Preparation for End-of-Life Decision Making in Mild Dementia
Phase: NA
Conditions: Dementia
Sponsor: Emory University

 
 
Preparation for End-of-Life Decision Making in Mild 
Alzheimer’s Disease  
 
 
NCT Number: NCT03311711 
 
 
 
 
Protocol Version Date: 15 July 2020 

Preparation for End-of-Life Decision Making in Mild 
Alzheimer’s Disease  
 
(Short title: SPIRIT in Mild AD)  
 
 
National Clinical Trial (NCT) Identified Number: NCT03311711 
Principal Investigator: Mi-Kyung Song 
Funded by: NIH/NIA, R01AG057714 
 
 
Version Number:  v.14 
15 July 2020 
 
 
Summary of Changes from Previous Version: 
 
Version 
No. 
Date 
Affected Section(s) 
Summary of Revisions 
Made 
Rationale 
V14 
7.15.2020 
1.1 Synopsis 
3 Objectives-Aim 2 
4.2 Scientific rational- 
study design 
6.1.1 Study 
intervention 
description 
6.3 Randomization 
6.4 Study intervention 
compliance 
9.2 Sample size 
9.4.2 Analysis of 
primary endpoints 
10.1.1.2 Consent 
process/documentation 
Eliminate SPIRIT in-
person modality and 
change the study design 
change to a 2-group 
(SPIRIT-remote vs usual 
care) RCT. 
 
Northwestern and Rush 
Universities will make 
potential participant 
referrals. 
In consideration of 
SARS-COV-2 Pandemic 
CDC guidelines 
 
 
 
 
Optimize study 
recruitment: Grady 
clinic withdrew 
participation due to 
space limitation during 
pandemic 

  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ....................................................................................................................................... 1 
1 
PROTOCOL SUMMARY ...................................................................................................................................... 2 
1.1 
Synopsis .................................................................................................................................................. 2 
1.2 
Schema ................................................................................................................................................... 2 
1.3 
Schedule of Activities (SoA): Randomization occurs at the clinic level ... Error! Bookmark not defined. 
2 
INTRODUCTION ................................................................................................................................................. 5 
2.1 
Study Rationale ...................................................................................................................................... 5 
2.2 
Background ............................................................................................................................................. 6 
2.3 
Risk/Benefit Assessment ...................................................................................................................... 10 
2.3.1 
Known Potential Risks ....................................................................................................... 10 
2.3.2 
Known Potential Benefits ................................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits ..................................................................... 10 
3 
OBJECTIVES AND ENDPOINTS ......................................................................................................................... 10 
4 
STUDY DESIGN ................................................................................................................................................. 11 
4.1 
Overall Design ...................................................................................................................................... 11 
4.2 
Scientific Rationale for Study Design .................................................................................................... 12 
4.3 
Justification for INTERVENTION ........................................................................................................... 14 
4.4 
End of Study Definition......................................................................................................................... 14 
5 
STUDY POPULATION ....................................................................................................................................... 14 
5.1 
Inclusion Criteria................................................................................................................................... 14 
5.2 
Exclusion Criteria .................................................................................................................................. 14 
5.3 
Lifestyle Considerations ....................................................................................................................... 15 
5.4 
Screen Failures ..................................................................................................................................... 15 
5.5 
Strategies for Recruitment and Retention ........................................................................................... 15 
6 
STUDY INTERVENTION(s) ................................................................................................................................ 18 
6.1 
Study Intervention(s) Administration ................................................................................................... 18 
6.1.1 
Study Intervention Description ......................................................................................... 18 
6.1.2 
Dosing and Administration ............................................................................................... 20 
6.2 
Preparation/Handling/Storage/Accountability .................................................................................... 20 
6.2.1 
INTERVENTIONIST TRAINING and accountability ............................................................. 20 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ......................................................... 21 
6.2.3 
Product Storage and Stability ........................................................................................... 21 
6.2.4 
Preparation ....................................................................................................................... 21 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...................... Error! Bookmark not defined. 
6.4 
Study Intervention Compliance ............................................................................................................ 21 
6.5 
Concomitant Therapy ........................................................................................................................... 21 
6.5.1 
Rescue Medicine ............................................................................................................... 21 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ............. 22 
7.1 
Discontinuation of Study Intervention ................................................................................................. 22 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................................................... 22 
7.3 
Lost to Follow-Up ................................................................................................................................. 22 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................................... 22 
8.1 
OUTCOME Assessments ....................................................................................................................... 22 
8.2 
Safety and Other Assessments ............................................................................................................. 24 
8.3 
Adverse Events and Serious Adverse Events ........................................................................................ 25 
8.3.1 
Definition of Adverse Events (AE) ..................................................................................... 25 

  
 
iii 
8.3.2 
Definition of Serious Adverse Events (SAE) ...................................................................... 25 
8.3.3 
Classification of an Adverse Event .................................................................................... 25 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .................................. 25 
8.3.5 
Adverse Event Reporting .................................................................................................. 26 
8.3.6 
Serious Adverse Event Reporting...................................................................................... 26 
8.3.7 
Reporting Events to Participants ...................................................................................... 26 
8.3.8 
Events of Special Interest.................................................................................................. 26 
8.3.9 
Reporting of Pregnancy .................................................................................................... 26 
8.4 
Unanticipated Problems ....................................................................................................................... 26 
8.4.1 
Definition of Unanticipated Problems (UP) ...................................................................... 26 
8.4.2 
Unanticipated Problem Reporting .................................................................................... 27 
8.4.3 
Reporting Unanticipated Problems to Participants .......................................................... 27 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 27 
9.1 
Statistical Hypotheses .......................................................................................................................... 27 
9.2 
Sample Size Determination .................................................................................................................. 27 
9.3 
Populations for Analyses ...................................................................................................................... 28 
9.4 
Statistical Analyses ............................................................................................................................... 28 
9.4.1 
General Approach ............................................................................................................. 28 
9.4.2 
Analysis of the Primary Endpoint(s) .................................................................................. 28 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 29 
9.4.4 
Safety Analyses ................................................................................................................. 29 
9.4.5 
Baseline Descriptive Statistics .......................................................................................... 30 
9.4.6 
Planned Interim Analyses ................................................................................................. 30 
9.4.7 
Sub-Group Analyses .......................................................................................................... 30 
9.4.8 
Tabulation of Individual participant Data ......................................................................... 30 
9.4.9 
Exploratory Analyses ........................................................................................................ 30 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................................... 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................................... 30 
10.1.1 
Informed Consent Process ................................................................................................ 30 
10.1.2 
Study Discontinuation and Closure ................................................................................... 31 
10.1.3 
Confidentiality and Privacy ............................................................................................... 34 
10.1.4 
Future Use of Stored Specimens and Data ....................................................................... 34 
10.1.5 
Key Roles and Study Governance ..................................................................................... 34 
10.1.6 
Safety Oversight ................................................................................................................ 35 
10.1.7 
Clinical Monitoring ............................................................................................................ 35 
10.1.8 
Quality Assurance and Quality Control ............................................................................. 36 
10.1.9 
Data Handling and Record Keeping .................................................................................. 36 
10.1.10 
Protocol Deviations ........................................................................................................... 37 
10.1.11 
Publication and Data Sharing Policy ................................................................................. 37 
10.1.12 
Conflict of Interest Policy .................................................................................................. 38 
10.2 
Protocol Amendment History ............................................................................................................... 38 
11 
REFERENCES .................................................................................................................................................... 43 
 

SPIRIT in mild AD Trial 
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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation 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 have been 
approved by the Institutional Review Board (IRB) at: 
Emory (Study No.: IRB0099738; approved on 10/24/2017) 
 
Any amendment to the protocol requires review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved. 
 
 
 

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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Preparation for End-of-Life Decision Making in Mild Alzheimer’s Disease 
Study Description: 
The proposed study will adapt and pilot test an efficacious advance care planning 
intervention, SPIRIT (Sharing Patient’s Illness Representations to Increase Trust), 
with patients with mild Alzheimer’s Disease and their surrogates to promote open, 
honest discussions while such discussions about end-of-life care are possible. 
Objectives: 
 
Aim 1.  Adapt SPIRIT (in person) to target patients with mild AD and their surrogates 
through a process of modification-pretesting-refinement using stakeholders 
(patients, family caregivers, and clinicians) and experts, including adapting the 
delivery mode to interactive web-based videoconferencing (SPIRIT-remote). 
Aim 2.  In a 2-group RCT with 120 patient-surrogate dyads, evaluate the feasibility 
and acceptability of SPIRIT-remote, and the preliminary efficacy compared to usual 
care (wait-list control) on preparedness outcomes for end-of-life decision making 2-
3 days after the intervention. 
Secondary Aim a.  Compare the completion of advance directives among the two 
treatment conditions at 1-year post-intervention. 
Secondary Aim b.  Using a qualitative method, in a sample of surrogates, explore 
their perceptions of SPIRIT at 1-year post-intervention for acceptability and 
preparation for end-of-life decision making.   
 
 
Endpoints: 
Preparedness for end-of-life decision making: 
a) Dyad congruence 
b) Surrogate decision-making confidence 
c) Surrogate preparedness for end-of-life decision making 
 
Study Population: 
Adults with dementia and their surrogates 
 
Phase: 
Phase I 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Outpatient clinics 
Description of Study 
Intervention: 
SPIRIT (Sharing Patient’s Illness Representation to Increase Trust), a patient and 
family-centered ACP intervention based on the Representational Approach to 
Patient Education, is to establish a testable model of how end-of-life care 
discussions could occur between a patient and his/her chosen surrogate (usually a 
spouse or adult child). The discussions, which are facilitated by a trained 
interventionist, are framed around addressing each individual’s representations of 
(beliefs about) the illness and views of life-sustaining measures at the end of life. 
SPIRIT follows a six-step learning objective over two-sessions, which together take 
about 60 minutes. 
Study Duration: 
5 years 
Participant Duration: 
In Phase I to modify and pretest SPIRIT for mild dementia, about three weeks 
In Phase II to pilot test the modified SPIRIT, about one year after randomization 
1.2 
SCHEMA  

SPIRIT in mild AD Trial 
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
Stage IA 
 
 
 
 
 
 
 
 
 
 
 
 
Stage IB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
With revision (V12) 
h revision (V12)

SPIRIT in mild AD Trial 
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With revision (V14) 

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INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Alzheimer's disease (AD), the most prevalent class of dementing illness, is a leading cause of death and affects 
over 5 million individuals in the US.1 Like most dementing illnesses, AD cannot be effectively prevented and is 
incurable. Progressive memory loss and impairment of reasoning and judgment are its main symptoms.2 For this 
reason, people in the early stages of AD are encouraged to engage in advance care planning (ACP) while they are 
still competent to appoint a surrogate decision maker and meaningfully participate in ACP discussions with the 
surrogate.3,4 Yet only a minority (39%) of older adults with early cognitive impairment complete any form of ACP 
following the diagnosis.5  
 
The most common type of ACP is completing a medical power of attorney or living will, which does not require 
the patient and/or the family to understand the complexity of the medical decision-making process faced by the 
surrogate as the patient progresses to advanced disease. The failure to engage in ACP before the window of 
opportunity closes (i.e., before loss of decision making capacity) has serious adverse consequences with the 
greatest impact on the surrogate. As a matter of course in AD, family members are left to make decisions 
regarding care transition, tube feeding, and other life-sustaining treatment without input from the patient and in 
the absence of a full understanding of the wishes, values and preferences of the patient.6-8 Unfortunately the 
culture of technological imperative to deliver aggressive or futile medical care to very frail older adults drives end-
of-life decision making especially when there has been no ACP.9,10 Of direct relevance to this proposed study, the 
vast majority of family members of patients with AD report not being prepared for these difficult decisions,11-13 
and they report experiencing considerable negative mental health sequelae after they face end-of-life decision 
making.12-23 Thus, while ACP is of great relevance to the dignity of the patient, the true emotional burden of care 
falls to the surrogate. 
 
To make an impact on the state of ACP for patients with AD and their surrogates, we will adapt and pilot test an 
efficacious ACP intervention, SPIRIT (Sharing Patient’s Illness Representations to Increase Trust), with patients 
with mild AD and their surrogates (NIH Stage I behavioral intervention development24 in PAS-17-027) to promote 
open, honest discussions while such discussions about end-of-life care are possible. SPIRIT is a brief, scalable 
patient- and family-centered ACP intervention based on the Representational Approach to Patient Education25,26 
with a goal to promote cognitive and emotional preparation for end-of-life decision making for patients with a 
serious or life-threatening illness and their surrogates. SPIRIT focuses on having both the patient and the 
surrogate fully understand end-of-life decision making in anticipation of a loss of decision-making capacity.  
 
Over the past decade, SPIRIT has been iteratively tested in 5 randomized controlled trials (RCTs) to establish 
feasibility, patient-surrogate acceptability, and efficacy in patient populations, including end-stage renal disease, 
advanced heart failure, and cardiac surgery.27-32 Patients and surrogates who received SPIRIT showed significant 
improvements in key outcomes reflecting preparedness for end-of-life decision making: a) increase in patient and 
surrogate agreement on end-of-life care goals, b) reduction in patient’s conflict about benefits and burdens of life-
sustaining treatments, and c) increase in surrogate confidence about the surrogate role, which in turn resulted in 
decreased post-bereavement psychological distress for surrogates. We designed SPIRIT as a testable model of 
how end-of-life care discussions could occur between patient and surrogate. The facilitated discussions are 
structured to address each individual’s representations of (i.e., beliefs about) the illness and views of life-
sustaining measures at the end of life. The overall goal of this project is to produce an effective and maximally 
implementable ACP intervention for patients with mild AD and their surrogates. Collaboration with researchers 
from NIH-funded AD research centers will set the stage for a future implementation study that could lead to 

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6 
 
improvements in patient- and family-centered outcomes at end of life.  
 
2.2 
BACKGROUND  
 
At the end of life, many patients with dementing illnesses receive burdensome interventions with no clear 
therapeutic benefits.  AD and related dementias (ADRD) are the 6th leading cause of death in the U.S. with no 
effective treatment.2,33 Mortality in patients with advanced ADRD is high (median survival=1.3 years34-36); most die 
after acute illnesses, such as pneumonia or a febrile episode rather than from “devastating” complications such as 
stroke or heart attack.37 For those with advanced ADRD, intensive or burdensome end-of-life care is common. 
Nearly 41% undergo at least one intensive intervention (e.g., tube feeding, mechanical ventilation) in the last 3 
months of life, which may prolong life but not address quality of life (or quality of dying).34,35,37,38 A major 
contributor to high intensity of care at the end of life is that many patients and their family members do not 
recognize that ADRD is a terminal disease.37 Since 2000, the use of mechanical ventilation for Medicare 
beneficiaries with advanced dementia has been doubled without any measurable survival benefit.39 The great 
challenge to the medical community is to prepare patients and families for very complicated end-of-life scenarios 
rife with medical decision making in the context of the patients’ progressive loss of cognitive functioning and 
selfhood. 
 
Most patients with mild AD and their surrogates miss the window of opportunity for meaningful ACP. Merely 
completing legal documents to indicate one’s preferences for medical care does not adequately improve end-of-
life care because family members often do not know or agree with the content of the directive, or do not know 
how to translate vague preferences into specific treatments at end of life40; and legally appointed surrogates lack 
knowledge of patients’ wishes and are poorly prepared for emotional turmoil during end-of-life decision 
making.21,41 In contrast, a process of developing an advance directive as an embodiment of a patient’s wishes 
based on discussions about ones values and illness representations can result in high quality ACP that improves 
quality of life during the end of life and, importantly in AD, and reduce stress for surrogates and caregivers. The 
practice of ACP has evolved to focus on psychological and practical preparation of patients and surrogates for 
treatment decision-making at the end of life.28,42-48 For example, for patients, ACP can involve exploring the 
personal meaning of illness and gaining knowledge about illness progression; for surrogates, ACP can involve 
gaining an understanding of the patient’s values and goals for end-of-life care and of the role and responsibilities 
of being a surrogate.28,49 The objective of a patient-centered ACP process is to prepare a surrogate to execute the 
patient’s wishes rather than simply react based on the instructions in an advance directive. 
 
Per usual care, clinicians advise people with early cognitive impairment and their families to complete an advance 
directive at the time of diagnosis. Typically, this involves providing the patient and family a brief information 
about how to prepare advance directives. Research has shown that only a minority of older adults with mild 
cognitive impairment or mild AD complete an advance directive after the initial diagnosis (39%), and if advance 
directives are not completed during the early stages of cognitive impairment, it is unlikely that this will happen as 
the patient progresses into an advanced stage.5 There are numerous AD support groups around the nation. These 
support groups may be one location to focus attention on ACP and financial planning (and thus are often led by a 
lawyer rather than a clinician) and provide important legal and technical information and social support. However, 
a meta-analysis of interventions with dementia caregivers suggests that those types of support groups do not 
effectively accomplish the goals of ACP described above.50   
 
There are several reasons that patients with mild AD do not engage in ACP discussions or complete an advance 
directive. Remaining functional independence in patients with mild AD may mask troubling declines in cognitive 
symptoms (e.g., memory lapses, impaired ability to plan complex activities).51 As a result, the patient and family 
members may not appreciate the need or urgency for preparing for future medical care, including end-of-life 
care.52 Patients and/or their families may be unwilling to believe that the patient will progress to an advanced 
stage, unaware of the progressive nature and terminality of AD, adopt a passive coping stance (e.g., future is fated 

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and cannot change), want to delay until a dire medical event presents itself (e.g., critical illness), or 
underappreciate the end-of-life decision making burden on family members.3,52-55 A typical scenario is that 
decision making about intensive, invasive, and expensive medical interventions is left to unprepared surrogates 
and/or clinicians who are likely unaware of the patient’s preferences.19,56,57   
 
Lack of preparedness for end-of-life decision making has serious negative consequences on patients, 
surrogates, and society at large. Studies, including our work,11,58 have demonstrated surrogates to be overly 
confident about their ability to act as a surrogate. We have shown that many surrogates lack an understanding of 
the patient’s preferences (assessed by comparing patient preferences and surrogate understanding of those 
preferences), yet report a high level of confidence in understanding patients’ wishes and high confidence that 
they will be able to execute their role as a surrogate.58 There are many deleterious consequences to an actual lack 
of preparedness for end-of-life decision making and these have been well documented, including high levels of 
intrapersonal and family conflict brought on by having to make life or death decisions (e.g., whether to withhold 
or withdraw mechanical ventilation, or other life-sustaining measures that are deemed futile); regrets over missed 
opportunities to benefit from palliative care or hospice; excessive distress for family members during decision 
making due to interfamily conflict and anguish, time pressure to make important decisions, lack of knowledge 
about options; and psychosocial sequelae for family members (e.g., depression, anxiety, and post-traumatic stress 
disorder) and complicated bereavement after the patient’s death.11,17,21,59-68  
 
Numerous studies, including those of dementia patients, indicate that families experience greater difficulty in 
decision making when they are uncertain about the patient’s wishes, when they feel unprepared for their role 
because they have never discussed it, and when they are called on to make decisions in a short period of time.12-19 
Dementia family members with a greater sense of burden for decision making are more likely to consent to life-
sustaining treatment.20 There is a high rate of psychiatric illness among family decision makers; in one study of ICU 
family members, nearly 40% of those who experienced a loved one’s death during the previous 3 to 12 months 
had at least one psychiatric illness meeting DSM-IV criteria, such as anxiety disorder or major depression.68 Even 
at 6-12 months after the patient’s death, studies show that family members experience intrusive thoughts of 
regret, guilt or search for evidence that they made the right decision.16,17,21-23 
 
SPIRIT, a patient- and family-centered ACP, has documented beneficial effects on a range of psychosocial 
outcomes for patients and their surrogates. The goal of SPIRIT is to promote cognitive and emotional preparation 
for end-of-life decision making for patients with a serious or life-threatening illness and their surrogates. SPIRIT is 
based on the Representational Approach to Patient Education.25,26 This approach melds two theories: Leventhal’s 
common sense model 69 and the conceptual change model.70 The common sense model proposes that individuals 
have representations of their illness or health problems. Representations are based on an individual’s 
experiences, cultural traditions, or media, and may not be medically accurate. It is critical to understand a 
patient’s representations because they filter new learning: representations serve as the cognitive framework that 
affects whether or not individuals accept or reject new information,25 and whether knowledge leads to behavior 
change.71,72 The conceptual change model proposes that the likelihood of learning increases when the individual 
has an opportunity to reflect and comment on current ideas, when the individual is dissatisfied with current ideas 
or recognizes their limitations, and when alternative information is seen as beneficial.25,26,70,73 Learning and 
change can occur through integrating new information into existing representations to fill gaps in understanding, 
by clarifying existing representations to reduce confusion, or through replacing existing ideas with new 
information.73,74 The scientific premise for this study is that the Representational Approach to Patient Education 
requires an interventionist to elicit the patient’s existing illness representations before providing new 
information.25,26 Then, the interventionist, the patient, and his/her surrogate have an opportunity to recognize 
gaps or confusions, and the interventionist can give new information that is specific and relevant, increasing the 
likelihood that it will be acted upon.  
 
SPIRIT is a two-session, 60-minute, structured psychoeducational intervention, targeting both patient and 
surrogate. SPIRIT was developed by our team and extensively evaluated in patients with end-stage renal disease, 

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advanced heart failure, and cardiac surgical patients and their surrogates.27-32 Using an interventionist   manual, 
the interventionist follows six steps: 1) assess illness presentation, 2) identify gaps and concerns, 3) create 
conditions for conceptual change, 4) introduce replacement information, 5) summarize, and 6) set goals and 
plan.75 SPIRIT first establishes an understanding of the cognitive, emotional and spiritual aspects of the patient’s 
representation of (ideas about) his/her illness. This understanding enables the interventionist to provide 
individualized medical information and to assist the patient in examining his/her own values related to life-
sustaining treatment at the end of life. In this way, the patient can more readily express his/her treatment 
preferences to the surrogate. SPIRIT also enables the surrogate to understand the patient’s illness experiences 
and values and to be prepared for the responsibility and emotional turmoil that can arise during decision making 
at the end of life. Each element of SPIRIT is designed to enhance the quality and authenticity of exchanges 
between patient and surrogate about experiences surrounding illness and values. During the process, the patient 
discovers his/her own representations about illness and examines thresholds and/or conditions for withholding or 
(dis)continuing life support measures. The surrogate also validates similarities or differences with the patient in 
regard to life support measures and examines his/her own ability to follow the patient’s wishes. This process is 
critical to preparation for end-of-life decision making.30,75 To deliver SPIRIT sessions, interventionists are trained in 
communication skills and end-of-life planning.  
 
Preliminary data on the efficacy of SPIRIT:  Over a decade, we have iteratively tested SPIRIT in 5 RCTs to establish 
feasibility, patient-surrogate acceptability, and efficacy in: patients undergoing major cardiac surgery who were 
“otherwise healthy,” seriously ill patients with end-stage renal disease (ESRD), and elderly patients with advanced 
heart failure who had a left ventricular assisted device implanted.27-32 Over the course of these studies, SPIRIT has 
been modified to target the particular patient population, to tailor content while maintaining theoretical core 
elements responsible for patient and surrogate outcomes, language complexity (current literacy level at Flesch-
Kincaid grade=7), and the number of sessions (1-2 sessions). SPIRIT has been adapted to be culturally tailored for 
African Americans with ESRD.75 All studies were in outpatient care settings (both academic and community 
settings). Importantly, in the study with patients undergoing major cardiac surgery, we demonstrated that a 
SPIRIT session prior to major surgery did not increase participants’ anxiety in spite of clinicians’ concerns and 
efforts to avoid such discussions.27 We have tested strategies for recruitment, retention, data collection, SPIRIT 
training, fidelity, and measurement. Recruitment rates have consistently been >80% with very low dropout (<4%) 
even in an RCT requiring long-term follow up (12 months). 
 
In a full-scale multicenter RCT of patients with ESRD and their surrogates (R01NR011464), we tested the efficacy 
of SPIRIT compared to usual care (wait-list control) in preparation for end-of-life decision-making. At 2, 6, and 12 
months, outcomes were dyad congruence, patient decisional conflict, and surrogate decision-making confidence 
(preparedness outcomes).30 We also tested whether SPIRIT reduced post-bereavement distress for surrogates (at 
2 weeks, 3 and 6 months post patient’s death). Dyads (N=210) of seriously ill dialysis patients and their surrogates 
from 20 free-standing dialysis facilities (mean age 62, 57% women, 67% African Americans) were randomized to 
SPIRIT or usual care. ITT analysis showed that, adjusting for time and baseline values, dyad congruence on goals of 
care (OR=1.89 [95% CI, 1.1 to 3.3]; p=.029) and surrogate decision-making confidence (β=0.13 [CI, 0.01 to 0.24]; 
p=.027) were significantly better in the SPIRIT group. Patient decisional conflict was significantly lower in SPIRIT at 
12 months (β=-0.19 [CI, -0.33 to -0.04]; p=.011).  
 
Mortality rates between the groups were similar. Among 45 
bereaved surrogates, adjusting for time and baseline values, 
those in SPIRIT had less anxiety (β=-1.13 [CI, -2.23 to -0.03]; 
p=.044), depression (β=-2.54 [CI, -4.34 to -0.74]; p=.006), and 
post-traumatic distress (β=-5.75 [CI, -10.9 to -0.64]; p=.027) 
than did controls. Our qualitative thematic analysis of post-
bereavement interviews with surrogates (Box 1) helps explain 
how SPIRIT reduced surrogates’ post-bereavement distress.14  
 
Box 1. Perceived impact of SPIRIT: Themes 
SPIRIT… 
a) was an eye-opening experience regarding the patient’s 
illness, prognosis, and end-of-life care 
b) strengthened relationships between patient and surrogate 
c) helped surrogates feel prepared during the time leading 
up to end-of-life decision-making 
d) helped surrogates have peace of mind during and after 
actual end-of-life decision-making 

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In the context of mild AD, we will focus on short-term preparedness outcomes, rather than end-of-life outcomes, 
including post-bereavement distress for surrogates, because such efforts are not feasible in this 5-year study due 
to the protracted nature of AD trajectories (i.e., death is not imminent). Instead, we will evaluate whether SPIRIT 
results in an embodiment of the patient’s wishes (i.e., advance directives) by 1 year post intervention as an 
exploratory aim. In another exploratory aim, we will interview a sample of surrogates at 1 year to assess the 
perceived impact of the intervention conditions. 
 
 
SPIRIT will be feasible for patients with mild AD and their surrogates but first needs to be modified and pilot-
tested.  While there is considerable heterogeneity in functional performance in the early stages of cognitive 
impairment due to AD,33,80,81 numerous studies have shown the feasibility of consenting patients with mild AD 
(defined as a Montreal Cognitive Assessment [MoCA] score 12-17 or a Mini-Mental State Examination [MMSE] 
score 18-23;) for research and the feasibility of survey completion.3,83 Further, Moye et al.84 demonstrated that 
most adults with mild dementia can participate in decision making as defined by legal standards for competency. 
In addition, several studies that examined the level of cognitive impairment and capacity to complete advance 
directives suggest that an MMSE score of 18-20 is a consistent threshold required for ACP.85-88 SPIRIT is focused on 
exploring patient and surrogate beliefs and values, and does not demand ability to process factually intensive 
information nor does it rely heavily on short-term memory. Thus, SPIRIT is feasible for those with mild AD. The 
first step of the proposed study is to carefully modify SPIRIT to make it suitable for patients with mild AD, their 
surrogates, and clinicians while maintaining the integrity of the intervention to achieve the desired patient and 
surrogate outcomes (i.e., the theoretical core elements),24,89 and then pilot test it (NIH Stage I behavioral 
intervention development24). 
 
At this time our plan is to accomplish the goals of SPIRIT in one session (as in the original version of SPIRIT) rather 
than two (which was used in recent RCTs) because patients typically do not return to the clinic for their next 
medical visit before 6 months. The content of SPIRIT, such as likely situations requiring surrogate decision making 
and end-of-life treatment, will be tailored to the AD context. Also, we will modify the delivery of content to 
incorporate techniques such as reducing information load by proceeding in manageable segments or chunks, 
offering repetition of material, opportunity for rehearsal, and using targeted questioning to verify adequate 
comprehension prior to eliciting preferences for goals of care.90-92 The feasibility of using these so-called 
“enhanced consent techniques” for people with early cognitive impairment has been demonstrated83 and will be 
applied to the adapted intervention. 
 
Another important modification will be to develop and test SPIRIT-remote, a face-to-face delivery of SPIRIT 
through web-based videoconferencing to facilitate wider future implementation. Videophone technology has 
been shown to capture critical, nonverbal communication necessary for psychoeducational interventions and is as 
effective as in-person delivery, with an additional benefit of reaching people in urban and rural areas with 
transportation challenges.93-95 Dr. Hepburn (Co-I) transformed an evidence-based intervention originally delivered 
face-to-face in-person (Savvy) to be a web-based intervention (Tele-Savvy),96 now being tested for efficacy at 4 
NIA-supported AD Centers (R01 AG054079; Lead PI, Hepburn). Two of the Site PIs (Drs. Morhardt & Shah) are Co-
Is on our proposed study. We will leverage the established collaboration between clinicians and scientists across 
these centers and the infrastructure created for the Tele-Savvy project. 
 
Role of and ethical consideration of a one-time intervention in ACP.  Hirschman et al.97 found that as patients’ 
cognitive impairment progresses to an advanced stage, family members used the ‘best interest standard’ 
(decision making based on what a reasonable person would do) more often than ‘substituted judgement’ 
(decision making based on what my loved one would have wanted), raising ethical questions about whose 
preferences are reflected in decisions. Furthermore, the primary reason for using the best interest standard was 
that there had been no previous discussion about the patient’s preferences.98 This highlights the value of SPIRIT 
because it allows patients and their families to discuss future wishes and preferences.  
 
SPIRIT can serve as a foundation to help family members navigate the decision-making journey as a patient 

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progresses to an advanced stage. It can facilitate open discussion about the trajectory of dementia, offer a deeper 
understanding about the patient’s values, goals of care, and possible future treatment choices. It can help family 
members understand their role in decision making. While there are interventions (e.g., decision aids) targeting 
surrogates of nursing home residents with advanced dementia59,101-104 to provide surrogates with decision support 
at the end of life, most surrogates would still have to formulate treatment decisions without intimate knowledge 
of the patient’s wishes or understanding of their role in substituted decision making. A recent systemic review of 
interventions for proxy decision making by family members of people with dementia found that no decision aids 
significantly reduced family members’ decision burden.59   
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The SPIRIT intervention has proven to be safe and efficacious. The proposed trial involves very minimal or low risk. 
Patient and surrogate participants may experience an emotional reaction (e.g., anxiety) or fatigue during the 
intervention or data collection. However, in our previous studies,17-20 intervention dyads were less apprehensive 
and more satisfied with the quality of communication than control dyads. It is expected that psychological burden 
caused by the SPIRIT intervention will be less than or equal to that of usual care.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Findings from our previous studies indicate benefits of the SPIRIT interventions for participants in the intervention 
group, including meeting needs to plan for future medical care and sharing values and beliefs. In addition, in our 
recent study, surrogates in the intervention group perceived the intervention to be highly beneficial during end-
of-life decision making for their loved ones and surrogates showed significantly lower post-bereavement distress 
symptom scores.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
As described above, it is expected that psychological burden caused by the SPIRIT intervention will be less than or 
equal to that of usual care. Previous studies have demonstrated the potential benefits of SPIRIT.  
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Aim 1 
 
 
Adapt SPIRIT (in person) to target 
patients with mild AD and their 
surrogates through a process of 
modification-pretesting-refinement 
using stakeholders (patients, family 
caregivers, and clinicians) and 
experts, including adapting the 
delivery mode to interactive web-
based videoconferencing (SPIRIT-
remote). 
No testable endpoints. 
 
We will modify SPIRIT (in person) 
for people with mild AD and their 
surrogates and pretest it to 
assess acceptability. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
Aim 2 
 
 
In a 2-group RCT with 120 patient-
surrogate dyads, evaluate the 
feasibility and acceptability of 
SPIRIT-remote and the preliminary 
efficacy compared to usual care 
(wait-list control) on preparedness 
outcomes for end-of-life decision 
making 2-3 days after the 
intervention 
preparedness for EOL decision 
making: 
1. Dyad congruence 
2. Surrogate decision-making 
confidence (scale) 
3. Surrogate preparedness scale 
The primary goal of SPIRIT is to 
prepare the patient and 
surrogate for end-of-life decision 
making. The preparedness 
outcomes will indicate whether 
or to what extent SPIRIT 
accomplished the goal. 
Exploratory  
 
 
Compare patient preparedness and 
patient and surrogate acceptability 
post-intervention and the 
completion of advance directives 
among the two treatment 
conditions at  
1-year post-intervention 
Patient preparedness scale, 
Patient acceptability and surrogate 
acceptability at 2-3 post-intervention 
Completion of an advance directive 
(binary) 
 
Using a qualitative method, in a 
sample of surrogates, explore their 
perceptions of the impact of SPIRIT 
at 1-year post-intervention.   
 
No testable endpoints 
We will interview a sample of 
surrogates at 1 year to assess the 
perceived impact of the 
intervention conditions. 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This research is a two-staged project to 1) modify SPIRIT for mild AD, and then 2) formally test its feasibility and 
efficacy, including a longer-term impact on surrogates, with 120 patient-surrogate dyads (240 individuals). 
 
Design Overview:  
Stage 1A 
SPIRIT adaptation, pretesting, and refinement, completed by Year 2, Quarter 2 
 
Initial adaptation of SPIRIT for early dementia by the investigative team 
→Formative review by a panel of clinicians and content experts 
→Analyzing review results and refining SPIRIT 
→Developing SPIRIT-remote (SPIRIT delivered via videoconference)   
→Pretesting of SPIRIT-in person, SPIRIT-remote, and refinement 
→Analyzing patient and surrogate input and final refinement 
Stage 1B 
Evaluation of feasibility/acceptability and efficacy, completed during the remaining years 

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
 
 

With revision (V12) 
 

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With Revision (V14) 

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4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
n (V12)
n
TIFIC RATIONALE FOR STUDY DESIGN
n (V14)

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As in our previous studies of SPIRIT, we chose individual randomization because intervention spillover to the 
control condition is very unlikely. The intervention will be delivered by a trained interventionist, not a care 
provider, in a private room at the clinic (or another private location for the convenience of the dyad) or via 
videoconferencing at home (after the COVID-19 outbreak, all SPIRIT sessions will be delivered via 
videoconferencing), and thus it is nearly impossible for care providers to obtain the knowledge and skill related to 
SPIRIT to change their ACP practice. Furthermore, once diagnosed with early stage AD, follow-up visits typically 
occur every six months unless there is a noticeable cognitive decline, and thus it is unlikely that participants in the 
SPIRIT group could share information with those in the control condition thereby influencing outcomes. In fact, all 
of our previous studies used individual randomization and successfully demonstrated the efficacy of SPIRIT. We 
considered a clinic-level cluster RCT in which a care provider delivers SPIRIT, but rejected this option because at 
Stage I intervention development it is important to determine if the intervention has been modified without 
compromised potency. In addition, a cluster RCT is too ambitious in the context of pilot testing since it would 
require many study sites. We chose race (white vs non-white) as a stratification factor to ensure equal allocation 
of race to each treatment condition to control for race as a confounding variable.14. 
 
The most challenging aspects of designing this intervention trial are: a) determining an optimal follow-up time 
point and data collection mode to minimize the potential influence of patients’ cognitive impairment on the 
outcome assessment, and b) maintaining blinding of data collectors. The first follow-up time point (Ideally 2-3 
days post intervention however, consideration is given to difficulty of scheduling dyads and extension may result) 
is to evaluate the impact of SPIRIT on preparedness outcomes while minimizing the potential influence of the 
patient’s impaired ability to recall what was discussed during the SPIRIT session (i.e., the patient needs to recall 
what he/she clarified as goals-of-care preferences). We considered measuring the outcomes immediately 
following the intervention, but this would preclude blinding the data collector because of the modality difference. 
The second follow-up time (12 months post intervention) was chosen to help maximize the number of patients 
whose conditions progress to an advanced stage within the study period so that we can explore how surrogates 
experience having or not having an in-depth ACP discussion before the window of opportunity has closed. 
Although not ideal for people with mild AD, telephone-based data collection was chosen to assure blinding of data 
collectors and to reduce participants’ travel burden. We have used phone-based data collection extensively in our 
previous studies with seriously ill patients and their surrogates using the procedures described above (see Post-
Intervention Assessment). 
 
As in our previous studies, we chose usual care as a comparison condition rather than an attention placebo 
control. In addition to the fact that there is no methodological standard for attention placebo controls in trials of 
psychosocial interventions,116 in the context of preparing for future medical care and end-of-life decision making, 
an attention placebo (information and discussion irrelevant to the context) would not meet the participants’ 
expectations or motivation to participate in the study, and could cause a high refusal rate, dissatisfaction, and 
disproportional dropouts.116 We will offer SPIRIT-remote to control dyads at the completion of the 1 year follow-
up if the patient has not progressed to moderate AD. The same protocol was used in our previous efficacy trial 
with 12-month follow-ups, and a wait-list control did not result in disproportional dropouts (SPIRIT [5.5%] vs usual 
care [2.0%]).30  
 
Revised study design (V12): 
In the effort to meet the target sample size, we expand study recruitment activities to 1) Georgia Memory Net 
sites (Augusta, Macon, Albany, and Columbus) in addition to Atlanta (Grady memory clinic serves as a memory 
assessment clinic for GA Memory Net), 2) Atlanta Regional Commission (ARC)/a federally designated Area Agency 
on Aging (AAA) serving older adults in 10 counties (Cherokee, Clayton, Cobb, DeKalb, Douglas, Fayette, Fulton, 
Gwinnet, Henry, and Rockdale), and 3) Alzheimer’s Association’s early stage program (e.g., early stage support 
groups, monthly lunch groups/Carpe Diem, High Museum tour groups, early memory loss support group series) 
and referrals to GA Memory Net that covers 33 counties.   

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Revised study design (V14): 
Due to the coronavirus pandemic and social distancing recommendations from CDC, it is necessary to eliminate 
SPIRIT in-person modality to minimize in-person physical contacts with study participants. This makes the study a 
2-group (SPIRIT-remote and usual care) RCT.  
 
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
The SPIRIT intervention is a one-time advanced care planning intervention that has been rigorously tested and has 
demonstrated its efficacy. The details about the intervention, including the rationale, are described above (2.2 
Background). 
 
4.4 
END OF STUDY DEFINITION 
 
Because the study includes two phases, the end of the study for participants will be the completion of the one-
year follow-up.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Patient eligibility criteria:  
a) Mild to moderate dementia based on one of the followings: 
a. a MoCA score ≥ 13, or MMSE score ≥ 18 (If other compatible cognitive tests are used at the 
clinic, the name of the test and score should be documented clearly);  
b) able to understand and speak English; and  
c) a UBACC score  ≥  11 or ( a score of 9 or 10 with consultation of PI) 
For Stage 1B, a UBACC score  ≥  11. 
There will be no age limitation, but nearly all patient participants will be 60 years old or older.   
 
In the case where no medical record is available to determine whether the patient has dementia, the  
Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly (Short IQCODE) score from 
the family caregiver interview must be 3.3 or higher. Study staff will also ask caregivers about the comorbid 
conditions of the person with Dementia. 
 
Surrogate eligibility criteria:  
a) 18 years or older (to serve as a surrogate decision-maker, the individual must be an adult);  
b) be chosen by the patient;  
c) have access to a computer and internet connectivity in a private setting, e.g., either the patient’s or the 
surrogate’s home and being able to use email (to receive URL links to a secure videoconferencing 
software, e.g., Zoom); and  
d) able to understand and speak English.  
 
5.2 
EXCLUSION CRITERIA 
 
Patient exclusion criteria:  

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a) lack of an available surrogate 
b) speech impairment 
c) uncompensated hearing deficits, and  
 
Surrogate exclusion criterion: 
a) Those who cannot complete questionnaires due to physical or cognitive limitations will be excluded. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable 
 
5.4 
SCREEN FAILURES 
 
The study participation requires both patient and surrogate as a dyad. It is possible that the patient provides 
written consent to participate in the study first with the assumption that his/her surrogate would be willing to 
participate (note that patients cannot complete the baseline without willing surrogates), and then the surrogate 
actually declines to participate.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment and Consent procedures: 
Stage 1A (pre-testing) 
 
Potential patient participants will be those who are currently receiving care from Emory’s Brain Health Center 
located at the Executive Park (2 miles from the School of Nursing). The Brain Health Center encompasses more 
than 20 clinics which serve a range of neurologic, psychiatric and cognitive conditions. The clinics are staffed by 
doctors, nurse practitioners, registered nurses, and clinical social workers. Patients who are appropriate for this 
study may interface with one or more of the clinics to receive services for a diagnosis of dementia.  
 
A study invitation letter signed by the Brain Health Center doctors, nurse practitioners, and PI will be mailed to 
patients with a recent MoCA score ≥ 13. This letter will explain briefly about the study and include the research 
staff contact information and an opt-out postcard. After 2 weeks, a research staff member will call potential 
patient participants who have not returned the opt-out postcard to explain the study further and schedule a brief 
meeting at the clinic during their upcoming return clinic visit. On the day of the return clinic visit, the research 
staff will review the patient’s medical record to confirm the patient’s eligibility (a through c) and approach the 
patient to obtain verbal consent to administer the UBACC to screen the patient for decision-making capacity. With 
a patient whose UBACC score is equal to or higher than 11 (or score of 9 or 10 with consultation of PI), the 
recruiter will determine whether the person accompanying the patient is an appropriate surrogate decision-
maker using the Surrogate Selection Guide. Written consent will be obtained from each member of the dyad. 
Location for consent meeting will typically be an Emory clinic although we will allow for some flexibility in order to 
meet the demands of patients and surrogates alike.  
 
Stage 1B (formal pilot testing) 
Participants will be recruited from: Emory’s Brain Health Center, Emory Geriatrics Clinics (Tucker, St. Josephs, and 
Domiciliary program), Grady’s Marcus Stroke and Neuroscience Center, Grady Primary Care, Grady Geriatrics, 
Assisted Living facilities, Atlanta Adult Day Care facilities, GA Memory Net sites in Augusta, Albany, Macon, and 
Columbus, Alzheimer’s Association early stage program, and Atlanta Regional Commission. Additionally, the 
current subcontract sites, Rush University and Northwestern University, will assist in recruitment by providing 

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potential participants who are deemed eligible and have agreed to be contacted by the research personnel at 
Emory. Patients at the Alzheimer’s Disease Research Center at Rush and Northwestern Universities have already 
provided a blank consent at enrollment for being contacted by researchers.  
 
In addition to the possible recruitment strategy listed under Stage 1A, another strategy for recruitment will be to 
review the medical records of patients seen at the above clinics. Patient medical records will be reviewed to 
determine eligibility (a through c of inclusion criteria). Study staff will identify patients deemed eligible, and at the 
patient’s next appointment, the patient’s care provider will gain permission for the study staff to explain the 
study. As stated above, study staff will then obtain verbal consent to administer the UBACC to screen the patient 
for decision-making capacity. With a patient who has met the UBACC criterion, the recruiter will determine 
whether the person accompanying the patient is an appropriate surrogate decision-maker using the Surrogate 
Selection Guide. Written consent will be obtained from each member of the dyad. If the surrogate decision-maker 
is not present at the time of the visit, study staff will offer consent to the patient and then obtain the name and 
phone number of the surrogate. Study staff will then call the surrogate within 2 days of the consent visit to assess 
the surrogate’s willingness to participate.  
 
We may also periodically receive lists of eligible patients from providers who have introduced the study to the 
patient at the time of a visit. In that case, we will follow up by phone with the surrogate and arrange a time to 
offer consent to the dyad at the clinic or over the phone. At the time of return clinic visit, study staff will review 
medical records to determine eligibility (a through c of inclusion criteria, and d of exclusion criteria). If eligible, 
study staff will follow the above procedures regarding UBACC screening, confirming the surrogate decision maker, 
and consenting each member of the dyad. 
 
To recruit participants through Emory’s domiciliary program, a study invitation letter signed by the domiciliary 
program director and PI will be mailed to patients/family caregivers. As done in Stage 1A, this letter will explain 
briefly about the study and include the research staff contact information and an opt-out postcard. After 2 weeks, 
a research staff member will review the medical records of domiciliary program patients/families who have not 
returned the opt-out postcard to screen for eligibility (i.e., dementia diagnosis and MoCA score). If they have met 
the criteria, the research staff member will call potential patient and/or family caregiver participants to explain 
the study further and schedule a screening and informed consent meeting at the assisted living facility.  
 
To recruit participants at the assisted living and independent living facilities who are not currently enrolled in 
the domiciliary program, study staff members may receive recommendations from facility employees. In these 
cases, study staff will follow the same procedure listed for Emory domiciliary patients (i.e. mailing a letter with an 
opt- out card and contacting those who do not return the opt out card). We may also receive direct referrals from 
facility staff who will introduce the study and gain permission from residents and their families to be contacted by 
a study team member.  Study staff members will additionally advertise the study in facility newsletters and/or 
attend family events at the community to introduce the study to residents and their family members. Study 
brochures will be made available at these events. Individuals who express interest at these events will be asked to 
provide contact information. A study staff member will follow up with the interested party and determine 
eligibility for the study through a screening and informed consent meeting. 
 
To recruit participants from GA Memory Net sites, the Community Services Educator (CSE) at the site will first 
identify patients who have been diagnosed with dementia and meet the MoCA criterion. When the potentially 
eligible patient and caregiver make a second visit to the memory assessment center (per GA Memory Net 
protocol), the CSE will briefly introduce the study to the patient and caregiver (using a script) and ask permission 
to release their names and contact information (including mailing address) if they are interested in learning more 
about the study from the research staff. Study brochures will also be made available at the site. Upon the receipt 
of names and contact information, the research staff will mail a copy of consent form before contacting.  A 

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research staff member will call the dyad to explain the study further, determine the remaining eligibility criteria 
(e.g., UBACC) and proceed informed consent if eligible. 
 
To recruit participants from Northwestern University and Rush University Alzheimer’s Disease Research Center, 
the co-investigators, Dr. Shah at Rush and Dr. Morhardt at Northwestern, will identify patients who are deemed 
eligible for the study. Their research staff will phone the potential patient participants (and their family 
caregivers/potential surrogate participants) to introduce the study and gain permission to share contact 
information with Emory research staff. Upon receiving referrals, Emory research staff will contact these potential 
participants by phone or email to determine interest and eligibility, explain the study in detail and obtain verbal 
consent using Verbal Informed Consent/HIPAA authorization format.  
 
To recruit participants from other recruitment avenues (adult day care programs, Alzheimer’s Association early 
stage program), study staff may send an invitation letter with the program’s permission. This invitation letter will 
follow the same procedures listed for Emory domiciliary patients (i.e. mailing a letter with an opt-out card and 
contacting those who do not return an opt-out card). Direct referrals may also be received from facility staff 
members as appropriate. Study staff may additionally coordinate IRB approved study advertisements to be placed 
in the facility (including newsletters).  If appropriate and with permission from the program, study staff will 
introduce the study at the program’s events. Individuals who express interest through these methods will be 
asked to provide contact information, and study staff members will subsequently follow-up with those individuals. 
We will also disseminate advertisements through program newsletters (in paper or electronic form). 
 
In the case of Atlanta Regional Commission/AAA), the county case manager, who typically knows the patient’s 
dementia severity and availability of family caregiver, will identify patients/caregivers who are likely to meet the 
study eligibility criteria. When the case manager is in contact with the caregiver, he/she will briefly introduce the 
study to the patient and caregiver (using a script) and ask permission to release their names and contact 
information (including mailing address) if they are interested in learning more about the study from the research 
staff. Study brochures will also be made available at the site. Upon the receipt of names and contact information, 
the research staff will mail a copy of consent form before contacting.  A research staff member will call the dyad 
to explain the study further, determine the remaining eligibility criteria (e.g., UBACC) and proceed informed 
consent if eligible. 
 
Because adult day care programs and other community organizations are social services, they typically may not 
keep health records. In the cases where a dementia diagnosis cannot be confirmed from reliable sources, study 
staff will administer screening questions and a valid questionnaire, “Short Form of the Informant Questionnaire 
on Cognitive Decline in the Elderly (Short IQCODE)”), to the family caregiver to determine whether a patient’s 
cognitive impairment is likely dementia or due to other neurodegenerative condition. The initial screening 
questions will consist of the following questions: 
• 
Has your loved one been evaluated for memory problems at the doctor’s office?  
o If yes, what was the formal diagnosis at that time? 
o Do you have any test results related to the diagnosis? 
• 
Does your loved one take any cognition- enhancing drugs, such as Aricept, Exelon, Reminyl, Namenda, or 
Provigil? 
• 
Has your loved one had a stroke before this memory problem? 
If a caregiver reports their loved one as having dementia based on the screening question and IQCODE (a score 
3.3 or higher), study staff will schedule a meeting to determine full eligibility of their loved one and consent.   
 

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For all recruitment sites, the location for consent meeting can be flexible to meet the demands of participants. 
 
Retention strategies: 
Stage 1A (pre-testing) 
Subject participation will last about three weeks. Each member of the dyad will receive a $30 gift card at 
completion of the post-intervention follow-up (Ideally 2-3 days after the intervention session). 
 
Stage 1B (formal pilot testing) 
To Maximize Participant Retention, strategies found effective in retaining dyads over 12 months (dropouts,  
3.8%) in our efficacy trial30 will be used: (a) obtain backup contact information, (b) make confirmation phone calls 
2 days prior to each appointment, (c) make scripted monthly check-in calls, (d) send holiday and special occasion 
cards, (e) assign the same data collector whenever possible, (f) compensate each member of the dyad as a token 
of appreciation ($20 at baseline, $25 at post-intervention assessment) and surrogates who complete the 1-year 
follow-up interview ($30 at 12 months); and (g) use a cell phone matched to the participant’s wireless network 
provider whenever possible (so that their minutes do not run out).  
 
6 
STUDY INTERVENTION(S) 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
SPIRIT Intervention prior to modification:  
In its current form, all sessions of SPIRIT are conducted in a private room in a clinic and follow the structured 
SPIRIT Interview Guide. The goals of SPIRIT are to assist patients to clarify their end-of-life preferences and to help 
surrogates understand the patient’s wishes and prepare for the surrogate role. Currently SPIRIT has two face-to-
face sessions with patient and surrogate together. During the first session (~45 min.), an interventionist assesses 
the patient’s and surrogate’s cognitive, emotional, and spiritual/religious representations of the patient’s illness, 
progression, and end-of-life care. This allows the interventionist to provide individualized information about 
topics, such as the effectiveness of life-sustaining treatment for people with progressive chronic illness (to be 
adapted for AD), and assist the patient to examine his/her values about life-sustaining treatment at the end of 
life. The interventionist also helps the surrogate prepare for end-of-life decision-making and for the emotional 
burden of decision-making by actively involving the surrogate in the discussion. If the surrogate is someone out of 
the order of the hierarchical compensatory model105 (e.g., a sibling is chosen instead of a spouse or child), the 
interventionist explores potential family conflicts and encourages the dyad to talk with other family members and 
complete a medical power of attorney. A Goals-of-Care tool is completed at the end of the session to indicate the 
patient’s preferences.  A brief second session (~15 min.) is conducted about 2 weeks later to address remaining or 
new concerns and questions raised after the first session. The patient’s Goals-of-Care tool is reviewed and 
assessed for the need for clarification or correction. The interventionist documents the patient’s end-of-life 
preferences and the surrogate’s name and relationship to the patient in the medical record. 
 
Planned adaptations of SPIRIT 
Modification 
type 
Nature of modification 
Format/modality 
• Virtual face-to-face via web-based videoconferencing for SPIRIT-remote 
Setting  
• Home for SPIRIT-remote 
Content 
• Condensing two sessions to one (combining Steps 5 & 6) 

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Guided by Stirman’s framework for adaptations of evidence-based interventions,106 we have identified 
modifications that are needed to target patients with mild AD. Drs. Song and Ward will draft the initial content 
adaptations and integrate the enhanced consent techniques into the SPIRIT Interview Guide and will work 
iteratively with Drs. Hepburn, Morhardt, and Shah to complete the initial modifications. The Treatment Fidelity 
Assessment Tool107 will also be modified accordingly.  
 
SPIRIT-remote. We will adapt SPIRIT to a videoconference format so that patients and surrogates can receive the 
intervention in their home. We anticipate SPIRIT delivery via videoconferencing will require minimal training of 
the interventionist and instructions for participants. The equipment needed for videoconferencing includes a 
computer, a webcam, a headset, a microphone (if not already built in the computer), and the Internet. We will use 
Zoom®, a videoconferencing platform supported in Window, Mac, Linux, and other virtual desktop environments. 
Zoom also includes a recording module that is consistent with HIPAA security requirements. A videoconferencing 
workstation will be set up in a private room in the School of Nursing, where the interventionist will conduct 
sessions. 
 
If a dyad is assigned to the SPIRIT-remote group, a research assistant trained to handle technical aspects of Zoom 
will schedule a phone call to take the surrogate through the steps of using email to follow URL links that open 
Zoom. He/she will also guide the surrogate through practice in using basic videoconference operations, e.g., 
accepting an incoming conference invitation, viewing shared documents, muting/unmuting the microphone or 
camera, and ending the call. For dyads with a computer without video capabilities, a loaner web cam (and headset 
and microphone as needed) will be shipped as soon as the group assignment is known. This research assistant will 
initiate the Zoom call for SPIRIT-remote sessions and silently observe sessions to troubleshoot difficulties the dyad 
or interventionist might encounter. These procedures have been used effectively in the Tele-Savvy pilot and 
current R01 project. The interventionist will confirm a follow-up call for outcome assessment to occur in the next 
2-3 days ideally. 
 
Usual Care at the Emory ADC. At the time of the diagnosis of a dementing illness, an advanced practice nurse 
provides written information on advance directives to a patient and his/her family caregiver and reviews this 
information and encourages them to complete an advanced directive. This typically takes about 10 minutes. 
Patients and their family members may be referred to attorneys who can assist them in completing an advance 
directive. If completed, the presence of an advanced directive is documented in the electronic medical record and 
a copy of the advance directive is scanned to the electronic chart. Patients and families may be referred to a 
support group program organized by a social worker in which legal and financial issues are discussed in a group 
setting (by a lawyer). We will review the patient’s medical records at the clinic at baseline and quarterly to track 
activities associated with usual care. To capture any changes in usual care, policy and procedures related to ACP at 
the clinic will be reviewed every 6 months by a research assistant. 
 
Usual Care in Emory Geriatrics, Grady’s Marcus Stroke and Neuroscience Center, Grady Geriatrics and Grady 
Primary Care. At the time of this writing, there are no standardized procedures in place to address the need for 
advance care planning. Some care providers may encourage patients and/or family caregivers to complete an 
advanced directive and provide written information during the patient’s clinic visit.  
 
• Tailoring illness trajectory discussion to AD 
• Tailoring the likely situations requiring EOL decision making and types of EOL 
treatment relevant to AD 
Delivery process 
• Integrating “enhanced consent techniques” 
Training & 
evaluation 
• Integrating “enhanced consent techniques” 
• Adding use of videoconferencing for SPIRIT-remote 

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Usual care at Georgia Memory Net by community services educator (CSE). During the second visit of a patient 
and caregiver at the memory assessment clinic, the CSE asks if the patient has an advance directive, provide 
written information about advance directives if the patient does not have one, and encourage the patient and 
caregiver to complete one. This procedure is standardized across the GA Memory Net sites. 
 
Usual care at Rush University’s Memory Clinic. Inquiry of completion of legal forms including a living will, POA 
health care and POA property is done. If incomplete, patients are provided with the forms and may be 
encouraged to complete before competency comes into question. DNR discussions are typically happening 
through the PCP, not in our clinic. If someone is truly advanced or at end-stage dementia, discussions about end 
of life may occur. If a patient or family has more questions, Rush often refers to a social worker for further 
discussion. A management plan is provided and completion of legal forms is recommended as a part of the 
management plan. 
 
Usual care at Northwestern University’s Memory Clinic. 
 
As applicable (i.e., patients recruited from a clinical care setting), we will review the patient’s medical records at 
the clinic at baseline and quarterly to track activities associated with usual care. For patients without accessible 
medical records (such as patients receiving care outside of Emory or Grady health systems), study staff will collect 
medical history from the surrogate decision maker about the patient with dementia. To capture any changes in 
usual care, policy and procedures related to ACP at the clinic will be reviewed every 6 months by a research 
assistant. 
 
6.1.2 DOSING AND ADMINISTRATION 
 
Described above (6.1.1). 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
For Stage 1B pilot testing, Dr. Paul (statistician/Co-I) will generate a randomization scheme using stratified (by 
race, white vs non-white study site, Emory vs Grady), permuted block randomization with block size 6, using a 
random-number generator. Dyads will be randomized with equal allocation (1:1:1) to SPIRIT-in person, SPIRIT-
remote, or usual care.  
 
With Revision 14, randomization will be stratified by race (white vs non-white) within recruitment site (Emory, 
Rush, and Northwestern), with equal allocation to SPIRIT-in person or usual care. 
 
Due to the nature of the intervention, blinding dyads to their group allocation is impossible, but the research staff 
assessing outcomes will be blind. Immediately after the completion of the baseline assessment by phone, the data 
collector will open a sealed envelope to identify group assignment and schedule an intervention session to take 
place ~2 weeks hence for SPIRIT- in person or –remote (with revision 14, all SPIRIT-remote), as well as a follow-up 
data collection session in the next 2-3 days.  
 
6.3.1 INTERVENTIONIST TRAINING AND ACCOUNTABILITY 

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Two interventionists will deliver both SPIRIT modalities. Interventionist minimal qualification is having at least 2 
years of clinical experience in caring for people with AD as a nurse (RN or APRN) or social worker. Interventionist 
training (led by Drs. Song and Hepburn) will consist of a 3½-day competency-based program used in our previous 
trials using training manuals. Module 1 (1 day) focuses on understanding AD and end-of-life care issues, 
communication as key to improving end-of-life care, and the Representational Approach (theoretical 
underpinnings of SPIRIT); Module 2 (1 day) is a skill-based session on delivery of the SPIRIT intervention (e.g., 
communication behaviors and enhanced consent techniques), including role plays; Module 3 (1/2 day) focuses on 
videoconferencing procedures and etiquette, features of Zoom, and handling technical problems (adapted from 
the Tele-Savvy Training manual). A 2-week practice period is then scheduled for integration of skills. Module 4 (1 
day) involves skill-demonstration and certification. 
 
6.3.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Not applicable. 
 
6.3.3 PRODUCT STORAGE AND STABILITY 
 
Not applicable. 
 
6.3.4 PREPARATION 
 
Not applicable. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
To promote consistency and quality of intervention delivery, the SPIRIT Interview Guide will be used during each 
session. To monitor fidelity, we will use two data sources. 1) The SPIRIT Interview Guide will direct the 
interventionist to document performance data after each patient-surrogate dyad encounter; these data will be 
entered into the Research Electronic Data Capture [REDCap] by the project director. The Guide has a checklist of 
SPIRIT components, including start and finish times, and brief self-evaluation. 2) As in our previous studies, all 
intervention sessions will be audio-recorded. Every 2 months, 50% of sessions randomly selected from SPIRIT-
remote will be reviewed by the PI (approximately 2 sessions from each group). Using the modified Treatment 
Fidelity Assessment Tool, the interventionist’s adherence to intervention content, process, and duration will be 
evaluated on a 3-point scale (1=appropriate, 3=skipped). Problems detected including drift from protocol will be 
discussed with the interventionist and re-training will be provided if adherence is <80% based on the Fidelity 
Assessment Tool. 
 
6.5 
CONCOMITANT THERAPY 
 
Not applicable (all patients receive usual care related to advance care planning). Patient participants will receive 
usual care only or usual care plus an intervention condition. 
 
6.5.1 RESCUE MEDICINE 
   
Not applicable. 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
SPIRIT is a one-time intervention. Any incomplete intervention will be tracked along with the reason. 
 
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 or withdraw a participant from the study for the following reasons: 
• 
If the participant meets an exclusion criterion that precludes further study participation. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the study REDCap. 
Subjects from the clinic randomized to initial SPIRIT who sign the informed consent form but do not receive the 
study intervention may be replaced.  Subjects in the initial SPIRIT who sign the informed consent form and receive 
the study intervention, and subsequently withdraw from the study will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A patient or surrogate participant will be considered lost to follow-up if he or she fails to complete the scheduled 
post-intervention follow-up (for studies in both Stages) and is unable to be contacted by the study site staff until 
the end of the 12-month follow-up period (for Stage 1B study). Or, a surrogate participant who has been selected 
for a semi-structured interview will be considered lost to follow-up if he or she fails to complete the scheduled 12-
month follow-up and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant is determined to be lost to follow-up: 
• 
The research staff will attempt to contact the participant and reschedule the missed appointment for 4 
weeks and ascertain if the participant wishes to continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter 
to the participant’s last known mailing address or local equivalent methods). These contact attempts will 
be documented in the participant’s record in REDCap.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
OUTCOME ASSESSMENTS  
 
In Stage 1A, 
 
Feasibility of recruiting and retaining patients with mild AD and surrogates for SPIRIT-in person and SPIRIT-remote 
will be assessed by tracking the numbers of dyads who are eligible and who agree to participate, and the reasons 
for refusal and withdrawals. Feasibility of conducting SPIRIT-in person and SPIRIT-remote will be assessed by 
tracking the number of dyads who complete their session, the number of incomplete or interrupted sessions, and 

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the minutes required to complete SPIRIT-in person and SPIRIT-remote. We will also explore whether these 
variables are associated with patients’ MoCA or MMSE scores.   
 
Acceptability. After the outcome assessment, the research assistant will conduct a brief semi-structured interview 
(10-15 minutes) with each member of the dyad to ask about: the overall experience with SPIRIT; any facets of the 
intervention that the participant found helpful/not helpful and the reasons; pacing, length, and modality; and 
suggestions for improvement. This interview will be audio-recorded and transcribed for analysis.  
 
Outcomes 
Preparedness for end-of-life decision making (measured at baseline and 2-3 days after the intervention or 
randomization) Note flexibility may be necessary due to challenges of the population and demands of 
scheduling both patients and surrogates:   
• 
Dyad congruence will be assessed using the Goals-of-Care Tool,28,30 which has been modified to include 
two scenarios relevant to the context of AD. In the first, the patient has progressed to advanced dementia 
and develops a severe infection and is admitted to a hospital; the medical team believes recovery unlikely 
and continuing life-sustaining treatment would no longer be beneficial. There are three response options: 
“The goals of care should focus on delaying my death no matter what, and thus I want to continue life-
sustaining treatment”, “The goals of care should focus on my comfort and peace, and thus I do not want 
life-sustaining treatment”, and “I am not sure”. In the second scenario, the patient has progressed to 
advanced dementia and develops a severe infection. The nursing home staff is asking whether the patient 
should be taken to an ED, which will lead to hospitalization with life-sustaining treatments. Patients and 
surrogates complete this tool independently and their responses are then compared to determine dyad 
congruence -- either congruent in both scenarios or incongruent. If both members of the dyad endorse “I 
am not sure”, they are considered incongruent.  
• 
Patient decisional conflict will be measured using the 13-item Decisional Conflict Scale (DCS), a validated 
measure in the context of end-of-life decision making27; higher scores indicate greater difficulty in 
weighing benefits and burdens of life-sustaining treatments and decision making (range 1-5; Cronbach’s α 
= 0.8 – .9327,28,30,121). 
• 
Surrogate decision-making confidence will be measured using the 5-item Decision Making Confidence 
(DMC) scale (Cronbach’s α = 0.81-0.9028,58); higher scores reflect greater comfort in performing as a 
surrogate (0=“not confident at all” to 4=“very confident”). DMC assesses a surrogate’s confidence in: 
knowing the patient’s wishes, ability to make treatment decisions even in a highly stressful situation, 
ability to seek information about risks and benefits of medical choices, ability to handle unwanted 
pressure from others, and ability to communicate with providers about the patient’s wishes.  
• 
We will also assess the overall preparedness for end-of-life decision making using the 26-item 
investigator-developed measure. The measure assesses the level of preparedness for end-of-life decision 
making in the cognitive, emotional, and behavioral dimensions on a 4-point scale (4=strongly agree to 
1=strongly disagree) with higher scores indicating higher levels of preparedness. Patient and surrogate 
each will complete this measure separately.    
 
In Stage 1B, 
 
Acceptability.  Patient and surrogate acceptability will be assessed using the 10-item ACP Acceptability  
Questionnaire developed from our previous trial.24  Participants are asked how strongly they agree or disagree  (4 
to 1) with statements about their experience with SPIRIT sessions, including duration, interactions with the 
interventionist, level of comfort and satisfaction. Higher scores indicate greater acceptability. Each patient and 
surrogate will complete this survey following the preparedness outcome measures after the intervention. 
 

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Preparedness for end-of-life decision making (measured at baseline and ideally 2-3 days after the intervention 
or randomization):   
• 
Dyad congruence will be assessed using the Goals-of-Care Tool,28,30 which has been modified to include 
two scenarios relevant to the context of AD. In the first, the patient has progressed to advanced dementia 
and develops a severe infection and is admitted to a hospital; the medical team believes recovery unlikely 
and continuing life-sustaining treatment would no longer be beneficial. There are three response options: 
“The goals of care should focus on delaying my death no matter what, and thus I want to continue life-
sustaining treatment”, “The goals of care should focus on my comfort and peace, and thus I do not want 
life-sustaining treatment”, and “I am not sure”. In the second scenario, the patient has progressed to 
advanced dementia and develops a severe infection. The nursing home staff is asking whether the patient 
should be taken to an ED, which will lead to hospitalization with life-sustaining treatments. Patients and 
surrogates complete this tool independently and their responses are then compared to determine dyad 
congruence -- either congruent in both scenarios or incongruent. If both members of the dyad endorse “I 
am not sure”, they are considered incongruent.  
• 
Surrogate decision-making confidence will be measured using the 5-item Decision Making Confidence 
(DMC) scale (Cronbach’s α = 0.81-0.9028,58); higher scores reflect greater comfort in performing as a 
surrogate (0=“not confident at all” to 4=“very confident”). DMC assesses a surrogate’s confidence in: 
knowing the patient’s wishes, ability to make treatment decisions even in a highly stressful situation, 
ability to seek information about risks and benefits of medical choices, ability to handle unwanted 
pressure from others, and ability to communicate with providers about the patient’s wishes.  
• 
We will also assess the overall preparedness for end-of-life decision making using the investigator-
developed measure. The measure assesses the level of preparedness for end-of-life decision making in 
the cognitive, emotional, and behavioral dimensions on a 4-point scale (4=strongly agree to 1=strongly 
disagree) with higher scores indicating higher levels of preparedness. Patient and surrogate each will 
complete this measure separately.    
 
Completion of Advance Directives (at 12 months).  A research assistant will review the patient’s medical record 
to determine if the patient has completed an advance directive (a medical power of attorney or living will) by 12 
months. If there is no documentation, the research assistant will call the surrogate to confirm.  
 
Surrogates’ Perceived Impact of SPIRIT (intervention group only). At 12 months, 44-46 surrogates will participate 
in a semi-structured interview by phone: approximately 26 surrogates of patients who have progressed to an 
advanced stage (CDR score > 1; 22% progression rate33,113-115) and 20% randomly selected surrogates of patients 
who have not progressed (~18-20 surrogates). A research assistant will review medical records to identify if a 
patient’s dementia has progressed. A trained interviewer/research assistant will conduct the interview using the 
Perceived Impact Interview Guide, which includes questions about surrogates’ experiences with the treatment 
condition, the perceived impact of the treatment condition on their loved ones and themselves, and what they 
found most and least helpful and why. This 15-30 minute interview will be audio-recorded and transcribed. 
 
Descriptors and Potential Covariates (collected at baseline). Patients and surrogates will each complete a 
Sociodemographic Profile which includes demographic information and previous end-of-life decision-making 
experience. Patients’ clinical characteristics, (date of dementia diagnosis, CDR score, MoCA or MMSE scores, and 
comorbid conditions) will be abstracted from the patient’s medical records. For patients whom we do not have 
access to their medical records, study staff will gather a patient’s clinical characteristics from the surrogate. The 
Medical Profile at Enrollment and the Quarterly Medical Record Review will both require surrogate report when 
medical records are unavailable.   
 
8.2 
SAFETY AND OTHER ASSESSMENTS 

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SPIRIT is a one-time psychoeducational intervention. The proposed trial involves very minimal or low risk. Patient 
and surrogate participants may experience an emotional reaction (e.g., anxiety). However, in our previous 
studies,17-20 intervention dyads were less apprehensive and more satisfied with the quality of communication than 
control dyads. It is expected that psychological burden caused by the SPIRIT intervention will be less than or equal 
to that of usual care.  
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
SPIRIT is a one-time psychoeducational intervention. The study involves very low risk and the potential risk may 
include emotional upset during the session, which is not a “medical occurrence”. SPIRIT has been extensively 
tested in previous trials and no safety concerns have ever arisen.  
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
SPIRIT is an advance care planning intervention to prepare these patients and their surrogates for end-of-life 
decision making. SPIRIT’s safety and beneficial effects (e.g., reducing psychological distress) have been 
consistently demonstrated. Participants’ deaths or hospitalizations, if any, during the trial will occur as part of the 
illness course and will extremely unlikely be related to the intervention or any study related procedures. However, 
any participant’s death will be reported to IRB through annual progress report and included in the NIH annual 
progress report.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
Not applicable. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
Not applicable.  
 
8.3.3.3 EXPECTEDNESS  
 
There are no known expected adverse reactions. SPIRIT has been tested in 5 RCTs with various patient 
populations with serious chronic conditions and in different U.S. regions and settings. Although possible adverse 
reactions to the intervention may include emotional distress during the intervention session, no such reactions 
have been observed in the previous studies. Thus, these reactions are very unlikely to occur. However, 
intervention sessions will stop if the participant appears to be emotionally distressed, and a break or rescheduling 
will be offered.   
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
Not applicable. 

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8.3.5 ADVERSE EVENT REPORTING  
 
The possible adverse reactions, such as emotional distress during the intervention session, if ever occurs, will be 
tracked (documented in the study REDCap) and the aggregated numbers will be reported at the upcoming 
biannual DSMC meeting.  
 
Between the post-intervention (or post-randomization for the usual care group) follow-up and the 12-month 
follow-up with selected surrogates, there will be no study procedures that are required for participants other than 
our monthly check-in calls and there will be no data collection involved. Thus, the study team will have no way of 
knowing if there are any disease-related events (DREs) in the study population.  However, any participant’s 
death, if known, will be reported to IRB through annual progress report and included in the NIH annual 
progress report.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Not applicable. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
 
Not applicable. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Unanticipated problems are defined by DHHS 45 CFR part 46 as any incident, experience, or outcome that meets 
all of the following criteria: 
• 
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 study population;  
• 
related or possibly related to participation in the research (in this guidance document, 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);  
• 
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. 

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It will be extremely unlikely in this study that the events of fatigue or emotional distress would meet the all of the 
criteria above. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
If we encounter any adverse event that meets the definition above and that is related to the intervention, the PI 
will notify the Emory IRB and NINR Program Official and the DSMC within 24 hours of the event being reported to 
the PI. The expedited report will be followed by a detailed, written SAE report as soon as possible. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
In Stage 1A, SPIRIT will be tested with the first 10 dyads. Based on the inputs from the first 10 dyads, SPIRIT will be 
modified and then tested with another 10 dyads. The purpose of this pretesting is to adapt SPIRIT for the target 
population and test the study procedures. Therefore, there will be no hypotheses to be tested.  
 
In Stage 1B,  
• 
Primary Endpoint(s):  
1) The number of intervention dyads who are congruent on goals of care at post-intervention will be 
significantly higher than that of control dyads. 
2) Surrogate decision making confidence (DMC) in the intervention group at post intervention will be 
significantly higher than those of control dyads. 
3) Surrogate preparedness scores in the intervention group at post intervention will be significantly 
higher than those of control surrogates.  
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Our sample size of 40 dyads per group in Stage 1B can detect preliminary efficacy of SPIRIT-in person or SPIRIT-
remote (compared to usual care) on two preparedness outcomes based on effect sizes of the SPIRIT intervention 
in our previous studies.27-30,32 For dyad congruence, we observed large effect sizes (OR=4.4-8.7) at 1 or 2 weeks 
post intervention,28,32 which would require only 10-20 dyads/group to achieve over 80% power. For surrogate 
DMC, a sizable treatment effect was observed at 2 months post intervention,30 but at short-term (2 weeks), the 
effect size was negligible (Cohen’s d=.02).32 Therefore we plan to carefully investigate trends and obtain an 
estimate of the effect size for the AD population instead of solely focusing on hypothesis testing. 
 
Revised sample size calculations (with V12): Due to changes in the study design, we revised our sample size 
calculation. In particular, the new study design will use 2 parallel RCTs:  (1) A 3-arm (SPIRIT-in person, SPIRIT-
remote and usual care) RCT for dyads residing in Atlanta and vicinities (within ~40 miles from Emory), and (2) a 2-
arm (SPIRIT-remote and usual care) RCT if the dyad resides in an area outside of the perimeter. Effect sizes 
estimates, corresponding to the preparedness outcomes from PI’s previous studies, formed the basis for power 
calculation.27-30,32 For dyad congruence, we previously observed large effect sizes (OR=4.4-8.7) at 1 or 2 weeks 

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post intervention,28,32 which would require only 10-20 dyads/group to achieve over 80% power. For surrogate 
DMC, a sizable treatment effect was observed at 2 months post intervention,30 but at short-term (2 weeks), the 
effect size was negligible (Cohen’s d=.02).32  
 
Based on the updated design, we are targeting n=48 dyads for the 3-arm RCT and n=72 dyads for the 2-arm RCT to 
meet our overall target of N=120 dyads. While we are still adequately powered to detect differences in dyad 
congruence in the standalone RCTs; However, for the surrogate DMC outcome, our goal will be to estimate the 
population parameters or effect sizes and investigate trends. In addition, effect sizes from both RCTs will be 
pooled, whenever appropriate, to improve power. 
 
Revised sample size calculation with V14: In light of the changes in study design, we revised our sample size 
calculation. Moving forward, the new study design will only use a 2-arm (SPIRIT-remote and usual care) RCT for all 
dyads included in the study based on 3 sites, both within and outside Georgia. Effect sizes estimates, 
corresponding to the preparedness outcomes from the previous studies, formed the basis for power 
calculation.27-30,32 For dyad congruence, we previously observed large effect sizes (OR=4.4-8.7) at 1 or 2 weeks 
post intervention28,32. We found that a total sample size of 72 obtained by sampling subjects from 3 sites with an 
average of 12 dyads per group (24 total from each site) will achieve adequate ( >80%) power to detect the 
smallest effect size  (odds ratio of 4.3). Because the effect size was negligible for surrogate DMC (Cohen’s 
d=.02).32, our goal will be to establish the population parameters. Considering attrition, the target sample size of 
120 dyads will achieve sufficient power. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Patient-surrogate dyads will be the primary unit of analysis; all analyses will be intent to treat with all available 
data from all participants. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Analyses will be intent to treat with all available data from all participants. Preliminary analyses will include 
summarizing variables with descriptive statistics and graphical displays or frequency tables. Distributional 
assumptions will be assessed and the data transformed as necessary. Baseline characteristics will be examined to 
explore possible between-group differences using analysis of variance and chi-square tests as appropriate. We will 
investigate missing data with pattern analysis for data missing at random or missing not at random, and use 
maximum likelihood or multiple imputation appropriate for each type to impute missing values. We will conduct 
sensitivity analyses to encompass different scenarios of assumptions and evaluate consistency or discrepancy 
among them. 
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
SPIRIT effects on the preparedness outcomes: For dyad congruence, a binary outcome (congruent or not 
congruent), a generalized mixed effects logistic regression model will be used. Specifically, a random intercept 
model will be used to account for dyad level variation over time while treatment group, time (baseline and post-
intervention), and treatment x time interaction will treated as fixed effects. If there is a significant treatment x 
time interaction (α<0.05) (an overall treatment effect), then two contrasts will be tested for individual treatment 
effectiveness (usual care vs SPIRIT-in person and usual care vs SPIRIT-remote). Adjustments for multiple pairwise 
comparisons will be made using Tukey’s test. Surrogate DMC and preparedness scores, we will use linear mixed 

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effects regression models, adjusting for potential covariates as appropriate. Since this is not a non-inferiority trial 
where two or more interventions that have been proven to be superior to usual care are being compared, the 
contrast, SPIRIT-in person vs SPIRIT-remote, cannot be tested. However, if superiority of the two modalities to 
usual care is determined, the estimated group differences could be used for selecting a non-inferiority margin or 
equivalence range124,125 for future studies. 
 
In light of the changes in study design (V12), we will update the statistical analysis plan. In particular, the 
preparedness outcomes from the 2-arm and 3-arm RCTs will be analyzed individually to evaluate the effect of the 
interventions. We will use mixed effects models as mentioned above and use contrasts to compare between the 
three and two intervention groups respectively. In addition to separate analyses, we will conduct pooled analysis 
by using analysis of variance methods (ANOVA) and incorporating an indicator variable for study and evaluate the 
(study x intervention group) interaction effect. We will also explore a meta-analysis approach to obtain a common 
intervention effect of SPIRIT-remote vs usual-care, from the two studies. If the effect sizes obtained from the 
individual studies are relatively homogeneous, their individual results may be combined to produce an estimate of 
the intervention effect. A weighted pooled estimate of effect size can be obtained, using the inverse of each 
study’s variance as the weight. Because the studies are almost identical, we anticipate the variance to be fairly 
similar in both cases; a fixed effects approach will be used to estimate the variance. 
 
With revision V14: The revised statistical analysis plan will be similar to that described in V12. Our primary aim will 
be to evaluate the effect of the SPIRIT- remote intervention group versus usual care on the outcomes of interest. 
We will use generalized linear mixed effect modeling and compare changes in treatment group means or 
proportions over time using contrasts. Because we only have 3 clusters (sites), fitting a multilevel model would 
not be feasible. We will instead adjust for site as a fixed effect in our mixed effects model. We will also compare 
our findings to those from Stage 1A to assess any substantial difference in effect sizes. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
SPIRIT effect on advance directive completion (secondary aim): This analysis will be limited to patients who did 
not have an advance directive at the time of enrollment. For this binary outcome (completed or not completed) 
measured post intervention, the probability of completion will be estimated for the three groups using logistic 
regression. Baseline characteristics that differ across groups will be adjusted. Adjusted group mean proportions of 
completion will be compared between the groups; adjustments for multiple comparisons will be made using 
Tukey’s test.   
 
Surrogates’ perceived impact (secondary aim): As in our previous work,126 qualitative analysis will use content 
and thematic techniques.127 Initial coding involves line by line examination, labeling, and organizing of data into 
segments, preserving detail in participants’ words.128 To optimize validity, codes and definitions will be reviewed 
and refined by the research team and applied to subsequent interviews.129 Related codes will be grouped into 
categories representing aspects of the surrogates’ experiences. Similarities, differences, and trends across cases 
will be examined.130 Then, data will be organized into themes. This work will be done by Drs. Song and Morhardt 
and the project director; discrepancies will be resolved by consensus. To explore differences in themes by AD 
progression and by treatment condition, we will count the occurrence of themes (“quantitizing”)131,132; the 
occurrence of each theme will be counted only once for a participant even if it is mentioned more than once. The 
data will be graphed to facilitate pattern interpretation.133 
  
9.4.4 SAFETY ANALYSES 
 
Not applicable. 
 

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9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
See 9.4.1 General Approach. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Not applicable. 
 
9.4.7 SUB-GROUP ANALYSES 
 
In order to evaluate whether the SPIRIT has differential effects according to demographic factors such as age, sex, 
race/ethnicity we consider the same generalized mixed effects model, mentioned in Section 9.4.1.  However, 
because of the small sample size, our sub-group analyses will be only exploratory. We will fit the same generalized 
mixed model by additionally including a subject level factor (e.g., race) and its’ interaction with the SPIRIT.  We 
will report p-values and importantly, standard errors and confidence intervals by recognizing the fact that we do 
not have power to detect significant interaction effects for examining all demographic factor combinations. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by measure and time point.  
 
9.4.9 EXPLORATORY ANALYSES 
 
None. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
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 are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering study 
intervention. Prior to going through the informed consent process with a potential participant, a study team 
member must receive permission to approach the potential participant. This permission may occur as a verbal 
consent given to a third party (e.g. medical provider or facility staff member) or as a refrain from returning a pre-
paid opt-out post card (after receiving an introductory letter). Study staff will then approach potential participants 
who have consented to being approached (either in person at the clinic or via telephone). Potential participants 
who agree to be approached by a study staff member will receive the opportunity to screen and consent to the 
study (if eligible). Once potential participants have demonstrated that they meet all eligibility criteria through the 
screening process, they may enroll in the study. The following consent materials are submitted with this protocol. 
 
• 
Patient Consent Form Phase I (Stage 1A) 
• 
Surrogate Consent Form Phase I (Stage 1A) 

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• 
Surrogate Verbal Consent Form Phase I (Stage 1A) 
• 
Patient Consent Form Phase II (Stage 1B) 
• 
Surrogate Consent Form Phase II (Stage 1B) 
• 
Verbal Screening Consent & HIPAA 
• 
Surrogate Verbal Consent Form Phase II (Stage 1B) 
• 
Patient Verbal Consent Form Phase II (Stage 1B) 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Stage 1A (pre-testing) 
Potential patient participants will be those who are currently receiving care from Emory’s Brain Health Center 
located at the Executive Park (2 miles from the School of Nursing). The Brain Health Center encompasses more 
than 20 clinics which serve a range of neurologic, psychiatric and cognitive conditions. The clinics are staffed by 
doctors, nurse practitioners, registered nurses, and clinical social workers. Patients who are appropriate for this 
study may interface with one or more of the clinics to receive services for a diagnosis of dementia.  
 
Study invitation letters signed by Brain Health Center doctors, nurse practitioners, and PI will be mailed to 
patients with a recent MoCA score ≥ 13. This letter will explain briefly about the study and include the research 
staff contact information and an opt-out postcard. After 2 weeks, a research staff member will call potential 
patient participants who have not returned the opt-out postcard to explain the study further and schedule a brief 
meeting at the clinic or a convenient location for the dyad. On the day of the meeting, the research staff will 
review the patient’s medical record to confirm the patient’s eligibility (a through c) and approach the patient to 
obtain verbal consent to administer the UBACC to screen the patient for decision-making capacity. With a patient 
whose UBACC score is equal to or higher than 11 (or 9 or 10 with consultation of PI), the recruiter will determine 
whether the person accompanying the patient is an appropriate surrogate decision-maker using the Surrogate 
Selection Guide. Written or verbal consent will be obtained from each member of the dyad. 
 
Stage 1B (formal pilot testing) 
Participants will be recruited from: Emory’s Brain Health Center, Emory Geriatrics Clinics (Tucker, St. Josephs, and 
Domiciliary program), Grady’s Marcus Stroke and Neuroscience Center, Grady Primary Care, Grady Geriatrics, 
Assisted Living facilities, Atlanta Adult Day Care facilities, GA Memory Net sites in Augusta, Albany, Macon, and 
Columbus, Alzheimer’s Association early stage program, Atlanta Regional Commission, Northwestern University 
and Rush University.  
 
In addition to the possible recruitment strategy listed under Stage 1A, another strategy for recruitment will be to 
review the medical records of patients seen at the above clinics. Patient medical records will be reviewed to 
determine eligibility (a through c of inclusion criteria). Study staff will identify patients deemed eligible, and at the 
patient’s next appointment, the patient’s care provider will gain permission for the study staff to explain the 
study. As stated above, study staff will then obtain verbal consent to administer the UBACC to screen the patient 
for decision-making capacity. With a patient who has met the UBACC criterion, the recruiter will determine 
whether the person accompanying the patient is an appropriate surrogate decision-maker using the Surrogate 
Selection Guide. Written consent will be obtained from each member of the dyad. If the surrogate decision-maker 
is not present at the time of the visit, study staff will offer consent to the patient and then obtain the name and 
phone number of the surrogate. Study staff will then call the surrogate within 2 days of the consent visit to assess 
the surrogate’s willingness to participate.  
 
We may also periodically receive lists of eligible patients from providers who have introduced the study to the 
patient at the time of a visit. In that case, we will follow up by phone with the surrogate and arrange a time to 

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offer consent to the dyad at the clinic or over the phone. At the time of return clinic visit, study staff will review 
medical records to determine eligibility (a through c of inclusion criteria, and d of exclusion criteria). If this is not 
possible due to SARS-COV2, eligibility will be determined using screening methods over the phone. If eligible, 
study staff will follow the above procedures regarding UBACC screening, confirming the surrogate decision maker, 
and consenting each member of the dyad. 
 
To recruit participants through Emory’s domiciliary program, a study invitation letter signed by the domiciliary 
program director and PI will be mailed to patients/family caregivers. As done in Stage 1A, this letter will explain 
briefly about the study and include the research staff contact information and an opt-out postcard. After 2 weeks, 
a research staff member will review the medical records of domiciliary program patients/families who have not 
returned the opt-out postcard to screen for eligibility (i.e., dementia diagnosis and MoCA score). If they have met 
the criteria, the research staff member will call potential patient and/or family caregiver participants to explain 
the study further and schedule a screening and informed consent meeting at the assisted living facility.  
 
To recruit participants at the assisted living and independent living facilities who are not currently enrolled in 
the domiciliary program, study staff members may receive recommendations from facility employees. In these 
cases, study staff will follow the same procedure listed for Emory domiciliary patients (i.e. mailing a letter with an 
opt- out card and contacting those who do not return the opt out card). We may also receive direct referrals from 
facility staff who will introduce the study and gain permission from residents and their families to be contacted by 
a study team member.  Study staff members will additionally advertise the study in facility newsletters and/or 
attend family events at the community to introduce the study to residents and their family members. Study 
brochures will be made available at these events. Individuals who express interest at these events will be asked to 
provide contact information. A study staff member will follow up with the interested party and determine 
eligibility for the study through a screening and informed consent meeting. 
 
To recruit participants from GA Memory Net sites, the Community Services Educator (CSE) at the site will first 
identify patients who have been diagnosed with dementia and meet the MoCA criterion. When the potentially 
eligible patient and caregiver make a second visit to the memory assessment center (per GA Memory Net 
protocol), the CSE will briefly introduce the study to the patient and caregiver (using a script) and ask permission 
to release their names and contact information (including mailing address) if they are interested in learning more 
about the study from the research staff. Study brochures will also be made available at the site. Upon the receipt 
of names and contact information, the research staff will mail a copy of consent form before contacting.  A 
research staff member will call the dyad to explain the study further, determine the remaining eligibility criteria 
(e.g., UBACC) and proceed informed consent if eligible. 
 
To recruit participants from other recruitment avenues (adult day care programs, Alzheimer’s Association early 
stage program), study staff may send an invitation letter with the program’s permission. This invitation letter will 
follow the same procedures listed for Emory domiciliary patients (i.e. mailing a letter with an opt-out card and 
contacting those who do not return an opt-out card). Direct referrals may also be received from facility staff 
members as appropriate. Study staff may additionally coordinate IRB approved study advertisements to be placed 
in the facility (including newsletters).  If appropriate and with permission from the program, study staff will 
introduce the study at the program’s events. Individuals who express interest through these methods will be 
asked to provide contact information, and study staff members will subsequently follow-up with those individuals. 
We will also disseminate advertisements through program newsletters (in paper or electronic form). 
 
In the case of Atlanta Regional Commission/AAA), the county case manager, who typically knows the patient’s 
dementia severity and availability of family caregiver, will identify patients/caregivers who are likely to meet the 
study eligibility criteria. When the case manager is in contact with the caregiver, he/she will briefly introduce the 
study to the patient and caregiver (using a script) and ask permission to release their names and contact 

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information (including mailing address) if they are interested in learning more about the study from the research 
staff. Study brochures will also be made available at the site. Upon the receipt of names and contact information, 
the research staff will mail a copy of consent form before contacting.  A research staff member will call the dyad 
to explain the study further, determine the remaining eligibility criteria (e.g., UBACC) and proceed informed 
consent if eligible. 
 
Because adult day care programs and other community organizations are social services, they typically may not 
keep health records. In the cases where a dementia diagnosis cannot be confirmed from reliable sources, study 
staff will administer screening questions and a valid questionnaire, “Short Form of the Informant Questionnaire 
on Cognitive Decline in the Elderly (Short IQCODE)”), to the family caregiver to determine whether a patient’s 
cognitive impairment is likely dementia or due to other neurodegenerative condition. The initial screening 
questions will consist of the following questions: 
• 
Has your loved one been evaluated for memory problems at the doctor’s office?  
o If yes, what was the formal diagnosis at that time? 
o Do you have any test results related to the diagnosis? 
• 
Does your loved one take any cognition- enhancing drugs, such as Aricept, Exelon, Reminyl, Namenda, or 
Provigil? 
• 
Has your loved one had a stroke before this memory problem? 
If a caregiver reports their loved one as having dementia based on the screening question and IQCODE (a score 
3.3 or higher), study staff will schedule a meeting to determine full eligibility of their loved one and consent.   
 
To recruit participants from Northwestern University and Rush University Alzheimer’s Disease Research Center, 
the co-investigators, Dr. Shah at Rush and Dr. Morhardt at Northwestern, will identify patients who are deemed 
eligible for the study. Their research staff will phone the potential patient participants (and their family 
caregivers/potential surrogate participants) to introduce the study and gain permission to share contact 
information with Emory research staff. Upon receiving referrals, Emory research staff will contact these potential 
participants by phone or email to determine interest and eligibility, explain the study in detail and obtain verbal 
consent using Verbal Informed Consent/HIPAA authorization format. 
 
For all recruitment sites, the location for consent meeting can be flexible to meet the demands of participants. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
It is very unlikely that this study may be suspended or prematurely terminated since the SPIRIT intervention has 
been extensively tested, including its safety and efficacy. Also, this study aim includes collecting feasibility and 
acceptability data and no planned interim analysis and stopping rules. Nonetheless, if suspension or termination 
occurs, written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, participating clinics, and regulatory 
authorities.  If the study is terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
appointment schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 

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Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy 
the sponsor and IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor. The study documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review 
Board (IRB), regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic), for the participants in this study. The 
clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored in REDCap study database for internal use 
during the study. At the end of the study, all paper records will continue to be kept in a secure location for as long 
a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be directly 
entered into and stored in REDCap study database (Stage 1A). During Stage 1B, all data collection from the 
participants will be completed using paper forms first and then entered into REDCap, followed by data 
verification. Individual participants and their research data will be identified by a unique study identification 
number.  All information collected during the study will be secured and password protected. At the end of the 
study, all study databases will be de-identified and archived at the Emory School of Nursing. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the Emory School of Nursing. After the study is 
completed, the de-identified, archived data will be transmitted to and stored in the REDCap study archive for use 
by other researchers including those outside of the study. When the study is completed, access to study data will 
be provided through the Emory School of Nursing. 
 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Mi-Kyung Song, PhD, RN 
Professor 
Emory University, School of 
Nursing 
1520 Clifton Rd NE, Atlanta, GA 
30322 
404-727-3134 
mi-kyung.song@emory.edu 
 
Project Manager 
Maria Bolanos 
Emory University, School of 
Nursing 
1520 Clifton Rd. NE, Atlanta, GA 
30322 
404-727-1978 
 
Consultant 
Sandra Ward, PhD, RN, 
Professor Emerita 
University of Wisconsin-
Madison 
608-257-0119 
sward@wisc.edu  
 
Co-Investigator 
Kenneth Hepburn, PhD 
Professor 
Emory University, School of 
Nursing 
khepbur@emory.edu 
 

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Co-Investigator/Statistician 
Sudeshna Paul, PhD 
Assistant Professor 
Emory University, School of 
Nursing 
sudeshna.paul@emory.edu 
 
Co-Investigator 
Darby Morhardt, PhD, LCSW 
Associate Professor 
Northwestern University 
d-morhardt@northwestern.edu 
 
Co-Investigator 
Raj Shah, MD 
Associate Professor 
Family Medicine and Rush 
Alzheimer’s Disease Center 
Rush University 
Raj_C_Shah@rush.edu 
 
 
 
 
10.1.6 SAFETY OVERSIGHT 
 
The SPIRIT in mild AD is a single-site, Stage I intervention development and testing research project involving 
minimal risk. The PI will be responsible for ensuring participants’ safety on a daily basis. The Data and Safety 
Monitoring Committee (DSMC) will act in an advisory capacity to the PI 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.  
 
The PI will convene weekly meetings with staff to review progress, subject accrual, and any anticipated and 
unanticipated problems. The weekly progress information will be aggregated for reports and presented at bi-
monthly or monthly all investigators meetings. 
 
The PI will convene a videoconference with the study investigators monthly. At these meetings the investigators 
will assess study performance related to subject recruitment (at least 5 dyads per month), review the quality of 
the data, and discuss any adverse events. The investigators will determine any need for re-training of study staff. 
We will set up a DSMC responsible for reviewing trial data on an ongoing basis. The DSMC will meet twice 
annually by teleconference call to review study progress, data quality, and participants safety. The PI will be 
informed of SAE as soon as they occur and will notify the NIA and DSMC within 24 hours of notification.  
 
The content of the data and safety monitoring report will include: 
• 
Overall study status 
• 
Enrollment (actual vs expected) and participant enrollment status 
• 
Reasons for screen failures and protocol deviations and violations 
• 
Participant demographic and key baseline characteristics 
• 
Summary of incidence of adverse events, serious adverse events, and unanticipated problems 
• 
Data quality, missing data. 
 
See the DSMP and DSMC Charter for more details. 
 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).  
 
All study data will be directly entered into REDCap. The data entry forms in REDCap will be set up such that out-of-
range values are not accepted, which will minimize data entry error.   
 

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• 
The PI and Project Director will conduct monitoring quarterly throughout the study. A random review of 
10% primary endpoint data and secondary endpoint data will be performed. A monitoring report will be 
generated at completion of review and will be shared with the study team.   
• 
Independent audits will not be conducted as this trial collects medical history and data related to the AD 
diagnosis at baseline and AD progression at 12 months.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
All research staff will complete competency-based training for recruitment and data collection activities. The PI 
and Project Manager will train staff in all study procedures. All project staff will complete university sponsored 
research integrity training, including modules on the protection of human subjects, HIPAA, and Good Clinical 
Practice. All roles, responsibilities, and a protocol with scripted subject contacts will be clearly delineated in the 
study Standard Operating Procedures (SOPs). These SOPs will be easily accessible to the research staff.  
 
Data collectors/recruiters will attend a competency based, one-day training session that the PI and Project 
Manager will convene. Following a demonstration by the PI or Project Manager on how to recruit participants and 
obtain informed consent, the recruiters will be expected to perform three satisfactory practice recruitment 
sessions before actual performance. After demonstrating satisfactory performance of consenting sessions, the 
recruiters will be authorized to recruit and enroll participants.  
 
Training for data collection will include scripted data collection techniques with special attention to assessing 
participant fatigue or discomfort during the data collection session. Data collectors will conduct a series of three 
practice baseline and follow-up data collections using volunteers. After demonstrating satisfactory performance 
on data collection, they will be authorized to perform data collection activities with enrolled participants. They 
will also need to demonstrate completeness of data collection activities using REDCap.  
 
The following strategies will be employed for internal quality management of study conduct, data collection, 
documentation and completion: 
• 
Use of data collection and data entry SOP 
• 
Using paper forms for data collection and then entering data into REDCap 
• 
Use of a second staff member to quality assure data entry between paper and database 
• 
Each data collector signs his/her work 
• 
Audit research staff members’ performance (e.g., consenting and data collection) biannually. 
 
We will also employ systematic checking of data quality: The project manager will run quality control checks on 
the database quarterly during active subject recruitment and data collection; any missing data or data anomalies 
will be reported to the PI for clarification/resolution.  
 
The PI/Dr. Song will convene weekly meetings with staff to review progress, subject accrual, and any 
unanticipated problems. The weekly progress information will be aggregated for reports and presented at 
monthly investigators meetings. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The School of Nursing at Emory University will maintain close contact with every entity within the study and will 
monitor study activities. We will use a common study web-portal using the Research Electronic Data Capture 

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(REDCap) created and managed in Emory SON. We will create and update study participants’ data through 
REDCap. During data entry, automated checks will be performed that will immediately flag problematic data (e.g., 
missing, out of range, inconsistent), allowing for the research staff member to address any discrepant data 
promptly thus increasing data quality. Data entered into the web-based form are immediately stored in a study 
database and tracked through a journaling process where they are accessible for review by the study team. 
Suspicious data can be flagged through a query management system, and automated alerts provided to the 
sites. A complete audit trail is stored for each database modification. Any discrepant data identified through 
analytic manipulations will be communicated to the sites. Once all queries have been resolved and the database 
has been deemed “clean”, it will be officially locked. All permissions to make changes (append, delete, modify or 
update) to the database by the sites will be removed at that time.  
 
Record keeping and data collection are the responsibilities of the research staff under the supervision of the PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility (if hardcopies of worksheets are 
used), and timeliness of the data reported. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
All study’s written records will be stored in a locked cabinet for 5 years. Study data will be de-identified and 
shared with future researchers per written request and IRB approval (Resource and Data Sharing Plans). 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference 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 are to be developed by the site and implemented promptly.  
 
It is 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.  See Protocol Deviation/Violation Report Form and the 
related SOP.  All deviations will be addressed in study source documents, reported to the Study Coordinator.  The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
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 has 
been 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.   
 
Authorship determination: Authorship confers credit and has important academic, social, and financial 
implications. Authorship also implies responsibility and accountability for published work. We will follow the 
recommendations by the International Committee of Medical Journal Editors (ICMJE) to determine authorship (vs. 

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non-author contributors). http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-
the-role-of-authors-and-contributors.html   
Authorship will be based on the following 4 criteria: 
1. Substantial contributions to the conception or design of the work or the acquisition, analysis, or 
interpretation of data for the work; AND 
2. Drafting the work or revision it critically for important intellectual content (simply participating in writing 
or technical editing of the manuscript is insufficient for authorship); AND 
3. Final approval of the version to be published; AND 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.  
Those who do not meet all 4 of the above criteria will be acknowledged as non-author contributors.  
 
Data sharing:  
We will make the final data from the study, including a codebook, available to researchers after acceptance for 
publication of the main findings from the final dataset. The final data will be a complete and cleaned data set free 
of identifiers. We will make the research data available to users with a data-sharing agreement that includes: (1) a 
commitment to using the data only for research purposes, (2) a commitment to securing the data using 
appropriate computer technology, (3) a commitment to destroying the data after analyses are completed and not 
redistributing to third parties, and (4) IRB approval and clear research questions. Data request and sharing 
procedures, data request forms, and a data-sharing agreement will be accessible through the website of Center 
for Nursing Excellence in Palliative Care, Nell Hodgson Woodruff School of Nursing. The requester will be able to 
download final dataset and codebook. Also, care providers or administrators who wish to use the SPIRIT 
intervention in their practice and care setting can place a request through the Center’s website and will be able to 
download the SPIRIT intervention manual. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
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 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 NIA 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 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Section 
Description of Change  
Brief Rationale 
V1 
10/17/2017 
 
Original version 
 
V2 
02/27/2018 
5.1 Inclusion criteria 
 
5.2 Exclusion criteria 
 
5.5 Strategies for  
recruitment & retention 
Inclusion criteria; modifying 
the initial steps of subject 
identification and 
recruitment based on the 
study clinic’s 
recommendations 
 
To include all types of 
dementia; To make 
the inclusion criteria 
and recruitment 
procedures 
consistent with the 
care setting. 

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V3 
 
05/01/2018 
1.1 Description of Study 
Intervention 
7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
 
10.1.1.1 Consent/assent 
and Other Informational 
Documents Provided to 
participants 
 
10.1.1.2 Consent 
Procedures and 
Documentation 
 
 
Removal of dialysis language 
from all descriptions of 
participant population. 
 
 
 
 
Adding language to describe 
verbal consent procedures 
for participants. 
 
Language removed to 
be consistent with 
the target patient 
population. 
 
 
 
To reduce burden on 
surrogate caregiver 
participants by 
enabling them to 
consent verbally by 
phone. 
 
 
 
 
 
 
V4 
 
6/19/18 
 
5.1 Inclusion Criteria 
 
5.5 Recruitment and 
Consent Procedures 
 
10.1.1.2 Consent 
Procedures and 
Documentation 
 
 
Adding language to Inclusion 
Criteria which reflects the 
tests used to diagnose 
dementia and the language 
used to document diagnosis 
within the patient medical 
chart. Removal of (a) due to 
redundancy with (b).Adding 
Zoom software. 
 
Clarifying that patient 
recruitment may occur at 
any clinic within the Brain 
Health Center network for 
stages 1A or 1B.. 
 
To increase our 
identification and 
recruitment of 
individuals in early 
stages of dementia. 
 
V5 
 
8.14.18 
 
2.2 Background 
 
5.1 & 5.5 Inclusion Criteria 
 
10.1.1.2 Informed Consent 
 
4.5 Scientific Rationale 
 
6.1.1 Study Intervention 
Description 
 
 
Removal of language which 
stipulates recruitment of AD 
Dementia patients only. 
 
 
Change screening UBACC 
floor to ≥ 11 or (score 9 or 
10 with PI consultation). 
 
 
 
Allow patients to 
enter study with any 
type of dementia. 
 
 
Ability to reason 
through the 
intervention is 
necessary even if 
patient has difficulty 

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40 
 
8.1 Outcome Assessment 
 
6.1 Study Intervention 
Description 
Outcome assessment ideally 
2-3 days after SPIRIT 
session. 
 
Location of consent 
procedures and SPIRIT 
sessions to allow for non-
Emory locations. 
 
Study personnel to 
complete outcome measure 
post-SPIRIT session. 
remembering the 
details.  
 
Timeframe loosened 
due to schedule 
challenges related to 
dyads availability. 
 
Incorporate 
convenience to dyads 
in selection of private 
location for consent.  
 
Study personnel 
required to complete 
outcome measure 
rather than 
interventionist. 
V6 
8.21.18 
5.5 Strategies for 
Recruitment and Retention 
Addition of and Grady 
Health System’s Marcus 
Stroke and Neuroscience 
Center, Geriatrics and 
Primary Care Clinics as sites 
for recruitment and 
enrollment. 
To increase the 
diversity of our 
patient population. 
V7 
11.26.18 
1.1 Synopsis, 3.0 Aim 2, 8.1 
Outcomes Assessment, 9.1 
Statistical Hypotheses, 9.2 
Sample size determination, 
9.4.2 Analysis of the 
Primary Endpoints 
 
5.5 Recruitment and 
Consent Procedures 
 
 
6.1.1 Usual Care 
 
 
 
10.1.1.2 Consent 
Procedures and 
Documentation 
 
10.1.8 Quality Assurance 
and Quality Control 
 
Revisions to primary and 
secondary outcomes 
 
 
 
 
 
Refining recruitment 
strategies at 1B sites 
 
 
Description of Usual Care 
practices at 1B sites 
 
 
Refining consent procedures 
at 1B clinic sites 
 
 
Data collection on paper 
Patient cognitive 
impairment that can 
results in a lot of 
missing data in 
primary outcomes 
 
 
Recruitment 
strategies customized 
to study site 
 
Availability of more 
information about 
usual care each site 
 
Customizing consent 
procedures to each 
study site 
 
Ensuring quality and 
accuracy of data 

SPIRIT in mild AD Trial 
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41 
 
V8 
 
4.24.19 
 
5.1 Inclusion criteria 
 
 
 
 
 
 
5.2 Exclusion criteria; 9.4.3 
Analysis of the secondary 
endpoints 
 
 
 
 
 
Removal of CDR from 
cognitive assessment 
description. Instead 
Inserting verbiage to 
describe moderate 
dementia 
 
Removal of the advance 
directive criterion; 
Specification of population 
to be analyzed for advance 
directive completion 
 
 
 
To reflect the level of 
cognitive impairment 
appropriate for 
advance care 
planning discussion 
 
 
To help reach the 
recruitment target 
without 
compromising the 
scientific goals 
 
 
V9 
5.9.19 
5.5 Strategies for 
Recruitment and Retention 
Include Emory domiciliary 
care program and assisted 
living facilities as areas for 
recruitment  
To increase access to 
this research study 
for people affected 
by dementia in other 
community settings 
 
 
V10 
 
 
7.31.19 
5.5 Strategies for 
Recruitment and Retention 
 
 
 
 
 
 
 
10.1.1.1 Consent 
Procedures and 
Documentation 
Expand avenues for 
recruitment at Assisted 
Living Facilities 
 
 
 
 
 
 
Elaborate on consent 
procedures 
To increase 
recruitment of 
eligible patients in 
independent and 
assisted living 
facilities (outside of 
Emory’s Domiciliary 
Program). 
 
To mirror updated 
recruitment 
procedures 

SPIRIT in mild AD Trial 
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42 
 
V11 
9.3.19 
5.5 Strategies for 
Recruitment and Retention 
 
 
 
 
 
 
 
 
 
Expand avenues for 
recruitment to Adult Day 
Care Facilities and Emory’s 
Brain Health Center (under 
1B) 
 
Addition of dementia 
screening questions and IQ 
CODE procedures for family 
caregivers 
 
 
 
 
To Increase 
recruitment of 
eligible patients  
 
 
 
 
To determine 
whether cognitive 
impairment is likely 
due to a 
neurodegenerative 
condition that is 
irreversible when 
medical records are 
not available.  
10.1.1.2 Consent 
Procedures and 
Documentation 
Elaborate on consent 
procedures 
To mirror updates to 
the recruitment 
strategy and process 
 
V12 
9.23.19 
1.2 Schema 
 
4. Overview of study design 
Add an additional pathway 
for participants from remote 
areas of recruitment (i.e., 
local [ATL and vicinities] vs. 
remote areas) 
Maintain study 
integrity while trying 
to meet the target 
sample size 
5.1. Inclusion criteria 
 
5.5 Strategies for 
Recruitment and Retention 
 
6.1.1 Study intervention 
description 
 
9.2 Sample size 
determination 
 
 
9.4.2 Analysis of the 
primary endpoints 
 
10.1.1. Informed consent 
process 
 
Expand avenues for 
recruitment and tailor the 
screening process to the 
avenues 
 
 
Add usual care description 
for additional avenues 
 
 
Revisit sample size for the 
design change 
 
 
Adjustment to the data 
analysis consistent with the 
design change 
 
To meet the target 
sample size 
 
 
 
 
 
 

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43 
 
10.1.1.2 Consent 
Procedures and 
Documentation 
 
Tailor the consent process 
to the avenues (e.g., 
participants from remote 
areas to be consented over 
the phone) 
V13 
11.18.19 
6.1.1 Study Intervention 
Description 
 
8.1 Outcome assessments 
Outline procedures for 
collecting patient medical 
characteristics when 
medical record is not 
accessible 
To accommodate 
participation from 
people receiving care 
outside of Emory or 
Grady 
 
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