OHRE Compliance Manager if they are uncertain 
about what information is reportable. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The reporting of any AE / SAE will be based on NIA and UNC IRB standards, on the severity of 
the AE, its level of attribution to the intervention, and whether or not it is anticipated.   
• 
All adverse events that are both serious (SAE) and unexpected would be reported to 
IRB, DSMB / SO, and NIA PO within 48 hours of the study's knowledge of SAE.   
• 
Summary of SAEs would be reported to NIA PO and to the DSMB / PO quarterly, 
unless otherwise requested by the DSMB or a Safety Officer.  
• 
Summary of all AEs regardless of classification would be presented for each DSMB 
meeting at 6-month intervals 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems as defined by the UNC Office of 
Human Research Ethics (OHRE). 
Unanticipated Problems are defined as  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
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Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized 
• 
UPIRSO - Unanticipated Problem Involving Risk to Subjects or Others is any incident, 
experience, or outcome that: 
o is unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied;  
o is related or possibly related to a participant’s participation in the research; and  
o is serious or suggests that the research places participants or others at a greater 
risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
Aim 1: To conduct a multi-site RCT of the ADRD-PC program (intervention arm) vs publicly 
available educational material for dementia caregivers (control arm) to compare 60-day 
hospital transfers (hospitalization and emergency room visits) for persons with late-stage ADRD 
(primary outcome). H1: 60-day hospital transfers will be lower in the intervention vs. control 
arm.  
Aim 2: To compare patient-centered secondary outcomes between intervention and control 
arms: a) symptom treatment (Palliative Care Domain index); b) symptom control (Symptom 
Management at the End of Life in Dementia scale, Neuropsychiatric Inventory Questionnaire); c) 
post-acute use of community palliative care or hospice; and d) new nursing home transitions. 
Patients in intervention vs. control arms will have better symptom treatment (H2a) and symptom 
control (H2b); increased use of community palliative care or hospice (H2c); and fewer new 
nursing home transitions at 60 days post-discharge (H2d). 
Aim 3: To compare caregiver-centered secondary outcomes between intervention and control 
arms:  a) communication about prognosis and goals of care; b) shared decision-making; and c) 
caregiver distress (Family Distress in Advanced Dementia scale and Zarit scale). Caregivers in 
intervention vs control arms will more often have documented communication about prognosis 
and goals of care (H3a); report more shared decision-making about hospitalization and 
treatments (H3b); and report less caregiver distress at 60-days post-discharge (H3c). 
9.2 
SAMPLE SIZE DETERMINATION 
 
Based on prior ADRD research, we project 15% dropouts (death, withdrawal) equally distributed 
between groups; caregiver data collection is completed after deaths as in our prior ADRD 

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research. Total sample size for analysis of 60-day follow-up outcomes is thus n=360. All 
statistical tests will be 2-tailed with an overall 0.05 significance level for pre-specified analyses. 
Statistical power is based on a 2-sided alpha of 0.05 significant tests and using standard 
deviation estimates from our pilot study (Table 3).  
 
Power calculations assume a “best guess” 15% dropout (death, withdrawal) rate based on prior 
ADRD research (n=180 per group at 60-day follow-up) and a “worst case” 25% dropout rate 
(n=159 per group). These rates consider 9% patient mortality and 92% caregiver retention rate 
in the pilot. In our pilot data, 0.52 is the lower bound of the 95% CI for the IRR comparing   
Table 3:  Power for Comparing Intervention and Control Arms Based upon the Study 
Design  
  
Aim  
Measure  
Control  
SD  
Difference  
Power, 15% 
dropout  
Power, 25% 
dropout  
1  
60-day hospital transfers 
(Poisson rate)  
0.53  
--  
0.25, 0.2  
0.96, 0.82  
0.95, 0.79  
60-day hospital transfers (overdispersed)  
0.53  
--  
0.25, 0.2  
0.81, 0.60  
0.76, 0.55  
2a  
PC Domain Index (0-10)  
2.7  
1.7  
5, 0.5  
>0.99, 0.80  
>0.99, 0.75  
2b  
60-day hospice use (%)  
3%  
--  
22%,8%  
>0.99, 0.85  
>0.99,0.80  
2c  
Symptom distress (SM-EOLD)  
36.4  
7.8  
4, 2.3  
>0.99, 0.80  
>0.99, 0.75  
2d  Transition to nursing home care (%)  
33%  
--  
30%,15%  
>0.99, 0.82  
>0.99, 0.78  
3a  
Discussion of dementia prognosis  
3%  
--  
87%, 8%  
>0.99, 0.85  
>0.99, 0.80  
3a  
Discussion of goals of care (%)  
25%  
--  
65%,14%  
>0.99, 0.82  
>0.99, 0.77  
3b  
Decision-making about 
hospitalization  
0%  
--  
13%, 4%  
>0.99, 0.78  
>0.99, 0.73  
3b  
Decision-making about treatments  
6%  
--  
47%, 9%  
>0.99, 0.80  
>0.99, 0.75  
3c  
Family Distress in Advanced 
Dementia   
2.4  
0.5  
0.15, 0.1   
0.81, 0.47  
0.76, 0.43  
 
Administrative Supplement Power Estimation:  
Given the early-stage nature of the proposed supplementary research, we do not anticipate adequate 
power to detect clinically meaningful differences for our primary and several secondary outcomes for 
Hispanic / Latino dyads alone. However, it is possible to detect promising trends in some secondary 
outcomes that had a large effect size in our pilot study.  
We anticipate using this supplementary grant to collect the pilot data for effectiveness of our intervention 
in the key outcomes of our interest in this particular population. 
9.3 
POPULATIONS FOR ANALYSES 
 
N/A 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 
Analysis: Descriptive analyses of variables will examine distributions, influential data points, 
and missing data. Means (standard deviations) will be reported for continuous variables and 
frequencies (percentages) for categorical variables. Continuous variables (e.g., PC Domain 
Index, etc) that are poorly distributed may be transformed or analyzed using non-parametric 

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tests. We anticipate missing data on independent variables will be minimal. We will use simple 
mean and mode imputation for those variables included in regression models if less than 5% of 
patients have missing data; else, conditional (i.e., regression) imputation will be used. Available 
case analysis will be conducted for 30-day outcomes. Missing 60-day dichotomous outcomes 
will be multiply imputed if missingness exceeds 10%. Caregiver data collection is completed 
after deaths as in our prior ADRD research. Primary analysis will use intention-to-treat 
analysis. We will evaluate the effectiveness of randomization by comparing intervention and 
control participants on baseline measures. Variables that are not equally distributed 
between arms could potentially bias results. We will include these variables in each initial model 
and use a change-in-effect method for determining whether they are confounders. If removing 
any of these variables from the model does not appreciably change the regression 
coefficient estimate of the intervention group variable, we will not need to include them in the 
final model. Given our randomized design, we anticipate little confounding. A priori exploratory 
analyses will examine effects by sex as a biological variable, race / ethnicity, and GDS stage.  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Aim 1: To conduct a multi-site RCT of the ADRD-PC program of dementia-specific palliative 
and transitional care (intervention arm) vs publicly available educational material for dementia 
caregivers (control arm) to compare 60-day hospital transfers (hospitalization and emergency 
room visits) for persons with late-stage ADRD (primary outcome).   
Analysis to Meet Aim 1: We will compare control and intervention arms on hospital transfers 
(primary outcome) during 60 days post-discharge. This count outcome is defined as the total 
number of emergency room visits plus hospital admissions per at-risk patient-days. We will 
use Poisson regression with empirical ‘robust’ standard errors allowing for overdispersion to 
compare the transfer rates between groups. We will use the length of follow-up as the offset 
variable, which means that patients who have data only from the 30-day interview will be 
included. The primary analysis will be based on the model with main effects for treatment group, 
study site, GDS Stage and patient and caregiver sex as biological variables. Evaluation of the 
treatment effect will be based on a Wald test. The covariate-adjusted treatment effect will be 
quantified as an incidence rate ratio (IRR) with a 95% confidence interval. Considering that over 
60% of patients in the pilot study did not have any hospital transfers, we will conduct 
a sensitivity analysis for the treatment effect on 60-day hospital transfers with a marginalized 
zero-inflated Poisson (MZIP) model, which may modestly increase power.  Secondary Poisson 
and MZIP analyses will compare study arms for 30-day hospital transfer rates. An exploratory 
analysis will be conducted to examine interactions of treatment group with study site, sex, race / 
ethnicity and GDS Stage, respectively, on 60-day hospital transfers. While the proposed study is 
powered to detect whether or not ADRD-PC is effective, a much larger study would be needed 
to have adequate power to detect differences by sex or GDS Stage and would be justifiable only 
after the completion of this initial trial. An interaction model will be used if an omnibus test for 
interactions is statistically significant at the 0.05 level. A second exploratory 
analysis will evaluate a dose-response effect of the intervention on the hospital 
transfer rate. A dose for patients receiving the intervention is defined as the number of 
key intervention components used in fidelity monitoring (range 0 to 4 with 0 for controls). The 
dose effect is the incremental benefit of adding a single component; its rescaling gives the per-
protocol effect of the full intervention.   
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 

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Aim 2: To compare patient-centered secondary outcomes between intervention and control 
arms: a) symptom treatment (Palliative Care Domain index); b) symptom control (Symptom 
Management at the End of Life in Dementia scale, Neuropsychiatric Inventory Questionnaire); c) 
post-acute use of palliative care or hospice; and d) transition to nursing home care.  
Analysis to Meet Aim 2: We will compare study arms during 60 days post-discharge on the 
following outcomes:    
2.a. Symptom treatment: This ordinal outcome is the summation of presence (=1) or 
absence (=0) of 10 domains of palliative care. We will treat it as a continuous variable due to a 
high variation observed in the pilot data. We will use Student’s t-test to compare the mean 
difference between study arms unless violation of assumptions warrants the Mann-Whitney test. 
We will use a multiple linear regression model with main effects for treatment group, study site, 
GDS Stage and patient and caregiver sex as a biological variable.   
2.b. Symptom control:  We will use Symptom Management (SM-EOLD) scale to 
measure caregiver report of patients’ uncontrolled symptom distress and Neuropsychiatric 
Inventory Questionnaire (NPI-Q) to measure caregiver report of patients’ neuropsychiatric 
symptom distress. Linear mixed models with random intercepts for patients will be used with 
a time indicator (30 vs 60 days follow-up) with the above main effects.  
2.c. Use of post-acute palliative care or hospice: This outcome will be defined by 
whether patients ever use hospice or outpatient palliative care during the time from discharge to 
60 days follow-up. We will compare the proportions using Pearson’s chi-square test. Logistic 
regression will be used for multivariable modeling with the same main effects as in Aim 2.a. 
Final estimates will be reported as covariate-adjusted odds ratios.   
2.d. Transition to nursing home care: This outcome will be defined by whether 
patients transition to nursing home care during the time from discharge to 60 days follow-up. We 
will compare proportions using Pearson’s chi-square test. Logistic regression will be used for 
multivariable modeling with the same main effects as in Aim 1. Final estimates will be 
reported as covariate-adjusted odds ratios.  
Aim 3: To compare caregiver-centered secondary outcomes between intervention and control 
arms:  a) communication about prognosis and goals of care; b) shared decision-making; and c) 
caregiver distress (Family Distress in Advanced Dementia scale, Zarit Burden interview).  
Analysis to Meet Aim 3: For the dichotomous outcome variables pertaining to communication 
(hypothesis 3a) and shared decision-making (hypothesis 3b), Pearson’s chi-square test will 
test for differences in proportions between study arms. We will use logistic regression for the 
multivariable modeling. Treatment effect estimates will be reported as adjusted odds ratios. To 
test hypothesis 3c, we will use Student’s t-test for mean difference since the outcome, Family 
Distress in Advanced Dementia (FDAD), is continuous. Linear mixed models as described for 
Aim 2.b. above will be used to test treatment effects for 30-day and 60-day outcomes jointly.   
Administrative Supplement Analysis: 
Supplement Aim 2: To determine the feasibility, acceptability and preliminary efficacy of 
the ADRD-PC intervention for n= 50 Hispanic / Latino dyads living with late-stage 
dementia in a pilot randomized clinical trial: Descriptive analyses of variables will examine 
distributions, influential data points, and missing data. Means (standard deviations) will be 
reported for continuous variables and frequencies with percentages for categorical variables. 
Continuous variables (e.g., PC Domain Index, etc) that are poorly distributed may be 
transformed, or analyzed using non-parametric tests. We anticipate that missing data on 
independent variables will be minimal. We will use simple mean and mode imputation for those 
variables included in regression models if less than 5% of patients have missing data; else, 
conditional (i.e., regression) imputation will be used. Available case analyses will be conducted 
for 30-day outcomes. Missing 60-day dichotomous outcomes will be multiply imputed if 

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missingness exceeds 10%. Caregiver data collection is completed after deaths as in our prior 
ADRD research.  
Analysis of feasibility outcomes:  Simple descriptive statistics will be used to assess feasibility.  
We will report frequencies for rates of screening, eligible vs. ineligible, and consented vs. 
refused dyads.  We will report on de-identified demographic and clinical characteristics of those 
who are eligible and consent vs refuse participation.  We will use similar descriptive 
comparisons to report on dyads who enroll and complete all study procedures compared to 
those who are not retained for complete outcome assessments.  ADRD-PC will be feasible for 
Hispanic / Latino dyads if we successfully achieve target enrollment (n=50 dyads), and study 
retention (80%) within 20% these goals.   
Analysis of acceptability outcomes:  Acceptability will be evaluated using qualitative methods to 
analyze results of open-ended questions in family caregiver interviews. Interview transcripts will 
be entered into ATLAS.ti software to facilitate qualitative content analysis and coding.  Dr. 
Fischer will oversee the qualitative coding process, and two Spanish-speaking CRCs will 
conduct paired coding of all transcripts. 
Analysis of preliminary efficacy outcomes data:  Primary analysis will use intention-to-treat 
analysis. We will evaluate the effectiveness of randomization by comparing intervention and 
control participants on baseline measures. Variables that are not equally distributed between 
arms could potentially bias results. We will include these variables in each initial model and use 
a change-in-effect method for determining whether they are confounders. If removing any of 
these variables from the model does not appreciably change the regression coefficient estimate 
associated with the intervention group variable, we will not need to include them in the final 
model. Given our randomized design, we anticipate little confounding. A priori exploratory 
analyses will examine the effects stratified by sex as a biologic variable, and GDS stage. 
As in the parent ADRD-PC randomized trial, we will compare control and intervention arms on 
hospital transfers (primary outcome) during 60 days post-discharge. This count outcome is 
defined as total number of emergency room visits plus hospital admissions per at-risk patient-
days. We will use Poisson regression with empirical ‘robust’ standard errors allowing for 
overdispersion to compare the transfer rates between groups. We will use length of follow-up as 
the offset variable, which means that patients who have data only from the 30-day interview will 
be included. The primary analysis will be based on the model with main effects for treatment 
group, study site, GDS Stage and patient and caregiver sex as biological variables. Evaluation 
of the treatment effect will be based on a Wald test. The covariate-adjusted treatment effect will 
be quantified as an incidence rate ratio (IRR) with 95% confidence interval. We will conduct a 
sensitivity analysis for the treatment effect on 60-day hospital transfers with a marginalized 
zero-inflated Poisson (MZIP) model, that may modestly increase power. Secondary Poisson and 
MZIP analyses will compare study arms for 30-day hospital transfer rates. An exploratory 
analysis will be conducted to examine interactions of treatment group with study site, sex and 
GDS Stage, respectively, on 60-day hospital transfers. An interaction model will be used if an 
omnibus test for interactions is statistically significant at the 0.05 level.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATION 

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10.1.1 INFORMED CONSENT PROCESS 
SEE STATEMENT OF COMPLIANCE 
 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks will be 
provided to the family caregiver, who provides consent for their participation and that of the 
person with late-stage dementia.  As described below, verbal consent will be accepted and 
documented for study enrollment.  Written documentation, including consent forms for review 
will be provided during in-person visits, or sent by mail or secure electronic communication 
when visits are conducted virtually. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Since family caregivers may be present in hospital or may be barred from visitation due to 
COVID-19 restrictions and safety concerns or may live at a great distance from the hospital, 
recruitment and enrollment procedures will include both in-person and telephone / virtual 
communication methods. These approaches are comparable to routine clinical communication 
used with family caregivers for people with dementia who lack decisional capacity.  Further, 
flexibility of communication is essential, because study enrollment and participation in the 
ADRD-PC intervention must both occur during acute illness hospitalization.  
Due to the low risk of study participation and the restrictions on immediate written consent 
described above, verbal consent will be accepted for participation in the enrollment caregiver 
interview, and for randomization with initiation of the ADRD-PC or control conditions. To ensure 
informed consent, the Site-CRC will provide verbal information about the study, indicate the 
participation is voluntary and he/she has the right to stop at any time. They will enumerate 
benefits and risks verbally during the consent process, reading from the consent form. 
Additionally, the informed consent verbal communication and written documents will include a 
specific statement relating to posting of deidentified clinical trial information at ClinicalTrials.gov.      
Site-CRCs will introduce the study to eligible family caregivers using in-person visits in hospital 
or scripted telephone calls when being present in hospital is not possible. When recruitment and 
enrollment is in-person, the Site-CRC will provide written and verbal study information (in either 
English or Spanish), review the informed consent form, obtain verbal consent, and complete the 
enrollment interview in-person.  When the Site-CRC conducts recruitment and enrollment via 
telephone, the Site-CRC will ask if the individual is in a private location and feels comfortable 
talking about the study at that time; they will schedule an alternative time if necessary. The Site-
CRC will explain the study over the phone using a telephone script. If the family caregiver is 
interested and wants to participate, the Site-CRC will review and complete informed consent 
with them verbally over the phone. If the family caregiver consents to participate, study 
informational materials and the informed consent form will be sent to them by mail or secure e-
mail for later review. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 

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The study will be closed after completion of target enrollment, and study procedures 
discontinued after follow-up data collection, and planned data analyses with appropriate 
presentation, publication and data sharing. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This 
confidentiality is extended to the data being collected as part of this study. Data that could be 
used to identify a specific study participant will be held in strict confidence within the research 
team. No personally-identifiable information from the study will be released to any unauthorized 
third party without prior written approval of the sponsor/funding agency.  
All research activities will be conducted in a private setting. The study participant’s contact 
information will be securely stored at each clinical site for internal use during the study. All 
collected data, including PHI, will be defined by the research protocol and limited to research 
purposes.  We will protect confidential medical information from EHR reviews by abstracting 
data directly into a secure database or onto coded paper forms separated from personal 
identifiers.  Data will be entered in a password protected secure database, and all paper 
documentation will be maintained in locked files.  The Sheps Information Technology group 
enables standard operating procedures required to secure the network and databases, including 
operational and technical controls. All servers are located within a hardened data center.  
Modes of communication between the study coordinating center at the University of North 
Carolina, and between Site-CRC, Site-PI and hospital attending physicians will be restricted to 
encrypted e-mail, secure text messages, or secure verbal communication to protect confidential 
health information.  
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or representatives 
from companies or organizations supplying the product, may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in 
biomedical, behavioral, clinical or other human subjects research funded wholly or in part by the 
federal government.  Recipients of NIH funding for human subjects research are required to 
protect identifiable research information from forced disclosure per the terms of the NIH Policy 
(see https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 
75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered by 
this Policy are required to establish and maintain effective internal controls (e.g., policies and 
procedures) that provide reasonable assurance that the award is managed in compliance with 
Federal statutes, regulations, and the terms and conditions of award. It is the NIH policy that 
investigators and others who have access to research records will not disclose identifying 
information except when the participant consents or in certain instances when federal, state, or 
local law or regulation requires disclosure. NIH expects investigators to inform research 
participants of the protections and the limits to protections provided by a Certificate issued by 
this Policy. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  

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At the end of the study, all records will be deidentified and then shared with the Palliative Care 
Research Collaborative Group, which will store deidentifed data and continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor/funding agency requirements. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
The research team will be led by Dr. Laura Hanson (PI) and managed by Project Manager 
reporting to Dr. Hanson.  Dr. Hanson and the Project Manager will provide administrative 
leadership and study coordination, to ensure timely completion of research tasks and 
consistency with protocol standards.  The University of North Carolina’s Cecil G. Sheps Health 
Services Research Center will be the administrative home for the UNC research investigators 
and staff, and will function as the data coordinating site to receive, house, clean and support all 
data analyses. Ms. Wessell (UNC research staff) will facilitate data management, and data 
analysis will be led by the study biostatistician Feng-Chang Lin. Staff from the Palliative Care 
Research Cooperative group’s Project Coordinating Center housed at the University of Denver 
(Dr. Kutner, Site-PI) will provide technical assistance to ensure good clinical practice, protocol 
version control and central coordination of IRB tasks necessary for a large-scale multi-site 
clinical trial. 
Research enrollment sites will be the University of North Carolina (Drs. Hanson, Kistler), Indiana 
University (Dr. Sachs, Site-PI), Massachusetts General Hospital affiliated with Harvard Medical 
School (Dr. Ritchie, Site-PI),  the University of Colorado-Denver (Dr. Lum, Site-PI), and Emory 
University (Drs. Lowers and Kavalieratos, Site-PIs).   
10.1.6 SAFETY OVERSIGHT 
This multi-site RCT will utilize a single IRB and a unified protocol for all study sites.  All study 
protocols and amendments, informed consent forms, and other study materials will undergo 
review by the Institutional Review Board at the University of North Carolina-Chapel Hill prior to 
initiating research, and will be subject to annual and other required reviews.   
In addition to study monitoring and oversight by Dr. Hanson (PI) and the Project Manager, we 
will work with the NIA Program Official to select a Data and Safety Monitoring Board (DSMB) 
with expertise relevant to the proposed multi-site clinical trial.  Members of the DSMB will be 
independent from the study conduct and free of conflict of interest. The DSMB will meet at least 
twice per year to assess safety and efficacy data from each arm of the study. The DSMB will 
operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. The DSMB will provide its input to the National Institute on Aging. 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion. All sites will follow a common quality management plan. 
 
Quality control (QC) procedures will be implemented as follows: 
Informed consent --- Study staff will review both the documentation of the consenting process 
as well as a percentage of the completed consent documents.  This review will evaluate 
compliance with GCP, accuracy, and completeness.  Feedback will be provided to the study 
team to ensure proper consenting procedures are followed.  
 

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Source documents and the electronic data --- Data will be initially captured on source 
documents and will ultimately be entered into the study database.  To ensure accuracy site staff 
will compare a representative sample of source data against the database, targeting key data 
points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored 
throughout the intervention phase of the study. Procedures for ensuring fidelity of intervention 
delivery are described in Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and 
will implement corrective actions when the quantity or nature of deviations are deemed to be at 
a level of concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by 
the sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a daily 
basis. The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to the NIA 
Director to monitor participant safety, evaluate the progress of the study, to review procedures 
for maintaining the confidentiality of data, the quality of data collection, management, and 
analyses. 
 
Data collection will be the responsibility of the site-based CRCs under the supervision of the 
site-based PI, with overall supervision from Dr. Hanson (PI) and the Project Manager. The Site-
PI will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Hardcopies of the study visit worksheets will be provided for use as 
source document worksheets for recording data for each participant consented/enrolled in the 
study.  Data recorded in the electronic case report form (eCRF) derived from source documents 
will be consistent with the data recorded on the source documents.  
 
All identifying information will be stored in a separate, locked file cabinet from data collected 
during the interview. All identifying information will be destroyed once all analysis and reporting 
is complete. At no time will personal identifying information be stored on portable laptop 
computer devices. 
 
All research data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the University of North Carolina at Chapel Hill. REDCap includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
 

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10.1.8.2 STUDY RECORDS RETENTION  
Study documents will be retained for a minimum of 3 years after will comply with all NIH and 
NIA data retention standards.  
 
10.1.9 PROTOCOL DEVIATIONS   
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP), or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
will be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the site investigator to use continuous vigilance to identify and 
report deviations within 7 working days of identification of the protocol deviation, or within 7 
working days of the scheduled protocol-required activity. All deviations will be addressed in 
study source documents, reported to National Institute on Aging Program Official and University 
of North Carolina at Chapel Hill IRB. Protocol deviations will be sent to the reviewing 
Institutional Review Board (IRB) per their policies. Laura Hanson, MD (PI) and other site 
investigator will be responsible for knowing and adhering to the reviewing IRB requirements. 
Further details about the handling of protocol deviations will be included in the MOP. 
10.1.10 
PUBLICATION AND DATA SHARING POLICY  
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be 
made to publish results in peer-reviewed journals.  Data from this study may be requested from 
other researchers 2 years after the completion of the primary endpoint by contacting the 
Palliative Care Research Collaborative Group. Considerations for ensuring confidentiality of 
these shared data are described in Section 10.1.3. 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 

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and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the National Institute on Aging has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ABBREVIATIONS AND SPECIAL TERMS 
 
ADRD 
Alzheimer’s disease and related dementias 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
EHR 
Electronic Health Record 
GCP 
Good Clinical Practice 
GDS 
Global Deterioration Scale 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Council on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
LAR 
Legally authorized representative 
MOP 
Manual of Procedures 
NIA 
National Institute on Aging 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
RCT 
Randomized Clinical Trial 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SPIRIT 
Standard Protocol Items Recommendations for Interventional Trials 
UP 
Unanticipated Problem 
UPIRSO 
Unanticipated Problem Involving Risk to Subjects or Others 
 
 
 

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10.3 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
16 February 2020 
Initial protocol 
 
1.1 
09 July 2021 
Removal of secondary written 
consent and authorization of verbal 
consent for all participants 
Verbal consent approval for 
low risk study by UNC IRB 
1.2 
02 September 
2021 
Revision of emotional distress 
screen threshold and response 
procedures to appropriately 
identify unusual or severe levels of 
emotional distress thresholds. 
Initial threshold was 
incorrectly set below the mean 
scoring range for the FDAD 
subscale, causing usual 
caregiver distress levels to 
trigger.  Threshold is now 
adjusted to one std dev above 
the mean and further clarifies 
response procedures. 
2.0 
 
Adding Spanish supplement 
information and added Emory 
University as a 5th site  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
N/A