D- PRESCRIBE-AD (The Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in Elderly With Alzheimer's Disease Study)
Phase: NA
Conditions: Alzheimer Disease
Sponsor: University of Massachusetts, Worcester

 
A Program to Reduce Inappropriate Medications  Among Older Adults With 
Alzheimer's Disease 
 
NCT05147428 
 
Study Protocol and Analysis Plan: Version 11 May 2023 
 

 
 
 Developing a PRogram to Educate and Sensitize Caregivers to Reduce the 
Inappropriate Prescription Burden in Elderly with Alzheimer's Disease Study (D-
PRESCRIBE-AD).   
Principal Investigator: Jerry H. Gurwitz, MD 
Sponsor: University of Massachusetts Medical School  
Grant Title: Developing a PRogram to Educate and Sensitize Caregivers to 
Reduce the Inappropriate Prescription Burden in Elderly with Alzheimer's 
Disease Study (D-PRESCRIBE-AD). 
Grant Number: 4R33AG069794-02 
Funded by: National Institute on Aging 
Version Number: V.3.0 
11 May 2023 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0  
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
Schedule of Activities .......................................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background ........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................. 11 
2.3.1 
Known Potential Risks ................................................................................................... 11 
2.3.2 
Known Potential Benefits .............................................................................................. 13 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 13 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 14 
4 
STUDY DESIGN ........................................................................................................................................... 16 
4.1 
Overall Design .................................................................................................................................... 16 
1. 
Diagnosis of AD/ADRD based on a modified list of the Chronic Conditions Data Warehouse codes, 
or treatment with a pharmacologic therapy used for AD (e.g., donepezil, rivastigmine, galantamine, or 
memantine) in the 365 days prior to or on cohort entry date. ............................................................................ 17 
2. 
Evidence of prescribing within the past 3 months prior to or on the cohort entry date ...................... 17 
3. 
Age ≥50 years of age as of cohort entry date .......................................................................................... 17 
4. 
Continuous medical and pharmacy insurance coverage for at least the prior year. .......................... 17 
4.2 
Scientific Rationale for Study Design .............................................................................................. 23 
4.3 
Justification for Intervention ............................................................................................................. 25 
4.4 
End-of-Study Definition ..................................................................................................................... 25 
5 
STUDY POPULATION ................................................................................................................................ 26 
5.1 
Inclusion Criteria ................................................................................................................................ 26 
5.2 
Lifestyle Considerations .................................................................................................................... 26 
5.3 
Screen Failures .................................................................................................................................. 26 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 26 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 27 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 27 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................. 27 
6.1.2 
Administration and/or Dosing ....................................................................................... 28 
6.2 
Fidelity ................................................................................................................................................. 28 
6.2.1 
Interventionist Training and Tracking .......................................................................... 28 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 29 
6.4 
Study Intervention/Experimental Manipulation Adherence .......................................................... 29 
6.5 
Concomitant Therapy ........................................................................................................................ 29 
6.5.1 
Rescue Therapy ............................................................................................................. 29 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 29 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 29 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 29 
7.3 
Lost to Follow-Up ............................................................................................................................... 29 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 29 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 29 

D-PRESCRIBE-AD Protocol 
 
Version 3.0  
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
  
8.2 
Safety Assessments .......................................................................................................................... 30 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 30 
8.3.1 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 30 
8.3.2 
Adverse Event Reporting .............................................................................................. 30 
8.3.3 
Serious Adverse Event Reporting ............................................................................... 32 
8.3.4 
Reporting Events to Participants ................................................................................. 32 
8.3.5 
Events of Special Interest ............................................................................................. 32 
8.3.6 
Reporting of Pregnancy ................................................................................................ 32 
8.4 
Unanticipated Problems .................................................................................................................... 32 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 32 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 32 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 33 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 33 
9.1 
Statistical Hypotheses ....................................................................................................................... 33 
9.2 
Sample Size Determination .............................................................................................................. 34 
9.3 
Populations for Analyses .................................................................................................................. 35 
9.4 
Statistical Analyses ............................................................................................................................ 35 
9.4.1 
General Approach .......................................................................................................... 35 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 36 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 37 
9.4.4 
Safety Analyses .............................................................................................................. 38 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 39 
9.4.6 
Planned Interim Analyses ............................................................................................. 39 
9.4.7 
Sub-Group Analyses ..................................................................................................... 39 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 39 
9.4.9 
Exploratory Analyses ..................................................................................................... 39 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 39 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 39 
10.1.1 
Informed Consent Process ........................................................................................... 39 
10.1.2 
Study Discontinuation and Closure ............................................................................. 40 
10.1.3 
Confidentiality and Privacy ........................................................................................... 41 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 42 
10.1.5 
Key Roles and Study Governance .............................................................................. 42 
10.1.6 
Safety Oversight ............................................................................................................. 43 
10.1.7 
Clinical Monitoring .......................................................................................................... 43 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 43 
10.1.9 
Data Handling and Record Keeping ............................................................................ 44 
10.1.10 
Protocol Deviations ........................................................................................................ 44 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 45 
10.1.12 
Conflict of Interest Policy .............................................................................................. 45 
10.2 
Additional Considerations ................................................................................................................. 45 
10.3 
Abbreviations and Special Terms ................................................................................................... 45 
10.4 
Protocol Amendment History ........................................................................................................... 48 
11 
REFERENCES ............................................................................................................................................. 50 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
1 
 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol and all participant materials will be submitted to the IRB for review and approval. 
Approval of the protocol must be obtained before any participant is enrolled. Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to 
the study. 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
2 
 
INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
Date: 
23 Nov. 2021 
 
Name*: Jerry H Gurwitz, MD 
 
Title*: Chief, Division of Geriatric Medicine 
 
Investigator Contact Information 
Affiliation*: University of Massachusetts Medical School  
Address: Worcester, MA 01605 
Telephone: (508) 791-7392 
Email: jerry.gurwitz@umassmed.edu 
 
 
 
 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
3 
 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Developing a PRogram to Educate and Sensitize Caregivers to Reduce 
the Inappropriate Prescription Burden in Elderly with Alzheimer's 
Disease Study (D-PRESCRIBE-AD).  
Grant Number: 
4R33AG069794-02 
Study Description: 
This will be a large, randomized, pragmatic trial to test a health plan-
based intervention leveraging the NIH Collaboratory’s Distributed 
Research Network, which uses the Food and Drug Administration (FDA) 
Sentinel Initiative infrastructure. Our study population will include 
community-dwelling patients with AD/ADRD, identified based on  
diagnosis codes of AD/ADRD or use of a medication for Alzheimer’s 
Disease, who have evidence of inappropriate prescribing of 
antipsychotics, /sedative-hypnotics, or strong anticholinergics. We will 
evaluate the effect of educational interventions designed to stimulate 
patient/caregiver-provider communication about medication safety 
(versus usual care) on the primary outcome defined as absence of any 
dispensing of the targeted inappropriate prescription class from day 91 
to day 270 during the 9 months following receipt of intervention. The 
trial will be conducted in two large, national health plans. The study 
design will be a prospective, randomized, comparative effectiveness 
intervention trial with three arms: (1) a combined patient/caregiver 
and provider educational intervention; (2) a provider only educational 
intervention; and (3) usual care. Our research hypothesis is that 
education on inappropriate prescribing among patients/caregivers and 
their providers can reduce medication-related morbidity in patients 
with AD/ADRD and lead to an improvement in medication safety for 
this vulnerable population. We plan to conduct two separate, 
consecutive pragmatic trials. This sequential approach will allow us to 
adapt the second trial based on the findings and experience gained in 
the first trial, with an expectation of increasing efficiency and 
effectiveness. Adaptations could include dropping the provider only 
arm and/or or further limiting the classes of inappropriate medications 
targeted. 
 
 
Objectives*: 
 
  
Primary Objective: To assess the impact of the patient/caregiver 
educational intervention on inappropriate prescribing to AD/ADRD 
patients. 
Secondary Objectives: To create: (1) a plan for disseminating study 
findings to stakeholders who might implement the intervention or 
make decisions about its future use; and (2) an implementation toolkit 
for health plans and health systems wishing to implement the 
intervention. 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
4 
 
Endpoints/Outcomes: 
Primary Endpoint: We will evaluate the effect of educational 
interventions 
designed 
to 
stimulate 
patient/caregiver-provider 
communication about medication safety (versus usual care) on the 
primary outcome. The primary outcome will be defined as absence of 
any dispensing of the targeted medication from day 91 to day 270 during 
the 9 months following receipt of intervention. 
Secondary Endpoints: Secondary outcomes are listed below.  
These will also be assessed specific to the 6-month observation period 
(days 91-270 following mailing/intervention) based on health plan claims 
data including:  
a) Any dose reduction (defined as ≥ 50% reduction in dose of the 
targeted medication), assessed at the participant level using 
health claims data (outpatient dispensing).   
b) Percentage of patients with polypharmacy. (defined as >5 
active prescriptions for different oral agents) 
c)  Decline in the rates of: emergency room visits; rates of 
hospitalizations; rates of non-acute institutional stays (e.g., 
skilled nursing facilities); and overall health care utilization 
(number of outpatient visits, days hospitalized, emergency 
department visits, and non- acute institutional days). 
d) In-hospital all-cause mortality.  (We can only study in-hospital 
all-cause mortality due to a delay in receipt of comprehensive 
death data.) 
We will use administrative claims data to identify encounters 
of interest (ED visits, hospitalizations, non-acute institutional 
stays, outpatient visits) and only assess oral formulations for 
medications. 
e) Among study subjects who discontinue the targeted 
medication, we will determine if another agent within the 
targeted class has been dispensed over the period of 
observation (day 91-270). 
Study Population: 
The patients in a randomized open label pragmatic trial D-PRESCRIBE-
AD will be randomly selected from the membership of the two 
participating health plans (HealthCore/Anthem and Humana) who meet 
eligibility criteria determined through administrative claims data as 
defined below.   
 
1. Eligibility criteria: To be eligible for enrollment in the study, the 
following inclusion criteria will be met: diagnosis of AD/ADRD 
based on the Chronic Conditions Data Warehouse codes,1 or 
treatment with a pharmacologic therapy used for AD (e.g., 
donepezil, rivastigmine, galantamine, or memantine) in the 365 
days prior to or on cohort entry date (e.g., Jan 1 2022). The two 
AD/ADRD ICD-10 diagnosis codes must be ≥7 day apart and at 
least one of the codes must be within 365 days of the cohort 
entry date. Treatment is defined as use of an ADRD drug based 
on either: (1) days’ supply of one or more dispensing, or (2) a 
dispensing in the 365 days prior to cohort entry date; (b) 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
5 
 
evidence of prescribing with the selected inappropriate 
medication classes including antipsychotics, sedative-hypnotics, 
and strong anticholinergics within the past 3 months prior to or 
on the cohort entry date; (c) age >50 years of age as of cohort 
entry date; and (d) continuous medical and pharmacy 
insurance coverage for at least the prior year. Exclusion criteria 
include evidence of a recent institutional stay encounter in a 
Skilled Nursing Facility, hospice, rehab center, nursing home, 
residential, overnight non-hospital dialysis and other non-
hospital stays within the previous 90 days prior to or on cohort 
entry date; incomplete/missing prescriber ID or incomplete 
contact information for either patient or prescribing provider, 
or on “do not contact” list. 
 
In our feasibility study during the planning year, we identified 130, 682 
participants with AD/ADRD diagnosis codes or prescription dispensing 
for ADRD medications, approximately 20% (n=26,259) also had current 
evidence of inappropriate prescribing and met our eligibility criteria. 
These individuals had a mean age of 78.8 years (SD +/- 9.2); 92% were 
age 65 or older and 28% were age 85 or older; 68.2% were women. 
Based on available data on race/ethnicity, we estimated that 82% were 
White, 15% Black or African American, 1% Asian, <1% Native Hawaiian 
or Pacific Islander, <1% American Indian or Alaska Native, and <1% 
more than one race.  
Phase* or Stage: 
N/A  
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
Our study will be conducted in two national health plans 
(HealthCore/Anthem and Humana).  The study will not include sites 
outside of the United States.  
    
Description of Study 
Intervention/Experimental 
Manipulation: 
The study design will be a prospective, randomized, comparative 
effectiveness intervention trial with three arms: (1) a combined 
patient/caregiver and provider educational intervention; (2) a provider 
only educational intervention; and (3) usual care.  
 
Study Duration*: 
Data collection will take 24 months overall from the cohort 
identification mailing until statistical analysis of data. 
Participant Duration: 
The observation period will extend 9 months (following a 3-month 
“blackout” period following the mailing) for each participant.  
 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
6 
 
1.2 
SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
Randomized 
(n~14,442) 
(~4,814) 
(~4,814) 
(~4,814) 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
7 
 
1.3 SCHEDULE OF ACTIVITIES  
 
 
Timeline 
Year 
1 
Year 2 
Year 
3 
Year 
4 
Year 
5 
Q1 Q2 Q3 Q4 
Q1 
Q2 
Q3 
Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 
R61 Planning Phase 
R33 Implementation Phase 
Identification of cohort #1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization #1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mailing of Intervention Materials 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blackout period 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-month observation period 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Primary and Secondary Outcome 
ascertainment 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Statistical analysis of 1st mailing 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Meeting with DSMB 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Implementation Phase 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identify Study Cohort #2 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Randomization #2 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Mailing of Intervention Materials 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Blackout period 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
6-month observation period 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Primary and Secondary Outcome 
ascertainment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Analysis of 2nd Mailing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Meet with DSMB 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Prepare manuscript 
Ongoing 
Dissemination 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Engagement with stakeholders 
and advisors 
Throughout the study 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
8 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Potentially inappropriate prescribing includes the use of medications that may no longer be necessary or 
that may increase the risk of harm. Inappropriate prescribing can lead to adverse drug events, falls, 
worsening cognitive impairment, and emergency hospitalizations. Inappropriate prescribing is a 
“morbidity multiplier,” increasing overall symptom burden, and adversely affecting health-related quality 
of life and function. Inappropriate prescribing of certain drug categories, such as sedative-hypnotics, 
antipsychotics, and strong anticholinergic agents, poses particular risks for older adults and may be more 
prevalent among those with Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) 
due to a higher prevalence of multimorbidity and associated polypharmacy.2 
Enhancing patient/caregiver communication with the healthcare provider about medications may help 
reduce inappropriate prescribing to persons with AD/ADRD. The overarching goal of our proposal is to 
develop, implement, and evaluate the effect of a patient/caregiver-centered, multifaceted educational 
intervention on inappropriate prescribing in patients with AD/ADRD. The Developing a PRogram to 
Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in Elderly with 
Alzheimer’s Disease Study (D-PRESCRIBE-AD) will be a large, randomized, pragmatic trial to test a health 
plan-based intervention leveraging the NIH Collaboratory’s Distributed Research Network, which uses the 
Food and Drug Administration (FDA) Sentinel Initiative infrastructure. In this study, we will enroll 
community dwelling AD/ADRD patients (based on a diagnosis of AD/ADRD or use of a medication for AD), 
who have evidence of inappropriate prescribing. We will evaluate the effect of educational interventions 
designed to stimulate patient/caregiver-provider communication about medication safety (versus usual 
care) on the cessation of inappropriate prescribing, the primary outcome of this study. The educational 
intervention will be an adaptation of an intervention proven effective in reducing the use of inappropriate 
medications in older adults,3 modified for the AD/ADRD population and their caregivers. 
 
2.2 
BACKGROUND  
Polypharmacy, commonly defined as use of five or more medications, is directly associated with 
multimorbidity and is prevalent among persons with AD/ADRD.4-7   Polypharmacy substantially increases 
the likelihood of being exposed to inappropriate medications and the likelihood that inappropriate 
medications will lead to adverse drug events, falls, worsening cognitive impairment, and emergency 
hospitalizations.8 Inappropriate prescribing includes the use of medications that may no longer be 
necessary or that may increase the risk of harm. While the characterization of a medication as 
“inappropriate” might be considered by some as absolutist, for the purpose of this application, the 
designation “inappropriate prescribing” or “inappropriate medication” indicates the need to carefully 
assess the risks of continued use versus the benefits. In a sense, inappropriate prescribing can be 
thought of as a “morbidity multiplier,” increasing overall symptom burden, and adversely affecting 
health-related quality of life and function. Certain drug categories, such as sedative-hypnotics, 
antipsychotic medications, and strong anticholinergic agents, pose special risks for older adults.9 
Patients with AD/ADRD are at particularly increased risk for inappropriate prescribing due to high levels 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
9 
 
of multimorbidity and polypharmacy, superimposed on the challenges and complexities of their care. 
Patient/caregiver communication with the healthcare provider regarding medications is often 
suboptimal. Addressing this challenge requires an intervention in which patients, caregivers, providers, 
and health systems can play an active role. 
Patients and family caregivers have important insights into their care, but often do not speak up about 
these concerns. Consequently, if healthcare providers are unaware of these concerns, they are unable to 
correct misperceptions or to address and correct actual care breakdowns, including medication safety 
issues. Some healthcare systems have sought to address this challenge, through a campaign called “We 
Want to Know”10 (conceived by Dr. Kathleen Mazor, a co-investigator on this application) that seeks to 
address patient concerns and questions about their care in real-time. While this initiative has been 
focused on engaging patients and families to speak up if they have a concern about their care in the 
hospital, “We Want to Know” serves as a model for activating patients and caregivers to engage 
providers with the purpose of identifying and addressing situations like inappropriate prescribing. The 
Alzheimer’s Association has also sought to activate patients and their caregivers through the use of a 
“Doctor’s Visit Checklist” that includes: (1) taking a list of concerns to the visit with the healthcare 
provider; (2) taking a medication list or medicine bottles to the visit; and (3) asking questions until you 
understand everything.11 
Several direct-to-patient educational efforts have been shown to be effective in improving the quality 
and safety of pharmacotherapy. Dr. Cara Tannenbaum, a consultant on our application, has led a 
number of Canadian studies focused on reducing inappropriate prescribing to older adults through 
direct patient education designed to elicit shared decision-making.12-14  Most relevant to our proposed 
study, Dr. Tannenbaum’s team conducted a consumer-focused educational intervention, targeting the 
inappropriate prescribing of several Beers Criteria medications in older adults (D-PRESCRIBE).3 In D-
PRESCRIBE, educational materials were distributed by pharmacy-based pharmacists by mail or in-
person, and contained information about why the medication may be inappropriate, potential 
alternative treatment options, and tapering protocols for sedative-hypnotics. In this modest-sized trial, 
at 6 months, 106 of 248 patients (43%) in the intervention group no longer filled prescriptions for 
inappropriate medication compared with 29 of 241 (12%) in the control group (risk difference 31% [95% 
confidence interval, 23% to 38%]). We will adapt Dr. Tannenbaum’s proven approach, modified 
specifically for the AD/ADRD population and their caregivers, for implementation in two national health 
plans. Our efforts will represent a substantial scaling-up of prior efforts focused on reducing 
inappropriate prescribing.  
Deprescribing is the clinically supervised process of stopping medications that could cause harm or that 
no longer provide benefits that outweigh potential risks.15-17  It is not an action that the patient and/or 
caregiver takes independent of the prescriber, as it occurs under the guidance and direction of the 
healthcare provider.  Recognizing the multiplicity of factors that influence and challenge deprescribing 
efforts, Linsky and colleagues recently published a unifying deprescribing conceptual framework, 
generalizable across healthcare settings, to advance the science of deprescribing research and to foster 
the design, conduct, and dissemination of deprescribing trials.18 Importantly, this new conceptual 
framework emphasizes the roles of the patient/caregiver, prescriber, and healthcare system, all of 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
10 
 
which influence the decision and ability to deprescribe. Linsky’s framework emphasizes that the 
deprescribing process (including the decision to deprescribe) is ideally shared by patients and healthcare 
providers. It takes into account effects and measures, including process measures of the performance of 
the intervention, and outcomes including ongoing use of inappropriate medications, hospitalization, and 
mortality. Linsky and colleagues also recognize the challenges and delays involved in disseminating and 
implementing effective interventions, highlighting that the findings of deprescribing studies “will be 
limited in impact unless successful approaches are broadly taken up across healthcare systems.” The 
figure below adapts and applies Linsky’s deprescribing conceptual framework to our proposed D-
PRESCRIBE-AD Study. ( Figure 1) 
Figure  1. Deprescribing Framework  
 
 
 
 
 
 
Our overarching hypothesis is that inappropriate prescribing of antipsychotics, sedative-hypnotics and 
strong anticholinergics in AD/ADRD patients can be addressed through enhanced communication 
between the patient/caregiver and the provider, facilitated by the patient’s health plan. The evidence 
of medication-related morbidity as a public health issue justifies large scale efforts to reduce 
inappropriate prescribing in vulnerable patient populations, such as those with AD/ADRD. Evidence also 
exists that simple direct-to-patient educational interventions can impact positively on medication use 
patterns, including discontinuation of potentially harmful therapies. However, existing evidence 
certainly does not prove effectiveness, or even the feasibility, of large-scale, simple educational 
interventions targeting persons with AD/ADRD and caregivers, in addition to their healthcare providers. 
New research is needed to: (1) demonstrate the feasibility of population-based outreach to AD/ADRD 
patients at high-risk for inappropriate prescribing and their family caregivers; (2) demonstrate the 
feasibility and effectiveness of a low-intensity educational intervention focused on reducing 
inappropriate prescribing involving AD/ADRD patients, their family caregivers, and healthcare providers; 
(3) demonstrate the value and efficiency of capitalizing on routinely collected health plan data to 
identify high-risk populations and to assess primary and secondary outcomes; and (4) demonstrate the 
potential to adapt, spread, and scale-up19 a proven intervention (D-PRESCRIBE3) to address 
inappropriate prescribing at a national level. 
Our proposed D-PRESCRIBE-AD study will take advantage of the NIH Collaboratory Distributed Research 
Network, which uses the FDA Sentinel Initiative infrastructure. The FDA Sentinel Initiative has 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
11 
 
previously initiated proof-of concept endeavors employing direct-to-patient strategies using the Sentinel 
infrastructure and the network of participating health plans.20 
Potential Public Health Impact. The proposed research will represent a rigorous evaluation of a large 
scale, health plan-based, educational intervention to improve medication safety and reduce preventable 
medication-related morbidity among high-risk AD/ADRD patients. By design, the proposed intervention 
will be transportable to other large health plans and healthcare systems. 
2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
The proposed study poses minimal risks to the participants. The primary risks to participants are risks 
associated with potential loss of confidentiality and risks associated with the research content area.  
There is a slight risk that research data files might be compromised and obtained or viewed by 
unauthorized persons and we also recognize that the content of the educational materials may be 
emotionally sensitive (related to health conditions and side effects of medications). Our procedures for 
protecting against such risks are described below:  
Risks associated with potential loss of confidentiality. The organizations proposing this study have 
systems, oversight, experienced personnel, and organizational cultures that support the appropriate 
use, access, and storage of confidential information. All persons collecting or handling data will be 
trained in human subjects’ procedures, confidentiality, and privacy protection. All investigators and 
project staff are required to receive and complete IRB and HIPAA training.  
Data for all participants will be kept strictly confidential. All hard copies of research files will be kept in 
locked file cabinets or a locked file room. Participants will be assigned a numerical code (Study ID) for 
identification in the files. Individual identifier information will be removed from study data files as soon 
as possible in the data processing steps. All computerized data will be kept on secured computers or 
networks. These data will be accessible only to research staff using confidential usernames and 
passwords. Statistical analyses will be performed using only limited datasets and only de-identified data 
will be reported. All data will be used for research purposes only; published data will not contain any 
individual identifiers.  
All patient-level electronic data will be maintained by the health plans which have routine access to 
these data.  Investigators who prepare reports, presentations, and publications based on this study will 
never have had access to identifiers of the complete study population. Investigators outside of the 
health plans will never have had access to any identifiers and will only receive deidentified data and 
results. 
HIPAA Authorization 
Electronic Data. Electronic data from the administrative health plan systems will only be collected with 
the appropriate HIPAA Waiver as approved by the IRB.  Electronic data will be collected for the purposes 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
12 
 
of: (1) recruitment for the clinical trial and to contact eligible patients with the intervention educational 
materials; and (2) outcomes assessment for those enrolled in the Clinical Trial. We believe the study meets 
the following criteria to obtain a waiver of HIPAA Authorization (followed by a rationale): 
1. The use or disclosure of protected health information involves no more than a minimal risk to the 
privacy of individuals. 
Rationale: The release of individual PHI will be only to the health plan entities which readily have access 
to those data. The intervention is also entirely consistent with a quality improvement initiative that the 
health plans could initiate on their own.   
2. There is an adequate plan to protect the identifiers from improper use and disclosure. 
Rationale: Identifiers will remain with the participating health plans; no disclosure of individual-level 
patient data will occur beyond the health plan of origin. Data will remain behind secure firewalls at the 
health plans and will not be accessed by any personnel who do not already have routine access as part 
of normal business operations.  
3. There is an adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct 
of the research unless there is a health or research justification for retaining the identifiers or such 
retention is otherwise required by law. 
Rationale: Identifiers, which will remain at the health plan of origin, will be destroyed as soon as all 
data are collected, verified, and analyzed.   
4. There are adequate written assurances that the protected health information will not be reused or 
disclosed to any other person or entity, except as required by law, for authorized oversight of the 
research study, or for other research for which the use or disclosure of the protected health information 
would be permitted. 
Rationale: PHI will not be disclosed beyond the health plan of origin nor for use beyond the scope of 
the research aims of this study. The Sentinel System has established systems for data management and 
security.   
5. The research could not practicably be conducted without the waiver or alteration. 
Rationale: There are several reasons why the research would be impractical without the waiver of 
authorization. First, contacting “control” and “provider only intervention” patients for authorization 
would be an intervention by itself and might affect the results of the study. Secondly, given the number 
of subjects to be included in the pilot and the trials, it would be impractical to collect authorization 
from the total study population included in the research.   
6. The research could not practicably be conducted without access to and use of the protected health 
information. 
Rationale: The research could not practicably be conducted without access to and use of the PHI as 
some PHI is required to identify eligible patients (e.g., date of birth, date of dispensing); PHI is further 
required to contact eligible patients with the intervention educational materials (name, address), and 
PHI is required to assess the outcomes (e.g., dates of dispensings of medications of interest). 
7. Access to the protected health information is necessary. 
Rationale: As described above, access to the PHI is necessary to conduct the research. 
 
We will be requesting a waiver of consent from the IRB for the Randomized Clinical Trial; see section 
10.1.1.1 for details.  
 
The waiver of informed consent is consistent with approach taken in several similar large clinical trials 
such as: 
• 
IMPACT-Afib (NCT03259373);  
• 
The HMO Research Network CERT: Acute Myocardial Infarction (NCT 00211172), 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
13 
 
• 
 Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial: A Randomized 
Evaluation of First-dollar Coverage for Post-MI Secondary Preventive Therapies NCT00566774. 
 
Emotional Distress. Regarding the minor risk of emotional distress from the content of the educational 
materials, we have developed the materials in collaboration with advisors and stakeholders and with 
feedback obtained through interviews with patients, caregivers, and providers to attempt to induce as 
little emotional distress as possible. All materials will be submitted to the IRB for review and approval 
prior to use with study participants in this study. 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
It is uncertain whether individual participants will directly benefit from participation. Some participants 
may learn something new about their health condition and/or treatment. Some participants may 
become motivated to specifically discuss medication management questions with their providers.  
 
The potential societal benefits from this study are substantial. Optimizing models of care for reducing 
inappropriate prescribing among AD/ADRD patients has the potential to enhance patient care greatly – 
including the potential to reduce both morbidity and mortality, as well as reduce costs. Further, quality 
of life benefits may be derived from reducing risk of adverse drug effects caused by inappropriate 
prescribing.  Society may benefit in the future, as this study may contribute to improving communication 
related to best prescribing practices for the AD/ADRD population, and results may be generalizable to 
other conditions and to the general population overall. The benefits to society and the medical practice 
community are seen to outweigh the minimal risks of participating in this study.     
 
Importance of the Knowledge to be Gained 
The products of this study will enhance scientific understanding of how to communicate with and 
educate patients and providers about inappropriate prescribing. These findings will likely be 
generalizable to other health conditions and diseases among older adults. In addition, the products 
which we will produce will be made publicly available for dissemination. The benefits of the knowledge 
to be gained are seen to outweigh the minimal risks of participating in this study. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The D-PRESCRIBE-AD intervention poses a low risk of harm to patients. 
 
The probability and magnitude of harm or discomfort anticipated in the research study are not greater in 
and of themselves than those ordinarily encountered in daily life or during the performance of routine 
physical or psychological examinations or tests. The intervention is entirely consistent with a quality 
improvement initiative that the health plans could initiate on their own. Health plans regularly conduct 
patient safety initiatives and remind physicians about the appropriate use of medications. 
 
The intervention only adds to the existing care of patients focusing on a high priority list of drugs in 
patients with AD/ADRD. There are no restrictions placed on the control group as a result of the trial. 
Additionally, the substantial potential benefits to participants in this study make for a favorable benefit 
to risk ratio.   
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
14 
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary 
 
 
 
To assess the impact of the 
patient/caregiver educational 
intervention on 
inappropriate prescribing to 
AD/ADRD patients. 
 
 
 
 
The primary outcome will be 
defined as absence of any 
dispensing of the targeted 
inappropriate prescription from 
day 91 to day 270 following 
receipt of intervention. 
We selected this 
endpoint 
because the 
absence of any 
dispensing for 
the selected 
inappropriate 
drug during the 
study window is 
likely to reflect a 
clinically 
meaningful effect 
of the 
intervention. 
Our research 
hypothesis is that 
education on 
inappropriate 
prescribing among 
patients/caregivers 
and their providers 
can reduce 
inappropriate 
prescribing in 
patients with 
AD/ADRD. 
 
 
Secondary Outcome: 
a)  Any dose reduction defined as 
a ≥ 50% decrease in the mean 
daily dose of the targeted 
medication, assessed at the 
participant level using health 
claims data (outpatient 
dispensings).   
b) Percentage of patients with 
prevalence of polypharmacy 
(defined as >5 active 
prescriptions for different oral 
agents). 
c) Rates of emergency room 
visits; rates of hospitalizations; 
rates of non-acute institutional 
stays (e.g., skilled nursing 
facilities); overall health care 
utilization (number of outpatient 
visits, days hospitalized, 
emergency department visits, 
and non- acute institutional 
days). 
d) In-hospital all-cause mortality. 
e) Substitution within classes 
 
 
We selected the 
endpoint of dose 
reduction as a 
secondary 
outcome because 
some of these 
potentially 
inappropriate 
medications 
require gradual 
taper and the 
effect of the 
intervention may 
only be reflected 
as a dose 
reduction. We 
set the threshold 
at 50% for dose 
reduction. 
We selected the 
endpoint  
polypharmacy 
which has been 
shown to be 
associated with 
adverse 
outcomes in this 
Education on 
inappropriate 
prescribing among 
patients/caregivers 
and their providers 
can reduce 
medication-related 
morbidity in 
patients with 
AD/ADRD and lead 
to an improvement 
in medication safety 
for this vulnerable 
population. 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
15 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
 
We will use administrative claims 
data to identify encounters of 
interest (ED visits, 
hospitalizations, non-acute 
institutional stays, outpatient 
visits) and only assess oral 
formulations for medications. 
 
 
population. We 
selected the 
endpoint of ER 
visits and health 
care utilization 
measures to 
assess whether a 
change in use of 
the targeted 
medications will 
have an impact 
on these metrics.   
Secondary 
 
 
 
To create: (1) a plan for 
disseminating study findings 
to stakeholders who might 
implement the intervention 
or make decisions about its 
future use; and (2) an 
implementation toolkit for 
health plans and health 
systems wishing to 
implement the intervention. 
Secondary aims will be measured 
by tracking website visits and 
downloads of website materials.   
The study team will also track 
dissemination by tracking 
presentations, publications, and 
any other dissemination 
activities. 
NA 
NA 
Tertiary/Exploratory  
 
 
 
N/A 
 
 
 
 
 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
16 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
 
Overview of intervention and methods: The overarching goal of D-PRESCRIBE-AD is to develop, 
implement, and evaluate the effect of a patient/caregiver-centered, multifaceted educational 
intervention on inappropriate prescribing in patients with AD/ADRD. For the purpose of our study, 
inappropriate prescribing will include sedative-hypnotics, antipsychotics, and strong anticholinergic 
agents. Our research hypothesis is that education on inappropriate prescribing among 
patients/caregivers and their providers can reduce medication-related morbidity in patients with 
AD/ADRD and lead to an improvement in medication safety for this vulnerable population.  We will 
evaluate the effect of educational interventions designed to stimulate patient/caregiver- provider 
communication about medication safety (versus usual care) on the cessation of inappropriate 
prescribing, the primary outcome of this study. The educational intervention will be an adaptation of 
an intervention proven effective in reducing the use of inappropriate medications,3 modified 
specifically for the AD/ADRD population and their caregivers. 
 
Our study will be conducted in two national health plans and will represent a substantial scaling-up of 
prior educational interventions focused on inappropriate prescribing.  The study design will be a 
prospective, randomized, “open-label” educational intervention trial with three arms: (1) a combined 
patient/caregiver and provider educational intervention; (2) a provider only educational 
intervention; and (3) usual care.  
 
It has two sequential phases. Planning phase (R61/phase). We have conducted a one-year R61 
planning phase to precede a four-year R33 implementation phase. During the one-year R61 planning 
phase, we have finalized the intervention and conducted feasibility testing, and stakeholder 
engagement and met the required milestones. The activities are described below.   
 
Planning phase Activities. 
Development and Finalization of Educational Intervention 
We conducted interviews with patients with AD, caregivers of such patients, and providers of such 
patients, to solicit feedback about educational materials pertaining to deprescribing from potentially 
harmful medications. We additionally met two times with an advisory panel and three times with a 
stakeholder panel to gather feedback on these materials. The feedback gathered from participants, 
advisors, and stakeholders was used to iteratively develop the materials. Intervention materials were 
piloted to 200 patients at each of the two participating health plans.  We are currently receiving 
responses to these mailings. 
 
R33 phase.  During the R33 phase we will sequentially implement two separate pragmatic trials 
(Implementation Phase 1 and Implementation Phase 2), the first enrolling up to 15,000 patients, with the 
second trial to be adapted based on the findings and experience gained in the first trial.  Adaptations 
could include dropping the provider only arm and/or or further limiting the classes of inappropriate 
medications targeted. 
 
Study setting: The study will leverage the NIH Collaboratory Distributed Research Network, which uses 
the FDA Sentinel Initiative infrastructure. The FDA Sentinel Initiative, established in 2009, is a long-term 
public health surveillance program designed to create a national electronic system for monitoring the 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
17 
 
safety of FDA-regulated drugs and other medical products. The Sentinel Initiative includes a wide array 
of collaborating organizations across the United States including health plans, which are referred to as 
Health Plans. The electronic data used in this initiative is accessed, maintained, and protected, as part 
of a “distributed network.” In a distributed network, data remain in their existing secure environments, 
rather than being consolidated into a single database; Health Plans maintain physical and operational 
control over their electronic health data behind their institutional firewalls. Health Plans transform 
their data into the Sentinel Common Data Model, execute standardized analytic queries distributed by 
the Sentinel Operations Center, which is based at Harvard Pilgrim Health Care Institute (HPHCI), then 
share the output of queries, with the Operations Center via a secure network portal. This system 
protects the privacy and confidentiality of individual-level health information and is preferred by 
participating health plans over a centralized data repository approach. The FDA Sentinel Initiative 
infrastructure has previously been leveraged to pursue novel efforts relevant to advancing population 
health such as IMPACT-AFib, the first large randomized pragmatic trial employing the Sentinel Initiative 
infrastructure.21  
Definition of Inappropriate Prescribing: We will target inappropriate prescribing of specific drug 
categories such as sedative-hypnotics, antipsychotics, and strong anticholinergic agents. While the 
characterization of a medication as “inappropriate” might be considered by some as absolutist, for 
the purpose of this study, the designation “inappropriate prescribing” or “inappropriate medication” 
indicates the need to carefully assess the risks of continued use versus the benefits. 
 
Study population: The patients in D-PRESCRIBE-AD will be randomly selected from the membership of 
the two participating health plans (HealthCore/Anthem and Humana) who meet inclusion and exclusion 
criteria determined through health plan administrative claims data as defined below.   See Section 4. 1 
and 4.2 in our manual of procedures for the eligibility criteria and cohort identification from this study 
setting. 
 
Eligibility criteria. To be eligible for enrollment in the study, the following inclusion criteria will be met: 
1. 
Diagnosis of AD/ADRD based on a modified list of the Chronic Conditions Data Warehouse 
codes, or treatment with a pharmacologic therapy used for AD (e.g., donepezil, 
rivastigmine, galantamine, or memantine) in the 365 days prior to or on cohort entry date.  
• 
The two AD/ADRD ICD-10 diagnosis codes must be ≥7 day apart and at least one of 
the codes is within 365 days of the cohort entry date.  
• 
Treatment is defined as use of an ADRD drug based on at least two dispensings in the 
365 days prior to or cohort entry date. 
2. 
Evidence of prescribing within the past 3 months prior to or on the cohort entry date 
3. 
Age ≥50 years of age as of cohort entry date  
4. 
Continuous medical and pharmacy insurance coverage for at least the prior year.  
 
Exclusion criteria: 
1. Evidence of a recent institutional stay encounter in a skilled nursing facility, hospice, rehab 
center, nursing home, residential, and other non-hospital stays within the previous 90 days 
prior to or on cohort entry date.. 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
18 
 
2. Incomplete/missing prescriber ID or incomplete contact information for either patient or 
prescribing provider.  
3. On “do not contact” list 
 
Provider Inclusion Criteria: 
1. 
Prescribing provider associated with most recent prescribing of a target drug  
 
 
Feasibility analysis. We conducted a feasibility analysis using data from January 1, 2019 to January 31, 
2021. During the study period, there were 99,826,441 unique members identified in the two health 
plans, of whom 66,862,829 were ineligible for research and excluded. After further excluding 32,832,930 
members due to exclusion criteria (lacking pharmacy and medical coverage, < 50 years, or no diagnosis 
codes of ADRD drug or dispensing for ADRD), there were 130,682 members with AD/ADRD. We 
additionally excluded 104,423 patients without current evidence of inappropriate prescribing, resulting 
in a cohort of 26,259 trial-eligible patients. The selection of participants for the feasibility analysis is 
shown in Figure 2. The flow diagram of participants is shown in Figure 3. 
 
Figure 2. Selection of participants for the feasibility analysis 
 
 
 
 
 
 
 
 
 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
19 
 
 
 
 
 
Figure 3. Flow diagram of participants 
 
 
Eligible Study Population and Demographic Characteristics for the Feasibility Analysis. We identified a 
total of 26,259 trial-eligible members who were living with AD/ADRD and had current evidence of 
prescribing of antipsychotics, sedative-hypnotics, and strong anticholinergics. This corresponds to 
approximately 20% of the 130,682 members with AD/ADRD (having diagnosis codes for AD/ADRD or 
dispensing’s for ADRD drugs). These individuals had a mean age of 78.8 years (SD 9.2); 92% were age 65 
or older and 28% were age 85 or older; 68% were women. They had a Charlson Comorbidly Score of 5.1 
(SD 3.2).  Based on available data on race/ethnicity, we estimate that 82% were White, 15% were Black 
or African American, 1% were Asian, <1% were Native Hawaiian or Pacific Islander, <1% were American 
Indian or Alaska Native, and <1% were more than one race. Approximately 3% were Hispanic.  
 
Proportion of AD/ADRD participants with Inappropriate Prescribing. Among members with AD/ADRD 
(n=130, 682) 9.6% were dispensed  antipsychotics, 5.1% were dispensed sedative-hypnotics, and 8.6% 
received strong anticholinergics. These findings which allowed patients to be on multiple inappropriate 
medication classes are shown (Table 1 A)  
Table 1A. Characteristics of AD/ADRD Population with current evidence of 
potentially inappropriate prescribing in Health Plans Jan January 2019-January 
2020* 
 Number of health plan members with AD/ADRD 
130,682 
Number of health plan members with AD/ADRD and evidence 
of potntially inappropriate prescribing N, % 
26,259, 
20.1% 
Antipsychotics N, % 
12,581, 9.6% 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
20 
 
 
 
 
 
 
 
 
 
 
*Members could be on multiple classes of medications and so sum of total inappropriate percentage > 20.1% 
 
Several patients in the study were on more than one class of inappropriate medications. We plan to 
evaluate the effect of the intervention on a single class of targeted inappropriate prescriptions in the 
trial.  In consultation with our Advisory panel and based on relevance and importance for this study 
population, for patients who were on multiple medication we will prioritize antipsychotics (9.6%) over 
sedative-hypnotics (3.9%) and sedative-hypnotics over strong anticholinergics (6.5%) as shown in Table 
1B. As a result, this analysis displays patients based on this hierarchy.  
 
  
 
 
 
 
 
 
 
 
 
Members prioritized with Antipsychotics > sedative-hypnotics>strong anticholinergics; Total inappropriate percentage=20.1 
 
 
R33 Implementation Phase Aims: The R33 Implementation Phase aims are:  
Aim 1: To assess the impact of the patient/caregiver educational intervention on the primary outcome of 
cessation of inappropriate prescribing among AD/ADRD patients, employing a prospective, randomized 
trial design with three arms: (1) a combined patient/caregiver and provider educational intervention; (2) 
a provider only educational intervention; and (3) usual care. Secondary outcomes will include any dose 
reduction of inappropriate medications, prevalence of polypharmacy; rates of emergency room visits; 
rates of hospitalizations; rates of non-acute institutional stays (e.g., skilled nursing facilities); overall 
health care utilization (number of outpatient visits, days hospitalized, emergency department visits, and 
non-acute institutional days); and inpatient mortality.  
Aim 2: To create: (1) a plan for disseminating study findings to stakeholders who might implement the 
intervention or make decisions about its future use; and (2) an implementation toolkit for health plans 
and health systems wishing to implement the intervention. 
 
R33 Phase (Aim 1): D-PRESCRIBE-AD is a prospective, randomized, “open-label” educational 
intervention trial.  
Sedative hypnotics N, % 
6,617, 5.1% 
Strong anticholinergics N, % 
11,228, 8.6% 
Table 1B. Characteristics of AD/ADRD Population with current evidence of 
inappropriate prescribing in Health Plans Jan January 2020-January 2021 after 
prioritization of Medication Classes # 
Number of health plan members with AD/ADRD 
130,682 
Antipsychotics N, % 
12,581, 9.6% 
Sedative hypnotics N, % 
5,122, 3.9% 
Strong anticholinergics N, % 
8,556, 6.5 % 
Number of health plan members with AD/ADRD and evidence of 
inappropriate prescribing N, % 
26,259, 
20.1% 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
21 
 
 
Patients with a diagnosis of AD/ADRD based on the Chronic Conditions Data Warehouse algorithm,1 or a 
prescription fill for a pharmacologic therapy used in the treatment of AD/ADRD (e.g., donepezil, 
rivastigmine, galantamine, and memantine) within the last 12 months, and who meet the additional 
inclusion (evidence of inappropriate prescribing, , age >50 years, and continuous medical and pharmacy 
insurance coverage of at least the prior year and exclusion criteria (no evidence of a recent institutional 
stay encounter in a Skilled Nursing Facility, hospice, rehab center, nursing home, residential, overnight 
non-hospital dialysis and other non-hospital stays within the previous 90 days prior to or on cohort entry 
date; ; incomplete contact information for patient or prescribing provider),will be randomized to the 
three treatment arms: usual care; provider only education; and patient/caregiver plus provider 
education.  
 
In the provider only arm, only the provider of the patient will receive intervention materials; in the 
patient/caregiver plus provider education arm, both the patient/caregiver plus the provider will receive 
intervention materials. Providers and patients/caregivers will receive applicable educational materials 
through a one-time mailing at trial start. In instances where a patient has been prescribed more than 
one inappropriate medication, only one educational intervention will be mailed based on the hierarchy 
described above (antipsychotics first, followed by sedative-hypnotics, and then strong anticholinergics). 
Within each of the three target drug categories, we included any drug that had a prevalence of 0.5% use 
or higher among potentially eligible subjects in either of the two plans. (see appendix A) 
 
Relevant to the provider only and the patient/caregiver plus provider arms of the trial, a dedicated D- 
PRESCRIBE-AD study website will be available for patients, caregivers, and healthcare providers. The 
website will provide online access to all mailed educational materials. It will also include 
stories/testimonials of patients/caregivers who successfully engaged in collaborative conversations 
with healthcare providers about inappropriate prescribing. The website will provide a study telephone 
number for the “Know Your Meds” study team so that patients, caregivers, and healthcare providers 
will be able to discuss any questions they have about mailed educational materials with a study clinical 
pharmacist. 
 
Over the course of the four-year R33 phase we will sequentially implement two separate pragmatic 
trials (Implementation Phase 1 and Implementation Phase 2, respectively), with the first enrolling up to 
15,000 patients; the second trial will be adapted based on the findings and experience gained in the 
first trial. Adaptations could include dropping the provider only arm and/or or further limiting the 
classes of inappropriate medications targeted. 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
22 
 
 
 
Method of assigning patients to treatment arms: A program, developed by the analytic coordinating 
center (HPHCI), will be used by the participating health plans to identify active members who meet 
eligibility criteria for the trial. Patients will be randomly assigned to the three treatment arms via the 
program.  
 
 
Each participating health plan site will identify its eligible health plan members via a distributed SAS 
program run on their electronic administrative claims data organized according to the Sentinel Common 
Data Model. Individuals who cannot be included in research studies for any reason will be excluded.  A 
programmer at each participating health plan site will use its locally stored patient ID numbers to 
identify the names and contact information (home addresses) of patients and utilize the locally stored 
provider ID numbers to identify the names and contact information of the prescribing provider. For 
patients with a dispensing of a target drug associated with a prescriber who is also associated with 
dispensings to other eligible patients, only one patient associated with each provider will be randomly 
selected. The list of eligible patients, along with the provider list will stay with the health plans and will 
be used by the health plan for the mailing of the intervention materials. The identifiable, patient-level 
data will not be shared with the analytic coordinating center, based at HPHCI.   
 
R 33 Phase (Aim 2): Dissemination: In the final phase of the project, we will develop a plan to 
promote study findings and resources, including the study website, placing a particular emphasis on 
dissemination beyond usual academic circles in order to reach policy and practice audiences whose 
efforts are most likely to be influenced by study findings. The research team will create an initial 
dissemination plan and will present it to the Advisory Committee and Stakeholder Panel for 
feedback and input. Dissemination activities will take advantage of Dr. Gurwitz’s leadership of the 
NIA-funded Advancing Geriatrics Infrastructure and Network Growth (“AGING”) Initiative 
(R33AG057806), a collaborative endeavor of the Health Care Systems Research Network (HCSRN) 
and the NIA-funded Claude D. Pepper Older American Independence Centers (OAICs or “Pepper 
Centers”), which has dissemination of research findings relevant to multimorbidity as a core 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
23 
 
function and key to its mission.22 Dissemination efforts will also be aligned with and facilitated by 
the NIA IMPACT Collaboratory and the NIA-funded US Deprescribing Research Network.  
Recognizing the potential impact and interest in the results of our project, we also plan for 
dissemination of our experience, tools, and research findings through various entities including the 
NIH Collaboratory Distributed Research Network, as well as professional, industry, and advocacy 
organizations such as, but not limited to, the American Geriatrics Society, Alzheimer’s Association, 
the American Pharmacists Association, the Academy of Managed Care Pharmacy, the American 
Society of Health-System Pharmacists, and America’s Health Insurance Plans. To facilitate 
widespread adoption of the intervention, we will create an implementation toolkit. The toolkit will 
provide detailed documentation, and practical “tips” on implementation. All interventional 
materials will be included in the toolkit. Our team has extensive prior experience in creating and 
distributing toolkits as part of dissemination efforts relevant to a number of studies focused on 
improving medication safety and outcomes in older adults.23,24 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The D-PRESCRIBE-AD study design, planning phase, implementation phase, and experimental approach 
will build on experience gained through IMPACT-AFib, an ongoing large scale pragmatic clinical trial, 
which uses the FDA Sentinel platform to implement an educational intervention targeting patients with 
atrial fibrillation and their providers to increase evidence-based use of oral anticoagulants for stroke 
prevention.21 In IMPACT-AFib, patient-level interventions include letters to patients with atrial 
fibrillation, who are not using oral anticoagulant therapy, encouraging them to discuss this with their 
healthcare providers. IMPACT-AFib has randomized over 80,000 patients; cohort identification and 
analysis of outcomes is using health plan claims data, a model which will be emulated in our D-
PRESCRIBE-AD Study. 
With funding from the National Institute on Aging (R56AG061813, PI Gurwitz), we have leveraged the 
NIH Collaboratory Distributed Research Network, which uses the FDA Sentinel System’s distributed data 
network architecture and established collaborative relationships with the participating health plans 
(HealthCore/Anthem and Humana) to identify and capture baseline information on inappropriate 
prescribing (including prescribing cascades). The health plans executed queries that characterized a 
cohort of health plan members with AD/ADRD as of January 1, 2020, defined using Chronic Condition 
Data Warehouse (CCW) codes1 for ADRD or use of medications specific for AD, excluding health plan 
members with an institutional stay. 
These efforts have provided a population-level assessment of the prevalence of inappropriate 
prescribing in the AD/ADRD population. This information serves to inform our description of the study 
population for our proposed D-PRESCRIBE-AD Study. As shown above in Tables 1A and 1B, we identified 
130,682 health plan members with a diagnosis of AD/ADRD or with use of a medication for AD at some 
time during the previous 12 months of whom 20% (n= 26,259) had evidence of inappropriate prescribing 
and were eligible for inclusion.  
Once the study population was identified, we used an iterative process to develop and evaluate patient 
materials for patients with AD/ADRD (see below Figure 4). We modeled our patient materials on 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
24 
 
materials developed by Dr. Cara Tannenbaum (consultant on our D-PRESCRIBE-AD application), the 
Canadian Deprescribing Network, and materials developed from previous research.13,25  The patient 
materials include: a) a cover letter presenting the subject of deprescribing and suggesting a conversation 
with one’s provider; and b) an informational sheet with the potential side effects and best courses of 
action. We iteratively revised the materials based on interviews with patients with AD/ADRD and their 
caregivers (9 caregivers, 2 independent patients, and 3 patient-caregiver dyads (n=17)).  Interviewees 
were receptive to the idea of bringing the materials to their next healthcare visit to initiate a 
conversation, and most indicated a caregiver would see the materials. The revised materials were 
reviewed by a Stakeholder Panel comprised of 3 caregivers of family members with AD/ADRD, 3 
geriatricians, and 2 national health plan leaders.  
We also conducted interviews with primary care providers (5 family medicine, 3 internal medicine, and 3 
geriatric medicine (n=11)) to review provider materials.  These materials included: a) a cover letter 
presenting the subject of deprescribing and stating which patients received materials; b) a deprescribing 
algorithm; and c) a tapering guide.  Providers were supportive of patients receiving the materials. The 
patient and provider materials were also reviewed and approved by collaborating national health plans 
(HealthCore/Anthem and Humana) prior to mailing. This foundational work created educational 
materials that gain patients’, caregivers’, and providers’ attention, are easily understood, address critical 
beliefs and attitudes, motivate conversations about inappropriate prescribing, and promote 
patient/caregiver discussions with prescribers that may ultimately result in deprescribing. The patient 
materials were reviewed and approved by the two collaborating national health plans 
(HealthCore/Anthem and Humana).  
See figure 4 which illustrates the process for creating educational materials.  
Figure 4. Material Development Process 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
25 
 
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
We have planned for a single educational intervention to be mailed by the health plan to 
patients/caregivers and providers. We chose this mode and frequency of delivery in this pragmatic trial 
based on replicating the usual mode and delivery of contacting providers by health plans, lessons 
learned from our provider and patient/caregiver interviews, and the potential for replication of this 
intervention. Health plans often mail letters to providers about medication use issues. We plan to 
replicate the usual mode, delivery and frequency used by health plans in contacting providers in this 
pragmatic trial and extend a similar a mode and frequency to the combined patient/caregiver and 
provider arm. Additionally, we want to minimize the number of mailings to providers based on feedback 
from interviews with providers (and patients/caregivers) who are already overburdened with the 
number of mailings from various sources. Although a single educational intervention may appear to be 
‘light touch’, it is more likely to ultimately be scalable.  
 
4.4 
END-OF-STUDY DEFINITION 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
26 
 
 
The end of the study is defined as completion of the 270-day review of health claims data as shown in the 
Schedule of Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
Study population: The patients in D-PRESCRIBE-AD will be randomly selected from the membership of the 
two participating health plans (HealthCore/Anthem and Humana) who meet inclusion and exclusion 
criteria determined through health plan administrative claims data as defined below.    
 
5.1 
INCLUSION CRITERIA 
Eligibility criteria: To be eligible for enrollment in the study, the following inclusion criteria will be met: 
a) diagnosis of AD/ADRD based on the Chronic Conditions Data Warehouse codes, or treatment with a 
pharmacologic therapy used for AD (e.g., donepezil, rivastigmine, galantamine, and memantine) in the 
365 days prior to or on cohort entry date. (N.B. The two AD/ADRD ICD-10 diagnosis codes must be ≥7 
day apart and at least one of the codes must be within 365 days of the cohort entry date. Treatment is 
defined as exposure to an AD drug based on either: (1) days’ supply of one or more dispensing; or (2) 
a dispensing in the 365 days prior to cohort entry date.) (b) evidence of inappropriate prescribing 
within the 3 months prior to cohort entry date; (c) age >50 years of age as of cohort entry date; and (d) 
continuous medical and pharmacy insurance coverage for at least the prior year.  
 
Exclusion Criteria: 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Evidence of a recent institutional stay encounter in a Skilled Nursing Facility, hospice, rehab 
center, nursing home, residential, overnight non-hospital dialysis and other non-hospital stays 
within the previous 90 days prior to or on cohort entry date.  
2. Incomplete/missing prescriber ID or incomplete contact information for either patient or 
prescribing provider.  
3. On “do not contact” list 
5.2 
LIFESTYLE CONSIDERATIONS 
 
N/A 
5.3 
SCREEN FAILURES 
 
N/A 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Each participating health plan will send approved intervention materials to their respective patients and 
providers as appropriate according to their random group assignment.  Providers and patients/caregivers 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
27 
 
will receive applicable educational materials through a one-time mailing at trial start. All patients who are 
assigned to a group will be considered enrolled.  Participants enrolled in the clinical trial will not receive a 
stipend. 
 
Trial participants will only be contacted once as detailed above.  Outcomes of interest will be provided by 
the health plan to the Analytic Coordinating Center at Harvard Pilgrim Health Care Institute (HPHCI), with 
identifiable patient-level data removed, relating to the 6-month observation period that follows a 3-
month “blackout” period after the initial mailing.  Retention of participants will be determined by their 
continued enrollment with their respective health plan, and as such, the study team will not require a 
specific plan for retention.  
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
 
The study will have two intervention arms; educational intervention to provider only and educational 
materials to patients/caregivers plus educational materials to providers. Educational materials will be 
distributed through a one-time mailing. The two intervention arms are described below.  
 
Provider Only Arm 
• 
 Patients do not receive any materials 
• 
 Providers receive: 
o Letter referencing a specific patient and drug 
o Algorithm to guide decision making about deprescribing 
o Patient information sheet  
o Sample “Tapering Plan” to help patients track dose reductions 
o Main messages: this drug may be inappropriate for this patient; consider deprescribing  
• 
Materials reference the study website  
 
Patient/Caregiver & Provider Arm 
• 
Patient/caregivers receive: 
o Letter referencing a specific drug 
o Information sheet referencing the drug class 
o Main messages: this drug may be inappropriate for you; talk to your provider 
• 
Providers receive: 
o Letter referencing a specific patient and drug 
o Algorithm to guide decision making about deprescribing 
o Patient information sheet 
o Sample “Tapering Plan” to help patients track dose reductions 
o Main messages: this drug may be inappropriate for this patient; consider deprescribing  
• 
Both sets of materials reference the study website  

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
28 
 
 
 
Study specific website. Relevant to the provider only and the patient/caregiver plus provider arms of the 
trial, a dedicated D-PRESCRIBE-AD study specific website will be available for patients, caregivers, and 
healthcare providers. The website will provide online access to all mailed educational materials. It will also 
include stories of patients/caregivers who successfully engaged in collaborative conversations with 
healthcare providers about deprescribing. The website will provide a study telephone number for 
patients, caregivers, and healthcare providers to discuss any study-related questions they have with a 
study clinical pharmacist. 
 
6.1.2 ADMINISTRATION AND/OR DOSING 
 
Providers and patients/caregivers will receive applicable educational materials through a one-time mailing 
at trial start. In instances where a patient has been prescribed more than one inappropriate medication, 
educational materials will be sent for one selected medication class according to the following hierarchy:  
antipsychotics, then sedative-hypnotic, then strong anticholinergic. 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
Level of Fidelity 
Procedures to Ensure Fidelity 
Monitoring 
Study Design 
• 
Protocol based on prior successful studies 
and builds upon well-established 
protocols. 
 
• 
Careful protocol review and regular 
monitoring to ensure accuracy. 
• 
Monitoring of all study documents 
after changes to ensure consistency. 
• 
Distribution of updated documents 
to all participating sites after any 
changes are made 
Intervention Delivery 
 
• 
Detailed Standard Operating Procedures 
(SOP) will be followed for identification 
and randomization of cohort. 
• 
SOPs will also be followed for actual 
mailing of intervention materials.  
 
• 
Regular meetings between research 
team and participating health plans 
to ensure version control and 
maintain consistency in cohort 
identification and intervention 
delivery. 
• 
Ad hoc meetings take place as 
needed for interim communication. 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
29 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Blinding is not required for this study as the intervention is delivered via mail and does not pose a risk for 
bias. As there may be the potential for within-provider “contamination,” such that some providers would 
be treating patients who are randomized to different study arms, for any provider with more than one 
eligible patient, only one patient will be randomly enrolled.   
 
6.4 
 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
N/A 
6.5 
CONCOMITANT THERAPY 
 
N/A 
 
6.5.1 RESCUE THERAPY 
 
N/A 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
N/A 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Patients will be censored from the analysis at the time of disenrollment from the health plan to which 
they were enrolled at the start of the trial, or at the time of death. We will use survival analysis to account 
for censoring of participants. Due to the limitations of health plan data, information on important 
variables such as reasons for disenrollment are not available on censored participants. 
7.3 
LOST TO FOLLOW-UP 
 
N/A 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
30 
 
 
Following a “blackout” period of 3 months after the mailing of the intervention materials to providers 
and patients/caregivers, outcomes will be assessed over a 6-month observation period. Outcomes will 
be identified in health plan claims data via a distributed program, similar to how the eligible members 
were initially identified. We will evaluate the effect of educational interventions designed to stimulate 
patient/caregiver-provider communication about medication safety (versus usual care) on the primary 
outcome defined as absence of any dispensing of targeted medication from day 91 to day 270 following 
receipt of intervention. Secondary outcomes will also be assessed specific to the 6-month observation 
period based on health plan claims data including: dose reduction,  prevalence of polypharmacy 
(defined as >5 active prescriptions for different oral agents); rates of emergency room visits; rates of 
hospitalizations; rates of non-acute institutional stays (e.g., skilled nursing facilities);  overall health care 
utilization (number of outpatient visits, days hospitalized, emergency department visits, comparison by 
drug class, and non-acute institutional days); switching within drug class, and in-hospital mortality. All 
outcomes will be ascertained from health plan claims data. 
 
8.2 
SAFETY ASSESSMENTS 
 
The Principal Investigator and research team will comply with the University of Massachusetts  
Institutional Review Board requirements for defining, collecting and reporting any unanticipated 
problems, adverse events, or serious adverse events during the conduct of research. 
 
All study procedures and recruitment procedures will undergo review by the Institutional Review Board 
at the University of Massachusetts prior to initiating research, and will be subject to annual and other 
required reviews. Investigators will work with NIA to convene a Data Safety and Monitoring Board to 
oversee the human subjects’ safety and adverse event reporting for this trial. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
In the context of this study there is no ascertainment of adverse events, either actively or passively.  
There will be information on clinical outcomes but that will not be available to the investigators until at 
least 12 months or more after the mailing as there are no interim analyses planned.  
 
8.3.1 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
As this study consists only of a mailed intervention, there will be no direct interaction with participants 
to be able to assess adverse events. 
 
In the context of this study there is no ascertainment of adverse events, either actively or passively.  
There will be information on clinical outcomes, but that will not be available to the investigators until at 
least 12 months after the mailing.   
 
8.3.2 ADVERSE EVENT REPORTING  
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
31 
 
In the context of this study there is no ascertainment of adverse events, either actively or passively.  
Adverse event reporting will be refined with input from the DSMB during its initial meeting, to address 
any specific concerns related to this study protocol.  
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Events will be reported to the DSMB at periodic intervals.  
 
Clinical information is not available to us to assess for presence of AEs. There is no contact at all with third 
arm (usual care) precluding any meaningful between- group comparisons. Phone line is available only for 
questions about mailing. The only way to become aware of an AE would be serendipitously on receiving 
a phone call or email from the patients/caregivers or providers which encourages them to contact us with 
any questions about the mailed educational materials. The message and information provided to patients 
regarding the contact information is presented below. 
 
Study personnel will report Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO)s to the 
PI in a timely manner. 
 
When a UPIRSO or AE is present, the PI and Project Manager will submit a report to the UMMS IRB within 
3 working days of receipt of this information. Generally, the report will contain the following: 
• Detailed information about the event or issue, including relevant dates. The report will not 
identify study participants by their names or other personal identifiers. 
• An assessment of whether any subjects or others were placed at risk or suffered any harm (e.g., 
physical, social, financial, legal, or psychological) as a result of the event. 
• If the event involves noncompliance, describe the result of the root cause analysis  
• Any corrective and preventative actions planned or already taken. 
• Any other information requested by UMMS IRB, if applicable. 
• If the report cannot be completed in its entirety within the required time period, the report will 
describe what information is still needed and when the investigator anticipates that a follow-up 
report will be submitted. 
 
Information previously unknown to the IRB that suggests new or increased risk to subjects or others 
(hereinafter referred to as New Safety Information) is promptly reportable to UMMS IRB within 7 calendar 
days of the investigator becoming aware of the information. 
• Information for which the sponsor requires reporting to the IRB, may be summarized and 
submitted to the IRB at continuing review. 
• Protocol deviations that did not harm subject(s) or others or place subject(s) or others at 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
32 
 
increased risk will be summarized and reported to the IRB at continuing review. 
•  Researchers may consult with the UMMS IRB Director if they are uncertain 
about what information is reportable. 
8.3.3 SERIOUS ADVERSE EVENT REPORTING  
In the context of this study there is no ascertainment of adverse events, either actively or passively.   
 
8.3.4 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
8.3.5 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.6 REPORTING OF PREGNANCY  
 
N/A 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, 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 Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied. 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
33 
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will include 
the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number. 
• 
A detailed description of the event, incident, experience, or outcome.  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP. 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor/funding agency within 48 hours of the investigator becoming aware of the event  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor/funding agency within 10 
business days of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 business days of the IRB’s receipt of the report of 
the problem from the investigator] 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Endpoint: 
  
We hypothesize that, compared to patients in the control group, patients who are in either intervention 
arm and receive information around inappropriate prescribing themselves along with their provider, or 
who have a provider that received the mailing, will have reduced inappropriate prescribing. Alternatively, 
our null hypothesis is that there will be no difference in the effects of the educational intervention at the 
end of the observation period.  
 
 
Secondary Endpoint(s): 
 
We hypothesize that education on inappropriate prescribing among patients/caregivers and their 
providers can reduce medication-related morbidity in patients with AD/ADRD and lead to an improvement 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
34 
 
in medication safety for this vulnerable population.  This will be measured by assessing evidence of dose 
reduction of the selected inappropriate medication, reduction in the prevalence of polypharmacy; 
reduction in the rates of emergency room visits; rates of hospitalizations; rates of non-acute institutional 
stays (e.g., skilled nursing facilities); overall health care utilization (number of outpatient visits, days 
hospitalized, emergency department visits, and non-acute institutional days); and in-hospital mortality. 
9.2 
SAMPLE SIZE DETERMINATION 
 
Sample Size and Power. Our target sample size for the first trial is 14,442 patients, 4814 patients in each 
of the three study arms.  The calculations below employ 80% power, overall Type I error rate of .05 with 
a Bonferroni correction for 3 pairwise comparisons of study arms (.05/3=.0167), and 2-sided hypothesis 
testing. Based on our prior analyses,26,27 we anticipate death or health plan disenrollment in 9.9% of 
sampled patients within 3 months of the intervention (receipt of the letter), with the remaining 90.1% 
contributing data in the 6-month interval of interest (days 91-270 post-intervention) – that is, we 
anticipate a per-arm sample size of 4814 × .901 = 4337. 
 
For analyses of the primary outcome, absence of dispensing of targeted inappropriate prescription 
classes in days 91-270, we anticipate censoring in this interval for 13.5% of participants based on prior 
data. To make maximal use of observed data, we will use survival analysis to model time until an 
inappropriate prescription (a “failure”) in days 91-270.  Detectable pairwise between-arm differences  
(e.g., between usual care and an intervention arm) are presented in Table 2 below for a range of 
possible percentages for “failure” = inappropriate prescribing of the targeted drug.   
Table 2. Detectable pairwise between-arm differences in hazard of inappropriate prescription classes in 
days 91-270 
Percent with inappropriate prescribing of 
targeted drug (“failure”), Study Arm 1 
Detectable hazard ratio for inappropriate 
prescribing, Arm 2 versus Arm 1 
40 
.8860 
50 
.8979 
60 
.9067 
70 
.9136 
75 
.9165 
80 
.9192 
85 
.9216 
90 
.9239 
95 
.9260 
99 
.9267 
 
For the range of “failure” percentages examined here, which reflect those seen in Martin et al,3 
detectable hazard ratios range from 0.89 to 0.93.  For example, if 75% of participants randomized to 
Arm 1 are observed to have a “failure” (prescription for a targeted inappropriate medication) by day 
270, the detectable hazard ratio for an inappropriate prescription for Arm 2 versus Arm 1 is 0.9165, a 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
35 
 
8.35% reduction in risk; the corresponding detectable “failure” probability for Arm 2 = 0.7193, a 
difference smaller – i.e., more precise – than that seen in Martin et al.3  Calculations for the secondary 
outcome of ≥50% reduction in dose are parallel.   
 
For additional secondary outcomes, such as per-patient number of hospitalizations or ED visits, based 
upon prior data (mean of 0.35 hospitalizations per 6-month period and 0.4 ED visits per 6-month 
period), we will be able to detect rate ratios of 0.8856 and 0.8927, respectively (corresponding to 
intervention-related reductions of 11.4% and 10.7%), accounting for censoring due to death or 
disenrollment. For between-arm differences in mortality, assuming usual care 6-month mortality of 
6.3% – likely an underestimate given a lag in ascertainment – and 7.6% censoring due to disenrollment 
based on information provided by the participating health plans, the detectable hazard ratio is 0.7356 
corresponding to per-arm survival percentages of 93.7% versus 95.33% (absolute difference of 1.63%).  
9.3 
POPULATIONS FOR ANALYSES 
 
Intention-to-Treat (ITT) Analysis Population (all randomized participants): 
All analyses will be intention to treat. We do not expect differential loss to follow up between the three 
arms of the study.  For the time to event analysis patients will be censored from the analyses at the time 
of death, disenrollment from the health plan, loss of medical or pharmacy coverage, or change in eligibility 
for research based on health plan membership.  
 
We will construct a detailed consort diagram showing the number of patients randomized to the three 
arms, the number of patients lost to follow up, excluded from analyses and the number of subjects 
included in the primary and secondary analysis. [See consort Draft. In section 1.2 (schema)] 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
In descriptive analyses, treatment arms will be compared regarding key patient characteristics, including 
age, gender, and renewal of inappropriate prescriptions in days 1-90, using percentages for categorical 
characteristics and means (standard deviations) or medians (interquartile range) for continuous 
characteristics, depending on the observed distributions.  Analyses of study outcomes will employ two-
sided hypothesis testing and an overall Type I error of 0.05, applying a Bonferroni correction to 
accommodate three pairwise comparisons of the three study arms.  Covariates of a priori interest 
include patient age, gender, and renewal of inappropriate prescriptions in the blackout period.  In 
addition, we will adjust for characteristics that are found to predict study outcomes, in order to increase 
precision for the comparison of study arms,28 as well as for characteristics found to be related to 
censoring or other missing data, in order to reduce possible nonresponse bias.29  All analyses will be 
intention-to-treat.    Sex as a biological variable will be factored into all analyses.  
 
 
 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
36 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
 
 
 
   Statistical Analysis of Primary Outcome: 
1. The primary outcome will be defined as absence of any dispensing of the targeted 
inappropriate prescription class from day 91 to day 270 following the day of mailing. 
Educational interventions will be targeted towards one specific drug class so participants 
who switch within one class (e.g, clonazepam to lorazepam) will not be considered as having 
met primary outcome. The intervention will only target one potentially inappropriate 
medication class for patients who are on more than one class of potentially inappropriate 
medication. 
 
2. Timing of Ascertainment: The timing of ascertainment is over a 6-month period beginning 3 
months after mailing/intervention – i.e., we will assess evidence of a dispensing in days 91 
through 270 after the date of mailing.   
 
3. Method of Aggregation: Hazard ratio. The data on primary outcome will be measured as 
the relative hazard of time to dispensing of any new incident inappropriate prescription of 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
37 
 
their initial drug class in the intervention vs control group. The index date for the survival 
analysis will be Day 91 for the trial. We chose the hazard ratio as method of aggregation as 
this allows the statistical analysis to account for censoring due to death or disenrollment.   
 
4. Any prescriptions dispensed during the blackout period will not be counted towards 
measurement of the primary outcome but may affect subsequent dispensing. In covariate-
adjusted survival analyses, we will adjust for whether any prescription for the same 
inappropriate medication class was dispensed during the blackout period and the duration 
of such dispensing because dispensing during the blackout period is an important factor 
which may affect the primary outcome. A blackout period was needed to allow time for the 
mailing and receipt of the intervention after randomization, and the opportunity to set up 
the appointment with or contact their provider to discuss the use of the potentially 
inappropriate medication. Alternatively, we may also consider stratification of survival 
analyses by prescriptions dispensed during the blackout period. 
  
 
For the primary outcome (i.e., any post-intervention discontinuation of inappropriate prescribing 
during the 6-month period beginning 3 months after the mailing), as a first step, we will calculate 
crude arm-specific percentages, as well as Kaplan-Meier curves and log-rank testing. Covariate-
adjusted comparisons of arms will be estimated using Cox proportional hazards modeling.  
Comparing active intervention arms to usual care, we hypothesize a hazard ratio of less than 1, 
indicating lower risk of an inappropriate prescription in days 91-270 in the active intervention 
arms.  The index date for the survival analysis will be day 91. We chose the hazard ratio as 
method of aggregation as this allows the statistical analysis to account for censoring due to death 
or disenrollment. To account for mortality, anticipated to be approximately 6%, we also will 
conduct competing risk analyses 30 as well as cause-specific hazards modeling.31      
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary outcomes. These will also be assessed specific to the 6-month observation period 
(days 91-270 following mailing/intervention) based on health plan claims data including:  
 
a) Any dose reduction of each of the targeted medications, assessed at the participant 
level using health claims data (outpatient dispensings).   
b) Percentage of patients with prevalence of polypharmacy (defined as >5 active prescriptions for 
different oral agents)32  
c) Rates of emergency room visits; rates of hospitalizations; rates of non-acute 
institutional stays (e.g., skilled nursing facilities); overall health care utilization (number of 
outpatient visits, days hospitalized, emergency department visits, and non- acute 
institutional days). 
 
d) In-hospital all-cause mortality  
 
e) Switching within classes 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
38 
 
We will use administrative claims data to identify encounters of interest (ED visits, 
hospitalizations, non-acute institutional stays, outpatient visits) and only assess oral formulations 
for medications.  
 
Measurement of Dose Reduction. We will consider dose reduction for each selected drug as being 
a ≥ 50% decrease in the mean daily dose comparing the 6 months immediately prior to the 
randomization with the 6-month study window period. (day 91-day 270).  We will measure 
average daily dose using dates of prescription dispensing, duration of prescription dispensing and 
strength of the prescription. We will measure the dose reduction as a dichotomous variable 
defined as the proportion of patients who achieved a more than 50% dose reduction in the daily 
dose during the study window period (day 91 to day 270) compared to the 6-month period prior 
to randomization.  Measurement of dose reduction over 6 month follow-up requires participants 
to complete follow-up through end of observation period (day 270). Censored participants – that 
is, those who have less than 6 months in days 91-270 – will be excluded for the analysis of dose 
reduction.  Analyses will adjust for correlates of missing data. Analyses for post-intervention 
polypharmacy prevalence will be analogous.  We will identify participants with evidence of 
dispensings of ≥5 oral medications over the respective 6-month periods [during the study window 
period (day 91 to day 270) compared to the 6-month period prior to mailing]. AD medications and 
the three potentially inappropriate medication classes will contribute to measure of 
polypharmacy. Injectables and topical or ocular medications will not be counted as evidence of 
polypharmacy.  
A combination drug will be considered a single medication for the purpose of this analysis. 
Additional analyses will examine within-patient change in number of inappropriate medications, 
where the maximum possible decrease equals the pre-intervention number of inappropriate 
medications. We will accommodate this between-patient heterogeneity as follows: within-
patient changes will be ranked separately by pre-intervention number of inappropriate 
medications, ranks will be transformed using normal scores to obtain comparable distributions 
across these strata, and treatment arms will be compared regarding transformed ranks34 using 
analysis of covariance.  In analyses of other secondary outcomes, count outcomes such as per-
patient number of emergency department (ED) visits will be analyzed using Poisson or negative 
binomial regression, accounting for “excess” zeros if warranted based on observed 
distributions.35  
 
Among study subjects who discontinue the targeted medication, we will determine if another 
agent within the targeted class has been dispensed over the period of observation (day 91-270). 
For sedative/hypnotics:  dispensing of a new generic agent within the class of sedative/hypnotics. 
For antipsychotics:  dispensing of a new generic agent within the class of antipsychotics.  
Analyses will be analogous to those for dose reduction. 
 
Mortality will be analyzed using survival analyses, including Kaplan-Meier curves, log-rank 
testing, and Cox proportional hazards (PH) modeling, accounting for censoring due to 
disenrollment 
 
9.4.4 SAFETY ANALYSES 
 
N/A 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
39 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Demographics and baseline characteristics. Baseline and demographic characteristics will be based on 
claims data at the time of randomization. Frequency distribution and summary statistics will be presented 
by three intervention groups. Key demographics to be summarized include age in 5-year categories, sex, 
ethnicity, geographic region, Combined Comorbidity score, health care utilization indices and current use 
of inappropriate prescribing drugs. Categorical variables will be presented as frequencies and continuous 
variables as mean and SD. We will not use inferential statistics at baseline. 
 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
N/A 
 
 
 
9.4.7 SUB-GROUP ANALYSES 
 
We will conduct analyses stratified by sex and we do not anticipate sex related differences in within- group 
correlations (ICC).  We will also conduct analyses of primary and secondary outcomes stratified by each 
individual drug class. Pre-specified analyses of primary and secondary outcomes will be conducted 
according to levels of polypharmacy at baseline (5+ medications at baseline; 7+ medications at baseline). 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
No individual participant data will be listed by measure.  
 
9.4.9 EXPLORATORY ANALYSES 
 
Analyses parallel to those conducted for the primary outcome will be conducted by targeted inappropriate 
medication class. 
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 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
40 
 
 
We will be requesting a waiver of consent from the IRB for the Randomized Clinical Trial.  We believe 
the study meets the following criteria to obtain a waiver of consent (followed by a rationale): 
1. The research involves no more than minimal risk to the subjects. 
Rationale: The probability and magnitude of harm or discomfort anticipated in the research are 
not greater in and of themselves than those ordinarily encountered in daily life or during the 
performance of routine physical or psychological examinations or tests. The intervention is 
entirely consistent with a quality improvement initiative that the health plans could initiate on 
their own. The intervention only adds to the existing care of patients. There are no restrictions 
placed on the control group as a result of the trial. 
2. The waiver or alteration will not adversely affect the rights and welfare of the subjects. 
Rationale: The waiver of consent will not impede on any rights or the welfare of subjects; the 
waiver will solely allow the research team to implement the educational intervention by mail 
which subjects may choose to entirely ignore.   
3. The research could not practicably be carried out without the waiver or alteration. 
Rationale: There are several reasons why the research would be impractical without the waiver 
of consent. First, contacting “control” and “provider only intervention” patients for consent 
would be an intervention by itself and might affect the results of the study. Secondly, given the 
number of subjects to be included, it would be impractical to collect informed consent from the 
total study population included in the trial.   
4. Whenever appropriate, the subjects will be provided with additional pertinent information after 
participation. 
Rationale: If necessary, we will provide additional information to patients, as deemed 
appropriate by the IRB.   
5. The research is not FDA-regulated. 
Rationale: The research does not include any FDA-regulated activities; there are no 
pharmaceutical agents or medical devices being implemented as part of the intervention.   
6. The research does not involve non-viable neonates as subjects. 
Rationale: The research only includes living adult patients aged 50 years of age or older and/or 
their medical providers.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
N/A 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the investigator and funding agency. If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform the 
Institutional Review Board (IRB) and the sponsor/funding agency and will provide the reason(s) for the 
termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to: 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
41 
 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance of study staff to the protocol (i.e., significant protocol violations) 
• 
Data that are not sufficiently complete and/or evaluable 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the funding agency, sponsor, IRB, Food and Drug Administration (FDA), or other 
relevant regulatory or oversight bodies (OHRP, DSMB). 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence and will not be shared beyond the health plan. No 
personally identifiable information from the study will be released to any unauthorized third party without 
prior written approval of the sponsor/funding agency.  
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of 
the Institutional Review Board (IRB), regulatory agencies or representatives from companies or 
organizations supplying the product, may inspect all documents and records required to be maintained 
by the investigator. 
 
The study participant’s contact information will be securely stored at each study site for internal use 
during the study. At the end of the study, all 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/funding agency 
requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Harvard Pilgrim Health Care Institute (HPHCI) and University of 
Massachusetts Chan Medical School and will not include the participant’s contact or identifying 
information. No individual level data will be shared with HPHCI; only aggregate level data will be shared 
for analysis. Deidentified individual level data will be shared with UMass Chan; a Data Use Agreement will 
be executed between both plans and UMass Chan.  The study data entry and study management systems 
used by sites, UMass Chan and by Harvard Pilgrim Health Care Institute research staff will be secured and 
password protected. At the end of the study, all study databases will be archived at the UMass Chan 
Medical School. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made available 
to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 
traceable to a specific study participant). Plans for archiving and long-term preservation of the data will 
be implemented, as appropriate.  
 
The organizations proposing this study have systems, oversight, experienced personnel, and an 
organizational culture that supports the appropriate use, access to, and storage of confidential 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
42 
 
information.  All persons collecting or handling data will be trained in human subjects’ procedures, 
confidentiality and privacy protection. All investigators and project staff are required to receive and 
complete IRB and HIPAA training. 
 
Data for all participants will be kept strictly confidential and will remain at the health plans. All hard 
copies of research files will be kept in locked file cabinets or a locked file room. Participants will be 
assigned a numerical code (Study ID) for identification in the files. Individual identifier information will 
be removed from study data files as soon as possible in the data processing steps and prior to receipt by 
Harvard Pilgrim Health Care Institute.  All computerized data will be kept on secured computers or 
networks. These data will be accessible only to research staff using confidential usernames and 
passwords. Statistical analyses will be performed using only limited datasets and only de-identified data 
will be reported. All data will be used for research purposes only; published data will not contain any 
individual identifiers.  
 
All patient-level electronic data will be maintained by the health plans which have routine access to 
these data. Investigators who prepare the reports, presentations, and publications that will be based on 
this study will never have had access to identifiers of study subjects. Investigators outside of the health 
plans will never have had access to any identifiers. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Query results returned to Harvard Pilgrim Health Care Institute (HPHCI) are retained onsite for a minimum 
of six years after the close of the study, followed by six years at an offsite storage facility. For file security, 
all desktops and laptops run encryption software from Credant Technologies, Inc. to prevent accidental 
loss or theft of data on computers or removable media from being usable. Network file storage is on a 
password protected server. Remote access to the Harvard Pilgrim network is available on Harvard Pilgrim 
laptops using the VPN software.     
The data extracted for this study will be stored on the health plans’ secured, encrypted, password-
protected servers accessible only by staff. Access to the data requires a secured login and password. Paper 
documents will be stored in a locked file. Electronic data for the research will remain secured and 
destroyed once the required retention period has been completed per IRB guidelines, state and federal 
laws, and according to the health plan IT and data security policies. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Jerry 
Gurwitz, 
MD, 
Executive 
Director 
Meyers Primary Care Institute, 
UMMS  
385 Grove St. Worcester, MA 
01605 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
43 
 
508-791-7392 
jerry.gurwitz@umassmed.edu 
 
The research team will be led by Dr. Jerry Gurwitz (PI). The PI and Project Manager will provide 
administrative leadership and study coordination, to ensure timely completion of research tasks 
and consistency with protocol standards. 
 
The research team will be complemented by an Advisory Committee with specific expertise relevant to 
the D-PRESCRIBE-AD pragmatic clinical trial and will meet on a quarterly basis.  
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including geriatric medicine, primary care, prescribing in 
clinically complex older adults, testing of clinical quality measures. Members of the DSMB will be 
independent from the study conduct and free of conflict of interest. The SMC will meet at least 
semiannually to assess safety and efficacy data from each arm of the study. The DSMB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to National Institutes of Health staff. 
 
The DSMB members are listed below: 
 
Chiang-Hua Chang, PhD, MS 
Research Assistant Professor 
University of Michigan 
 
Laura C. Hanson, MD, MPH 
Professor, Geriatric Medicine 
Medical Director, UNC Palliative Care Program 
University of North Carolina, Chapel Hill 
 
Michael Steinman, MD 
Professor of Medicine, School of Medicine 
University of California, San Francisco, CA 
10.1.7 CLINICAL MONITORING 
 
N/A 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
All health plans for this study are participants of the FDA Sentinel project and will use their approved 
local implementation of the Sentinel Common Data Model (SCDM) for querying. As participants in the 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
44 
 
Sentinel project, all health plans must undergo a rigorous data management and quality assurance 
process before their data is approved for use in querying. The frequency of each health plan’s quality 
assurance approval process depends on their specific contract with Sentinel, but occurs at a minimum 
on an annual basis. In addition to quality assurance of data elements, Harvard Pilgrim Health Care 
Institute (HPHCI) adopts standard SAS programming quality assurance and quality control processes 
used by the Sentinel System to check SAS programs and deliverables.   
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The electronic data used in this protocol will be accessed, maintained, and protected, as part of a 
“distributed system.” In a distributed system, data remain in their existing secure environments, rather 
than being consolidated into a single database. Health plans maintain physical and operational control 
over their electronic health data behind their institutional firewalls. Health plans transform their data into 
the Sentinel Common Data Model, execute standardized analytic queries distributed by the Sentinel 
Operations Center, which is based at Harvard Pilgrim Health Care Institute (HPHCI), then share the output 
of queries, with the Operations Center and UMass Chan via a secure portal.  
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents will be retained for a minimum of 3 years and will comply with all NIH and 
NIA data retention standards. 
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the 
study site staff. As a result of deviations, corrective actions will be developed by the site and implemented 
promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the investigators to use continuous vigilance to identify and report deviations 
within seven working days of identification of the protocol deviation, or within seven working days of the 
scheduled protocol-required activity. All deviations will be addressed in study source documents, 
reported to National Institute on Aging Program Official and UMMS IRB. Protocol deviations will be sent 
to the reviewing Institutional Review Board (IRB) per their policies. The Principal Investigator will be 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
45 
 
responsible for knowing and adhering to the reviewing IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
 
Protocol deviations will be recorded in the Protocol Deviation Log, including the following information: 
• 
Text description 
• 
Protocol deviation category  
All deviations will be reported quarterly to National Institute on Aging Program Official and University of 
Massachusetts IRB and will be summarized for each meeting of the study DSMB. 
 
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 will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.  Data from this study may be requested from other researchers 3 years after the completion of 
the primary endpoint by contacting Harvard Pilgrim Health Care. Considerations for ensuring 
confidentiality of these shared data are described in Section 10.1.3. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical. Therefore, any actual 
conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect 
of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest 
will be required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial. The study leadership in conjunction with the National Institute on Aging 
has established policies and procedures for all study group members to disclose all conflicts of interest 
and will establish a mechanism for the management of all reported dualities of interest. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
46 
 
 
ADRD 
Alzheimer’s disease and Alzheimer’s disease-related dementias 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
47 
 
 
 
 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
48 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Section of 
Protocol 
Description of 
Change  
 Rationale 
1.1 
June 16, 
2021 
1. Protocol 
Summary 
 
9.4 Analysis of the 
secondary 
endpoint(s) 
Assessment of 
polypharmacy 
will be limited to 
“oral” 
medications.  
On the recommendations of the DSMB at 
the meeting on June 1, 2021 we will now 
limit our assessment of polypharmacy to 
oral medications only as opposed to 
medications administered via other 
routes (e.,g., topical, ocular routes etc). 
These orally use medications were most 
clinically relevant to the assessment of 
polypharmacy  
1.2 
Nov. 22, 
2021 
 
6.3 Measures to 
minimize bias: 
randomization 
and blinding 
 
9.2 Sample size 
determination 
Randomize 
patients at the 
individual-level, 
as opposed to 
the cluster-level 
by MSA.  
 
This was necessitated by the unique 
privacy, data source and proprietary 
constraints of this pragmatic trial. The 
analytic program for identification of 
participants and randomization will be 
developed by the Data Coordinating 
Center at the HPHCI, and will be 
implemented in a distributed 
environment across the two participating 
national health plans (Humana and 
Health Core/Anthem). To operationalize 
block randomization and ensure balance 
across clusters in a cluster RCT, we need 
to determine the number of participants 
within each MSA prior to randomization.  
These data are proprietary to the health 
plans.  Although our Data Coordinating 
Center can have access to this data in a 
masked format, this complicates 
programming efforts increasing the 
chance for errors that will possibly lead to 
delays in implementing the trial. 
Preliminary work also indicates the 
potential for a significant imbalance in 
the number of participants that are likely 
to be randomized from each plan if 
cluster-level randomization by MSA is 
employed. In addition, all geographic 
areas across the U.S. are not 
encompassed within MSAs, potentially 
adversely impacting the number of 
eligible subjects available for the trial. In 
summary, we have weighed the benefits 
of cluster randomization against 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
49 
 
pragmatic considerations and the need to 
operationalize a robust, consistent 
distributed analytic randomization 
scheme across the health plans, with 
adequate quality checks and quality 
control measures. We have chosen to 
randomize patients at the individual-
level. 
 
 To address potential within-provider 
contamination, for providers with 
medication dispensings of target 
medications to more than one eligible 
patient, only one patient per provider will 
be selected (randomly) for inclusion. This 
strategy allows us to operationalize 
quality control measures early in the 
process, and address the operational 
challenges identified above. 
2.0 
July 18, 
2022 
4.1 Overall Design 
 
 
9.2 Sample Size 
and Power 
Updated sample 
size for trial 1 
and updated 
associated power 
calculations. 
When unexpected data issues arose at 
one health plan and we were not certain 
they would be resolved in time for 
intervention implementation (the 
mailing), we were able to increase the 
sample size for the other health plan to 
11,250 to ensure that we would maintain 
the planned sample size for the study 
(n=11,250).  Fortunately, the issues at the 
first health plan have been resolved and 
we were able to randomize the originally 
planned number of subjects from that 
site.  This has resulted in an increase in 
our overall sample size from 11,250 to 
14,442. 
3.0  
May 
11,2023 
2.3.1 Known 
potential risks 
 
9.4.3 ANALYSIS OF 
THE SECONDARY 
ENDPOINT(S) 
 
10.1.3 
Confidentiality 
and Privacy  
 
10.1.9.1 Data 
Collection and 
Updated text to 
reflect that 
UMass will 
receive 
deidentified 
patient level data 
from both plans.  
The complex multivariate nature of the 
analyses requires deidentified individual 
level data for analyses rather than just 
deidentified aggregate data. For this 
reason, we will be executing Data Use 
Agreements between UMass Chan 
Medical School and the health plans in 
order to receive the data directly at 
UMass for analyses. We have also added 
a secondary outcome to investigate 
switching between classes, at the request 
of the DSMB. 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
50 
 
Management 
Responsibilities  
 
 
 
11 REFERENCES  
 
1. 
Chronic Conditions Data Warehouse. 2020. https://www2.ccwdata.org/web/guest/condition-categories. 
Accessed January 4, 2020. 
2. 
Hukins D, Macleod U, Boland JW. Identifying potentially inappropriate prescribing in older people with 
dementia: a systematic review. Eur J Clin Pharmacol. 2019;75(4):467-481. 
3. 
Martin P, Tamblyn R, Benedetti A, Ahmed S, Tannenbaum C. Effect of a Pharmacist-Led Educational 
Intervention on Inappropriate Medication Prescriptions in Older Adults: The D-PRESCRIBE Randomized 
Clinical Trial. JAMA. 2018;320(18):1889-1898. 
4. 
Mueller C, Molokhia M, Perera G, et al. Polypharmacy in people with dementia: Associations with adverse 
health outcomes. Exp Gerontol. 2018;106:240-245. 
5. 
Lau DT, Mercaldo ND, Harris AT, Trittschuh E, Shega J, Weintraub S. Polypharmacy and potentially 
inappropriate medication use among community-dwelling elders with dementia. Alzheimer Dis Assoc 
Disord. 2010;24(1):56-63. 
6. 
Clague F, Mercer SW, McLean G, Reynish E, Guthrie B. Comorbidity and polypharmacy in people with 
dementia: insights from a large, population-based cross-sectional analysis of primary care data. Age 
Ageing. 2017;46(1):33-39. 
7. 
Parsons C. Polypharmacy and inappropriate medication use in patients with dementia: an 
underresearched problem. Ther Adv Drug Saf. 2017;8(1):31-46. 
8. 
Fried TR, O'Leary J, Towle V, Goldstein MK, Trentalange M, Martin DK. Health outcomes associated with 
polypharmacy in community-dwelling older adults: a systematic review. J Am Geriatr Soc. 
2014;62(12):2261-2272. 
9. 
American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated 
AGS Beers Criteria(R) for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 
2019;67(4):674-694. 
10. 
MedStar Institute for Quality and Safety. We Want to Know. https://www.medstariqs.org/research-
programs/we-want-to-know/#q={}. Accessed January 21, 2020. 
11. 
Alzheimer's Association. Communicating with doctors or health care professionals. 
https://www.alz.org/media/documents/alzheimers-dementia-communicating-doctor-health-care-pro-
ts.pdf. Published 2012. Updated March 2020. Accessed January 20, 2020. 
12. 
Tannenbaum C, Martin P, Tamblyn R, Benedetti A, Ahmed S. Reduction of inappropriate benzodiazepine 
prescriptions among older adults through direct patient education: the EMPOWER cluster randomized 
trial. JAMA Intern Med. 2014;174(6):890-898. 
13. 
Martin P, Tamblyn R, Ahmed S, Tannenbaum C. An educational intervention to reduce the use of 
potentially inappropriate medications among older adults (EMPOWER study): protocol for a cluster 
randomized trial. Trials. 2013;14:80. 
14. 
Martin P, Tannenbaum C. Use of the EMPOWER brochure to deprescribe sedative-hypnotic drugs in older 
adults with mild cognitive impairment. BMC Geriatr. 2017;17(1):37. 
15. 
Gurwitz JH, Kapoor A, Rochon PA. Polypharmacy, the Good Prescribing Continuum, and the Ethics of 
Deprescribing. Public Policy & Aging Report. 2018;28(4):108-112. 
16. 
Thompson W, Farrell B. Deprescribing: what is it and what does the evidence tell us? Can J Hosp Pharm. 
2013;66(3):201-202. 
17. 
Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate polypharmacy: the process of deprescribing. 
JAMA Intern Med. 2015;175(5):827-834. 

D-PRESCRIBE-AD Protocol 
 
Version 3.0 
 
 
11 May 2023 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
51 
 
18. 
Linsky A, Gellad WF, Linder JA, Friedberg MW. Advancing the Science of Deprescribing: A Novel 
Comprehensive Conceptual Framework. J Am Geriatr Soc. 2019;67(10):2018-2022. 
19. 
Greenhalgh T, Papoutsi C. Spreading and scaling up innovation and improvement. BMJ. 2019;365:l2068. 
20. 
Platt R, Tenaerts P, Archdeacon P, et al. Developing approaches to conducting randomized trials using the 
Mini-Sentinel distributed database. 2014. 
21. 
Cocoros NM, Granger CB, Platt R, Pokorney S. IMPACT-AFib: An 80,000 Person Randomized Trial Using the 
Sentinel Initiative Platform. In. NIH Clinical Center Grand Rounds2018. 
22. 
Tisminetzky M, Bayliss EA, Magaziner JS, et al. Research Priorities to Advance the Health and Health Care 
of Older Adults with Multiple Chronic Conditions. J Am Geriatr Soc. 2017;65(7):1549-1553. 
23. 
Field TS, Tjia J, Mazor KM, et al. Randomized trial of a warfarin communication protocol for nursing 
homes: an SBAR-based approach. Am J Med. 2011;124(2):179 e171-177. 
24. 
Tjia J, Field T, Mazor K, et al. Dissemination of Evidence-Based Antipsychotic Prescribing Guidelines to 
Nursing Homes: A Cluster Randomized Trial. J Am Geriatr Soc. 2015;63(7):1289-1298. 
25. 
Canadian Deprescribing Network. Patient handouts. https://www.deprescribingnetwork.ca/patient-
handouts. Published 2017. Accessed January 5, 2020. 
26. 
Fisher KA, Nguyen N, Crawford S, Fouayzi H, Singh S, Mazor KM. Preferences for COVID-19 vaccination 
information and location: Associations with vaccine hesitancy, race and ethnicity. Vaccine. 
2021;39(45):6591-6594. 
27. 
Singh S, Cocoros NM, Haynes K, et al. Antidopaminergic-Antiparkinsonian Medication Prescribing Cascade 
in Persons with Alzheimer's Disease. J Am Geriatr Soc. 2021;69(5):1328-1333. 
28. 
Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline 
comparisons in clinical trial reporting: current practice and problems. Stat Med. 2002;21(19):2917-2930. 
29. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data. 3rd ed. Hoboken, NJ: Wiley; 2019. 
30. 
Fine J, Gray R. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the 
American Statistical Association. 1999;94(446):496-509. 
31. 
Kalbfleisch J, Prentice R. The statistical analysis of failure time data, 2nd ed. . New York: Wiley; 2011. 
32. 
Kristensen RU, Norgaard A, Jensen-Dahm C, Gasse C, Wimberley T, Waldemar G. Polypharmacy and 
Potentially Inappropriate Medication in People with Dementia: A Nationwide Study. J Alzheimers Dis. 
2018;63(1):383-394. 
33. 
Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. 2nd ed. Hoboken, NJ: Wiley; 2011. 
34. 
Evans DA, Beckett LA, Albert MS, et al. Level of education and change in cognitive function in a community 
population of older persons. Ann Epidemiol. 1993;3(1):71-77. 
35. 
Hu MC, Pavlicova M, Nunes EV. Zero-inflated and hurdle models of count data with extra zeros: examples 
from an HIV-risk reduction intervention trial. Am J Drug Alcohol Abuse. 2011;37(5):367-375.