Trial to Reduce Antimicrobial Use In Nursing Home Residents With Alzheimer's Disease and Other Dementias (TRAIN-AD)
Phase: NA
Conditions: Dementia, Infection, Bacterial
Sponsor: Hebrew SeniorLife

TRAIN-AD protocol June 30, 2017 
i 
  
 
TRAIN-AD (Trial to Reduce Antimicrobial Use In Nursing home residents with Alzheimer’s 
disease and other Dementias) 
Principal Investigator: 
Susan L. Mitchell, MD, MPH 
Senior Scientist, Institute for Aging Research, Hebrew Senior Life,  
Professor of Medicine, Harvard Medical School 
Supported by: 
_NIH-NIA 2R01AG032982 
Version 1  
June 30, 2017 
 
NCT03244917 
 

TRAIN-AD protocol June 30, 2017 
2 
1 
TABLE OF CONTENTS 
Page 
1 
TABLE OF CONTENTS ..................................................................................................... 2 
2 
PRÉCIS .................................................................................................................................. 5 
2.1 
Study Title:  TRAIN-AD (Trial to Reduce Antimicrobial Use In Nursing home 
residents with Alzheimer’s disease and other Dementias) ......................................................... 5 
2.2 
Objective ......................................................................................................................... 5 
2.3 
Design and Outcomes ..................................................................................................... 5 
2.4 
Design ............................................................................................................................. 5 
2.5 
Outcomes ........................................................................................................................ 5 
2.6 
Interventions and Duration ............................................................................................. 5 
2.7 
Sample Size and Population............................................................................................ 6 
3 
STUDY TEAM ROSTER..................................................................................................... 7 
3.1 
Principal Investigator ...................................................................................................... 7 
3.2 
Co-Investigators: ............................................................................................................. 7 
3.3 
Consultants ...................................................................................................................... 8 
3.4 
Research Team Members:............................................................................................... 9 
4 
PARTICIPATING STUDY SITES ................................................................................... 11 
4.1 
Primary Objective ......................................................................................................... 11 
4.2 
Secondary Objectives.................................................................................................... 11 
5 
BACKGROUND AND RATIONALE .............................................................................. 11 
5.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 11 
6 
STUDY DESIGN ................................................................................................................. 14 
7 
SELECTION AND ENROLLMENT OF PARTICIPANTS .......................................... 15 
7.1 
Inclusion Criteria .......................................................................................................... 15 
7.2 
Exclusion Criteria ......................................................................................................... 16 
7.3 
Study Enrollment Procedures ....................................................................................... 16 
8 
STUDY INTERVENTIONS ADMINISTRATION AND DURATION ........................ 17 

TRAIN-AD protocol June 30, 2017 
3 
8.1 
Provider-directed Interventions .................................................................................... 18 
8.2 
Proxy Education: ........................................................................................................... 20 
8.3 
Handling of Study Interventions ................................................................................... 20 
8.4 
Facility Start-Up............................................................................................................ 20 
8.5 
On-going implementation ............................................................................................. 22 
8.6 
Concomitant Interventions ............................................................................................ 24 
8.7 
Intervention fidelity ...................................................................................................... 24 
9 
DATA COLLECTION ELEMENTS AND PROTOCOL .............................................. 25 
9.1 
Facility Data .................................................................................................................. 25 
9.2 
Resident assessments .................................................................................................... 25 
10 HUMAN SUBJECT PROTECTIONS .............................................................................. 28 
10.1 
Sources of Data ............................................................................................................. 28 
11 POTENTIAL RISKS OF STUDY PROCEDURES ........................................................ 29 
The study meets criteria for minimal risk. ................................................................................ 29 
11.1 
Potential Medial Risk to Study Participants ................................................................. 29 
11.2 
Potential psychosocial (non-medical) risks, discomforts, inconveniences of study 
procedures ................................................................................................................................. 29 
11.3 
Adverse Events and Serious Adverse Events ............................................................... 30 
11.4 
Reporting Procedures .................................................................................................... 30 
11.5 
Follow-up for Adverse Events: ..................................................................................... 30 
11.6 
Safety Monitoring ......................................................................................................... 30 
12 INTERVENTION DISCONTINUATION........................................................................ 31 
13 STATISTICAL CONSIDERATIONS (SEE SAP) .......................................................... 31 
13.1 
Data Use Agreements ................................................................................................... 31 
13.2 
Identifiers to be stored separately from resident data ................................................... 32 
13.3 
Data security measures ................................................................................................. 32 
13.4 
Data Collection Forms .................................................................................................. 32 
13.5 
Data Management ......................................................................................................... 33 
13.6 
Quality Assurance ......................................................................................................... 34 
14 PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 34 

TRAIN-AD protocol June 30, 2017 
4 
14.1 
Institutional Review Board (IRB) Review .................................................................... 34 
14.2 
Informed Consent Forms .............................................................................................. 35 
14.3 
Participant Confidentiality ............................................................................................ 36 
15 STUDY DISCONTINUATION ......................................................................................... 36 
16 ETHICAL CONSIDERATIONS ....................................................................................... 36 
17 COMMITTEES................................................................................................................... 37 
18 PUBLICATION OF RESEARCH FINDINGS ................................................................ 38 
19 REFERENCES .................................................................................................................... 38 
20 SUPPLEMENTS/APPENDICES ...................................................................................... 43 
 
 
 

TRAIN-AD protocol June 30, 2017 
5 
2 
PRÉCIS 
2.1 
Study Title:  TRAIN-AD (Trial to Reduce Antimicrobial Use In Nursing home 
residents with Alzheimer’s disease and other Dementias) 
2.2 
Objective  
Conduct a cluster randomized controlled trial of an education and training intervention on 
infection management outcomes of 480 residents with advanced dementia (N=240/arm) in 24 
Boston-area nursing homes (NHs) (N=12/arm). 
2.3 
Design and Outcomes 
2.4 
Design 
36 month cluster randomized controlled trial (RCT) to evaluate a multicomponent intervention 
that merges best practices in infectious diseases and palliative care to improve infection 
management for suspected urinary tract infections (UTIs) and lower respiratory tract infections 
(LRIs) among 480 advanced dementia residents (240/arm) living in 24 Boston area nursing 
homes (NHs) (12/arm). Randomization and intervention implementation will be at the facility 
level. Outcomes will be measured at the resident level.  
2.5 
Outcomes 
The following 12-month outcomes related to suspected UTIs and LRIs will be compared 
between the intervention and control arms (usual care):  
PRIMARY OUTCOME:  
I. 
Total number of antimicrobial courses for suspected UTIs and LRIs/person-year  
 
SECONDARY OUTCOMES: 
II. 
Number of antimicrobial courses prescribed for suspected UTIs and LRIs when minimal 
criteria for treatment initiation were absent based on consensus guidelines/person-year  
III. 
Advance care planning about infection management over 12 months defined as a 
documented discussions between proxies and providers or a new advance directives to 
withhold antimicrobials by any route oral, intramuscular, or intravenous. 
IV. 
Number of burdensome procedures used to evaluate suspected LRIs and UTIs (hospital 
transfer, bladder catheterization, chest x-ray, and blood draws)/person-year.  
2.6 
Interventions and Duration  
Each facility will participate for a total of 27 months, including a 3-month start-up/planning 
period and 24 month intervention implementation (intervention NHs only) and data collection 
period. Residents will be enrolled during the first 12-months at each facility, and each resident 
will be followed for up to 12 months. 
The intervention has two main components, provider training and proxy education. 

TRAIN-AD protocol June 30, 2017 
6 
1. Provider Training: Multifaceted approach to education of providers with direct care 
responsibilities for patients with advanced dementia.  Components include: 
a. In-person training 
b. On-line course 
c. Infection management algorithms 
d. Guidelines for communicating with proxies 
e. Prescribing feedback 
2. Proxy Education: A booklet mailed to proxies of residents with advanced dementia 
describing issues related to infection management in advanced dementia upon resident 
enrollment in study.  
2.7 
Sample Size and Population  
The study sample will included 480 NH resident with advanced dementia (N=240/arm). See 
statistical analytic protocol (SAP) for a full explanation of sample size calculations. 
 
 

TRAIN-AD protocol June 30, 2017 
7 
3 
STUDY TEAM ROSTER  
3.1 
Principal Investigator 
Susan Mitchell, MD, MPH  
Senior Scientist, Institute for Aging Research, Hebrew SeniorLife, 
Professor of Medicine, Harvard Medical School  
http://www.instituteforagingresearch.org/    
Address:  1200 Centre Street, Boston, MA 02131 
Phone:   617-971-5326, Fax: 617-971-5339   
Email:    smitchell@hsl.harvard.edu 
Role:  Lead investigator on all aspects of the trial.  Working with other members of the research 
team and with outside resources, Dr Mitchell has developed and designed the implementation of 
all aspects of the TRAIN-AD program.  Dr. Mitchell will direct the overall logistics of the study, 
including: recruitment of nursing homes, field operations, and data collection, management, and 
analyses. As HSL is the prime institution for the grant, Dr. Mitchell will be the project’s primary 
liaison to the NIH and oversee regulatory activities (primary Institutional Review Board approval, 
coordination of Data Safety and Monitoring Board (DSMB)). Her involvement as both a clinician 
and investigator is essential to the success of this project. 
3.2 
Co-Investigators: 
Erika D’Agata MD, MPH 
Infection disease specialist and epidemiologist, Rhode Island Hospital 
Associate Professor of Medicine, Brown University 
Address:  593 Eddy Street, Providence, RI, 02903  
Phone:   401-444-5113, Fax:  401-444-4061 
Email:    edagata@lifespan.org 
Role: Co-investigator,  works with Dr. Mitchell to develop and implement the TRAIN-AD 
program.  D’Agata will take primary responsibility for the intervention implementation in the 
nursing homes and assist Dr. Mitchell with the overall management and conduct of this project, 
training and supervising of staff in data collection, guiding the analysis, presenting the work at 
national meetings and preparing the work for publication. 
 
 

TRAIN-AD protocol June 30, 2017 
8 
Laura Hanson, MD, MPH 
Professor, Geriatric Medicine, University of North Carolina, Chapel Hill 
Address:  5003 Old Clinic Road, Chapel Hill, NC, 27599  
Phone: 919-966-5945  
Email: lhanson@med.unc.edu 
Role: Co-investigator, working helping to optimize program planning and implementation, 
providing on-going expertise on study design, intervention design, and data analysis. 
Michele Shaffer, PhD 
Associate Professor, Seattle Children’s Hospital, Biomedcial Statistics 
Address:  4800 Sand Point Way, NE, Seattle, WA, 98105 
Phone: 206-884-1423  
Email: michele.shaffer@seattlechidrens.org 
Role:  Study statistician who remains blinded throughout the trial. Dr.  Shaffer has helped in the 
analytic design, randomization scheme, and power calculations for this application, and will 
continue to provide statistical leadership as the study progresses. She will supervise the data 
analyses, prepare and maintain the trial statistical analytic plan, and assist in the preparation of 
data for presentations, data safety monitoring board reports, and publications.. 
3.3 
Consultants 
Ruth Anderson, PhD 
Associate Dean for Research, University of North Carolina, School of Nursing 
Address:  Carrington Hall, Chapel Hill, NC, 27599 
Phone: 919-966-8785  
Email: rutha@email.unc.edu 
Role:  Consultant working with investigators to optimize intervention roll-out. Dr. Anderson is 
an expert in the application of complexity science and the adaptive leadership framework to 
research aimed at improving the quality of care for older adults in long term care.  She helped 
develop the implementation plan for this trial and will continue to provide guidance on how the 
research field staff can best work with the nursing home leadership to adapt the intervention 
implementation in their nursing homes. 
 
 

TRAIN-AD protocol June 30, 2017 
9 
3.4 
Research Team Members: 
Elaine Bergman, MGS 
Project Director, Institute for Aging Research, Hebrew Senior Life 
Address:  1200 Centre Street, Boston, MA 02131 
Phone: 617-971-5335 
Email:  elainebergman@hsl.harvard.edu 
Role: Project manager; main responsibilities for the proposed project will include, i. lead all 
organizational processes (e.g., create time and events chart, coordinate all meetings), ii. Create 
and maintain all essential trial documents (e.g., protocol, manual of operating procedures), iii. 
Manage human subjects and data safety documentation, iv. Supervise the creation of REDCap 
data collection instruments, v. coordinate provider on- line course registration and completion 
with Harvard Medical School Department Continuing Medical Education, and vi. Supervise 
tracking of all protocol elements (recruitment, data collection). 
Ruth P. Carroll, RN 
Project Director, Institute for Aging Research, Hebrew Senior Life 
Address:  1200 Centre Street, Boston, MA 02131 
Phone: 617-971-5314 
Email:  rcarroll@hsl.harvard.edu 
Role: Project field director for the project and co-lead the implementation of the intervention in 
the experimental facilities.  Ms. Carroll will recruit all nursing homes, serve as a liaison between 
the NH administrators/facility site champions and the research team, coordinate subject 
enrollment, and supervise the intervention implementation. 
Daniel Habtemariam, MPH 
Data Analyst, Institute for Aging Research, Hebrew Senior Life 
Address:  1200 Centre Street, Boston, MA 02131 
Phone: 617-971-5343 
Email:  danielhabtemariam@hsl.harvard.edu 
Role: Help develop and manage REDCap electronic data capture systems, prepare weekly data 
collection tracking schedules for the field staff, generate monthly recruitment tracking reports, 
prepare data for DSMB reports, create the analytic file, and assist Dr. Shaffer perform the data 
analyses. 
 
 

TRAIN-AD protocol June 30, 2017 
10 
Tim Tsai 
Programmer/Data Analyst, Institute for Aging Research, Hebrew Senior Life 
Address:  1200 Centre Street, Boston, MA 02131 
Phone: 617-971-5668 
Email:  TimothyTsai@hsl.harvard.edu 
Role: Data analyst; member of data team which develops and produces data analytics including 
recruitment and ongoing data collection, NIH and data safety reports throughout the trial;  
maintains project report site and ongoing event tracking. 
Maliaka Lindsey, LPN 
Research Assistant 
Address:  1200 Centre Street, Boston, MA 02131 
Phone: 617-971-5375 
Email:  lindsey@hsl.harvard.edu 
Role:  Responsible for screening subjects, conducting baseline nurse interviews to ascertain the 
residents’ functional status (~ 1 minute/interview), and conduct all chart reviews (~20 
minutes/review)..  Maintenance of participant code sheet/database within each participating 
facility. 
Andrea Loizeau 
Doctoral student 
Address:  1200 Centre Street, Boston, MA 02131 
Email:  AndreaLoizeau@hsl.harvard.edu 
Role:  Assists with intervention planning and implementation. 
Erin Scott, MD 
Address:  1200 Centre Street, Boston, MA 02131 
Email:  emscott@mgh.harvard.edu 
Role:  Physician educator, will lead training seminars in intervention NHs 
Erin Stevens, MD 
Address:  1200 Centre Street, Boston, MA 02131 
Email:  Erin_Stevens@dfci.harvard.edu 
Role:  Physician educator, will lead training seminars in intervention NHs 
Jeremy Whyman, MD 
Address:  1200 Centre Street, Boston, MA 02131 
Email:   jeremy.whyman@mssm.edu 
Role:  Physician educator, will lead training seminars in intervention NHs 
 
 

TRAIN-AD protocol June 30, 2017 
11 
4 
PARTICIPATING STUDY SITES  
The study is being conducted at 24 NH Boston area NHs. Eligible homes must have at least 60 
long stay beds and be within 60 miles of Boston. Sites are recruited from a pool of 95 eligible 
NHs in the Boston area.  Recruitment, randomization and study enrollment will be done in 4 
waves over a 12-month period, with each wave starting three months apart. In each wave, 6 NHs 
will begin the study (3 Control NHs and 3 Intervention NHs/wave).  
 
STUDY OBJECTIVES 
4.1 Primary Objective 
Aim 1. To conduct a cluster RCT of an intervention to improve infection management among 480 
residents with advanced dementia (N=240/arm) residing in 24 NHs (N=12/arm) and compare the 
total number of antimicrobial courses for suspected UTIs and LRIs/person-year (primary outcome) 
over 12 months in the intervention vs. control (usual care) arms. Data will be obtained from review 
of the residents’ charts and medication administration records q2months up to 12 months.  
H1. The number of antimicrobial courses/person-years will be lower in the intervention vs. control 
arms. 
4.2 Secondary Objectives 
Aim 2. To compare the number of antimicrobial courses prescribed for suspected UTIs and LRIs 
when minimal criteria for treatment initiation are absent based on consensus guidelines/person-
year in the intervention vs. control arm over 12 months.  
H2. The number of courses prescribed when minimal criteria are absent /person-year will be lower 
in the intervention vs. control arm.  
Aim 3. To compare the following 2 outcomes in the intervention vs. controls arms over 12 
months: i. Advance care planning about infection management (e.g., documented discussions 
between proxies and providers, advance directives to withhold antimicrobials), and ii. Number of 
burdensome procedures used to evaluate suspected LRIs and UTIs (hospital transfer, bladder 
catheterization, chest x-ray, blood draws)/person-year.  
H3a. Advance care planning about infections will be higher in the intervention vs. control arms. 
H3b. The number of burdensome procedures/person-days will be lower in the intervention vs. 
control arms. 
5 
BACKGROUND AND RATIONALE  
5.1 Background on Condition, Disease, or Other Primary Study Focus 
The advanced stage of Alzheimer’s disease and other dementias is characterized by the onset 
infections, which prior work suggests are widely mismanaged. Antimicrobials are extensively 
prescribed, most often without evidence to support a bacterial infection. Antimicrobial exposure 
is the main factor leading to multidrug- resistant organisms (MDROs); a growing public health 
threat. Moreover, the benefits of antimicrobials remain unclear for patients with advanced 
dementia, for whom infections are often a terminal event and comfort is most commonly the goal 
of care.  

TRAIN-AD protocol June 30, 2017 
12 
In 2015, our group completed the Study of Pathogen Resistance and Exposure to Antimicrobials 
in Dementia (SPREAD) which prospectively examined antimicrobial use and MDRO 
acquisition in 363 NH residents with advanced dementia.9, 22 Antimicrobials were prescribed for 
72% of suspected infections, but only 44% of these episodes met guideline-based criteria for 
treatment.23 Suspected urinary tract (UTIs) and lower respiratory tract (LRIs) accounted for 94% 
of mistreated episodes. Criteria were more likely to be met when the residents’ proxies were 
counseled about antimicrobials. Two- thirds of residents were colonized with MDROs. 
Antimicrobial use was the major risk factor for MDRO acquisition. Motivated by these findings, 
we conducted a pilot study (NIH R21) of a multi-faceted intervention to improve management of 
suspected UTIs and LRIs. Unlike standard NH antimicrobial stewardship programs.18,24 The 
intervention merged best practices in infectious diseases and palliative care, and targeted this 
unique population for whom the need and opportunity to improve infection management are 
particularly compelling. 
5.1.1 Epidemiology  
In the Choices, Attitudes, Strategies and Care of Advanced Dementia (CASCADE) study, led by 
Dr. Mitchell, 41% of participating NH residents with advanced dementia had suspected 
pneumonias and 53% had febrile episodes over 18 months. 1 In SPREAD, we found 66% of NH 
residents with advanced dementia had suspected infections over 1 year, most often UTIs and 
LRIs. 9 Approximately 50% of advanced dementia patients are diagnosed with pneumonia in the 
last 2 weeks of life.8, 9 The 6-month mortality rate following pneumonia is 50%. 1, 34 
Antimicrobial use is extensive.6, 8, 35-37 In prospective studies, 52-66% of NH residents with 
advanced dementia received antimicrobials over 12 months, and 42% in the last 2 weeks of life.9, 
37 Much of this use may be inappropriate as antimicrobials are often started without adequate 
clinical evidence to support a bacterial infection. 9-15, 23, 38   Infections are often treated 
empirically in NHs without the benefit of objective tests (e.g., cultures). Thus, the Society for 
Healthcare Epidemiology of America endorsed minimal clinical criteria to initiate antimicrobials 
in NHs.13  
5.1.2 Advanced dementia patients are reservoirs for multidrug resistant organisms (MDROs 
The emergence of MDROs is a major public health threat,39-44 and growing concern in NHs.14, 16, 
19, 45-47 Between 43-62% of NH residents are colonized with either methicillin-resistant 
Staphylococcus aureus, vancomycin-resistant enterococci, or multidrug-resistant gram-negative 
bacteria.48, 49 MDRO colonization in NHs is associated with increased mortality,50-53 costs,54 
hospitalizations.55, 56 NH residents bring MDROs into hospitals.57-59  Our prior work showed that 
advanced dementia residents are 3 times more likely to have MDROs than other residents. 17 In 
SPREAD, we found 64% of the cohort was colonized with MDROs over 12 months.9 
Antimicrobial exposure is the strongest risk factor for MDRO acquisition,49, 51, 53, 60-64 Thus, 
reducing antimicrobial misuse in advanced dementia is a key opportunity to limit MDROs 
colonization in the NH setting. 
5.1.3 Benefits and burdens of treatment 
Two potential benefits may motivate treating suspected infections in advanced dementia; 
prolonging life and symptom relief. In the absence of RCTs, observational studies help inform 
decision-making regarding these outcomes.6, 21, 65-68 In CASCADE, residents with pneumonia 

TRAIN-AD protocol June 30, 2017 
13 
treated with antimicrobials lived longer, but had more discomfort, than those who were not 
treated. 6 In SPREAD, treating suspected UTIs with antimicrobials had no effect on survival.21  
Both the work-up and treatment of infections can be burdensome for these frail patients.69  In 
SPREAD, 74% of suspected infections involved a bladder catheterization, hospital transfer, 
blood draw, or chest x-ray. 69 Infections are the most common reason advanced dementia patients 
are hospitalized70 but can often be managed with similar efficacy in the NH. 6, 71, 72 Even oral 
antimicrobials may cause discomfort, as these patients often have swallowing problems.  Finally, 
older patients are more susceptible to adverse effects of antimicrobials such as Clostridium 
difficile infections, allergic reactions, MDRO acquisition, and drug-drug interactions. 6, 37, 65, 73-75  
5.1.4 Treatment must align with the goals of care:  
A-quarter of all treatment decisions faced by proxies of NH residents with advanced dementia 
relate to infections. 76 Given the burdens and questionable benefits of antimicrobials, infection 
management should be approached using a framework of shared decision-making similar to 
other end-of-life treatment choices.77-80  This approach requires adherence not only to infectious 
disease guidelines, but also to the goals of care (e.g., life prolongation or comfort). In prior work, 
over 90% of proxies state comfort is the goal of care.1, 9 For these patients, the burdens of 
assessing and treating infections may outweigh the benefits, particularly when the likelihood of a 
bacterial infection is low.  
Several features characterize optimal shared decision-making. Ideally, counseling should be done 
as part of advance care planning rather than at the time of a crisis, and preferences documented 
in advance directives, such as the Physician Orders for Life Sustaining Treatment (POLST) 
form. 81 Proxies should be told to expect infections in end-stage disease, apprised of what an 
appropriate evaluation entails, and cautioned about common pitfalls leading to unnecessary 
antimicrobial use (e.g., asymptomatic bacteriuria). The benefits and burdens of evaluating and 
treating suspected infections should be presented, and the option of a purely palliative approach 
described (e.g., analgesics, antipyretics). Finally, providers should help proxies align the 
management approach with the goal of care. If the goal is to optimize comfort, it is reasonable to 
suggest that no evaluation be initiated for infections and palliation provided. For the minority of 
patients for whom the goal remains to prolong life, evaluation and treatment is reasonable but 
only when there is adequate clinical evidence to support a bacterial infection. Optimal decision-
making does not routinely occur in practice, but when it does, data suggest care is improved. In 
SPREAD, only 45% of proxies were asked about preferences for antimicrobial use, and only 
34% were counseled to expect infections or about treatment options. However, when they were 
counseled, minimal criteria for initiating antimicrobials were more likely to be met. 9 
5.1.5 Interventions to improve infection management in advanced dementia:  
The need to improve infection management in the general NH setting is well-recognized, 10, 24 as 
reflected in The Centers for Disease Control’s (CDC) recent call to expand antimicrobial 
stewardship activities in NHs.18  Although many NH residents have advanced illnesses, this CDC 
initiative as well as most standard NH antimicrobial stewardship programs, focus solely on 
infectious disease guidelines, 46, 72, 82-87 and fail to integrate patient preferences or palliative care 
principles into prescribing algorithms, training materials, and evaluation metrics. At the same 
time, a growing literature has highlighted concerns about infection management at the end-of-
life.88 Our intervention merges best practices in infectious diseases and palliative care, and 

TRAIN-AD protocol June 30, 2017 
14 
focuses on a unique subset of NH patients for whom the need to improve infection management 
is particularly compelling. 
While not focused on advanced dementia, prior antimicrobial stewardship NH research informs 
our study design. 46, 72, 82-87 Loeb conducted two cluster RCTs in 22 Ontario NHs. In one, a 
facility-wide intervention to improve UTI management reduced antimicrobial use. 82 In the other, 
a clinical pathway for LRIs resulted in fewer hospitalizations. 72 These studies and others, 46, 72, 82, 
86, 87, 89 demonstrate that rigorous RCTs of NH interventions to improve infection management 
can be conducted and improve outcomes. Most successful interventions have multiple 
components, and include prescribing feedback to providers to motivate behavior change. 18, 24, 86, 
87, 89, 90 More recent efforts have also recognized that for interventions to be adoptable and 
sustainable, they must target the many interacting factors that influence NH care, and engage key 
stakeholders (e.g., medical providers, nurses, families, administrators) in learning, 
communication, self-monitoring, and on-going adaption. 86, 87, 91, 92 One pilot study of a quality 
improvement program incorporating these features in 12 NHs significantly reduced antimicrobial 
prescriptions. 86, 87 
5.1.6 Summary of significance.  
The significance is summarized as follows: 1. Advanced dementia is a leading cause of death. 
Most patients receive their care in NHs; 2. Advanced dementia residents are commonly 
suspected of having infections, for which antimicrobials are extensively prescribed. Minimal 
criteria to support a bacterial infection are absent for most treated episodes; 3. These residents 
are reservoirs for MRDOs. Antimicrobial use is the main risk factor for MDRO colonization; 4. 
As these residents are in the terminal phase of dementia, they may not clinically benefit from 
antimicrobials, especially when the likelihood of a bacterial infection is low; 5. Comfort is the 
goal of care for > 90% of these residents. The burdens associated with work-up and treatment of 
infections, generally do not promote comfort; 6. Most proxies are not counseled about infection 
management, but when they are, antimicrobials are more likely to be used in accordance with 
guidelines; 7. NH interventions to improve infection management can be successfully tested in 
RCTs, but to be sustainable they must target the many factors that influence NH care, 8. 
Traditional NH antimicrobial stewardship programs do not include patient preferences or 
palliative care principles; and 9. TRAIN-AD builds on prior work and address the existing gaps, 
by applying state-of-the-art methodology for cluster RCTs 95, 96 and conceptual underpinnings for 
successful program implementation in NHs, 86, 87, 91, 92, 97 to evaluate an intervention that merges best 
practices in infectious diseases and palliative care in a unique population for whom the need and 
opportunity to improve infection management is especially compelling.  
With this foundation and leveraging a network of NHs and research infrastructure established in 
4 prior NIH R01s, TRAIN-AD (Trial to Reduce Antimicrobial Use In Nursing home residents 
with Alzheimer’s disease and other Dementias), is a cluster randomized controlled trial (RCT) of 
an intervention to improve infection management in advanced dementia. All intervention 
components integrate infectious disease and palliative care principles.   
6 
STUDY DESIGN 
This cluster RCT will evaluate an infection management education and training program 
targeting direct care providers and proxies of residents with advanced dementia, on infection 
management in 480 (Control=240/ Intervention=240) patients 60 years or older with advanced 

TRAIN-AD protocol June 30, 2017 
15 
dementia residing in 24 (12 Control/12 Intervention) participating Boston area nursing homes.  
The unit of randomization is the facility but the unit of analysis is the patient, clustered within 
the facility. The intervention will be implemented facility-wide, thus all patients with advanced 
dementia, cared for in the NHs during the 24-month implementation period are potential subjects 
in this study.  Data will be obtained from bi-monthly chart review of enrolled eligible residents 
for up to 12 months. 
Outcomes to be compared between patients in the intervention and control NHs include: total 
number of antimicrobial courses for suspected UTIs and LRIs/person-year (primary outcome)  
over 12 months in the intervention vs. control (usual care) arms (Aim 1), number of 
antimicrobial courses prescribed for suspected UTIs and LRIs when minimal criteria for 
treatment initiation are absent based on consensus guidelines/person-year (secondary outcome) 
in the intervention vs. control arm over 12 months.(Aim 2), and : i. advance care planning about 
infection management (e.g., documented discussions between proxies and providers, advance 
directives to withhold antimicrobials), and ii. Number of burdensome procedures used to 
evaluate suspected LRIs and UTIs (hospital transfer, bladder catheterization, chest x-ray, blood 
draws)/person-year (Aim 3) 
7 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
The intervention will be rolled out facility-wide. Participation occurs at 3 levels.  Nursing homes 
will be recruited, randomized and enrolled into the study.  Site administrators who agree to 
participate in the study will serve as gatekeepers within their facility.  Providers will be recruited 
to participate in the infection management training program, and eligible residents will be 
enrolled for ongoing chart reviews to assess program effect on infection management. 
7.1 Inclusion Criteria  
7.1.1 Facility inclusion criteria 
1) More than 60 beds  
2) Within 60 miles of Boston 
7.1.2 Resident inclusion eligibility criteria 
• Age > or = to 60 years  
• A diagnosis of dementia (any type)  
• Global Deterioration Scale (GDS) score of 7  
• NH length of stay >90 days 
• An individual who can communicate in English has been formally or informally designated as a 
health care proxy 
• Not comatose 
GDS stage 7 features include: profound memory deficits (cannot recognize family), total 
functional dependence, speech <= 5 words, incontinence, and non-ambulatory. GDS 7 was 
chosen to define advanced dementia as it has been successfully operationalized and validated in 
or prior studies, and experts agreed to use this definition in research studies. A 90 day minimum 
length of stay was chosen to exclude short-stay patients.  

TRAIN-AD protocol June 30, 2017 
16 
7.1.3 Provider inclusion criteria 
TRAIN-AD intervention will target the “usual” providers including nurses, MDs, NPs and PAs 
routinely caring for advanced dementia patients. Nurses should be providing care for these 
residents for a minimum of 2 shifts most weeks. MDs, NPs, and PAs should have at minimum 2 
residents with advanced dementia on their regular resident panel.  We estimate there will be 15-
20 targeted providers/NH (12-16 nurses, 1-3 physicians, 0-3 NPs/PAs). 
Eligibility criteria for providers in the intervention nursing homes include:  
• Direct care provider of advanced dementia residents (a nurse, nurse practitioner, 
physician or physician assistant identified by a senior administrator as an individual who 
cares for residents with advanced dementia)  
• Can communicate in English (because intervention materials are all in English),  
• Over 21 years of age.  
7.2 Exclusion Criteria  
7.2.1 Facility exclusion criteria 
• Population not primarily English speaking 
• Evidence of institutional instability at time of recruitment 
7.2.2 Provider exclusion criteria 
• Do not provide direct care to residents with advanced dementia 
• Not a “usual” provider within the NH (i.e. visiting hospice provider) 
• Does not speak English 
• Is less than 21 years old 
7.2.3 Resident exclusion criteria 
• Less than 60 years of age 
• Living in nursing home for less than 90 days 
• Does not meet GDS score of 7 
• Does not have a proxy that communicates in English 
• Proxy has communicated wish to opt-out of study  
• Resident has fallen into a coma or has expired prior to baseline 
7.3 Study Enrollment Procedures  
7.3.1 Facility Enrollment 
A total of 24 Boston area NHs will be recruited from a pool of 95 eligible NHs in the Boston 
area. NHs will be recruited, randomized and enrolled into the study in groups of 6 (3 Control / 3 
Intervention) every 3 months for one year.  The project director will mail study information and 
a recruitment letter to the senior administrators of eligible NHs. The letter introduces the 
intervention and implications of participation including randomization.  One week after the 

TRAIN-AD protocol June 30, 2017 
17 
mailing, the project director contacts the NHs’ administrators by telephone to answer questions 
and seek their participation. Face to face meetings to further explain the study are held with 
administrators upon request.  
One month before the three-month planning period is scheduled to start, the list of 6 newly 
recruited homes will be randomized.  (see SAP for details on randomization procedures).  
Immediately following randomization, the project director contacts each facility informing them 
of their study assignment and initiating the 3-month planning procedures. 
7.3.1.1 
Facility Randomization and Stratification Procedures:  See SAP 
7.3.2 Provider Recruitment 
The research team works with the intervention NH leadership team and designated site champion 
to facilitate provider recruitment and orientation throughout the intervention period.  At the start 
of the intervention and every 6 months throughout intervention period, the project director 
requests a list of eligible providers from the site champion. The research team sends a packet of 
information to the providers introducing the trial, and providing them with intervention 
materials, contact information, and information related to upcoming TRAIN-AD training 
seminars. All aspects of provider participation are optional.  They can chose to participate in all, 
some or no aspects of the intervention, and can request exclusion at any time by contacting the 
research project manager, whose contact information is provided in all outreach materials. 
7.3.3 Resident Enrollment 
We have obtained an IRB waiver of individual authorization for disclosure of personal health 
information (PHI) to screen and identify eligible residents.  At the start of the study and every 2 
months for 12 months in each NH, the RA will interview unit nurses to identify eligible 
residents. Eligibility and proxy information will be confirmed by chart review. Within one week 
of eligibility screening, proxies of eligible residents in the intervention NHs will be mailed study 
information, including the infection management booklet and the project director’s (PD’s) 
contact information if they wish to opt out.  In addition, flyers will be posted in ALL 
participating facilities (control and intervention) explaining that the study is being conducted and 
that it includes data collection from the charts of residents with advanced dementia. The flyers 
will include contact information for the PD to ask further questions and an opportunity for 
proxies to “opt-out”.  If proxies do not contact the PD within two weeks, the resident will be 
enrolled and included in bi-monthly chart review with data abstraction.  
PHI will not be removed from the facility. For purposes of recording and tracking eligible 
residents, study IDs will be assigned to eligible residents at the point of eligibility screening.  A 
code sheet containing the names associated with assigned study IDs will be stored in a secure 
location within the participating NH.  
8 
STUDY INTERVENTIONS ADMINISTRATION AND DURATION 
The entire trial will be conducted over. 36 month, each intervention facility will be involved for 
27 months which includes 3 months planning period 24 months of intervention implementation 
in each intervention NH (See below).  At each facility residents will be enrolled for the first 12 
months of the implementation period, and each resident will be followed for up to 12 months 

TRAIN-AD protocol June 30, 2017 
18 
Control homes will follow the same timeline for resident enrollment and data collection, while 
they continue to receive usual care.  During the 3 month planning period, the research team 
works with the leadership and site champion in each NH to optimize program roll-out within 
each unique environment.   
The study intervention is a multi-component training and education program targeting direct care 
providers and healthcare proxies for advanced dementia NH residents, intended to improve the 
management of urinary and lower respiratory tract infections in advanced dementia patients.  In 
partnership with NH leadership, the intervention is rolled out as a new program within the 
facility. There are two components to this practice intervention: 1. Provider Training, and 2. 
Proxy Education.  Intervention components aimed at the provider include: Professionally led 
infection management training seminars, online infection management course, and infection 
management guidance algorithms.  Additionally participating prescribing providers will be sent 
bimonthly infection management feedback reports.  Proxy Education is completed by providing 
an infection management in Advanced Dementia booklet to proxies of patients with AD upon 
resident enrollment in study.    
 
8.1 Provider-directed Interventions 
Provider Training: Multifaceted approach to education of providers with direct care 
responsibilities for patients with advanced dementia.  Training initiatives focus on appropriate 
diagnosis and treatment of suspected UTIs and LRIs in patients with advanced dementia.  All 
training initiatives include application of recommended diagnostic criteria, inclusion of goals of 
care in development of treatment plan, and provider communication training to optimize 
communication with healthcare proxies throughout the process.  Communication training 
provided in the seminar and online course is further reinforced with provision of a 
communication tips pocket card. 
8.1.1 In-person training: 
At each NH during the start-up period and q6 months during the 24 month implementation 
period, the research team including a PI or trained physician educator, and one or both PDs will 
lead on-site 1-hour group training seminars to present principles of infection management in 
advanced dementia, intervention components, and approaches to proxy counseling. Seminars 
will include a didactic presentation, open discussion, and communication training for common 
challenging scenarios (e.g., proxy requesting a resident get antimicrobials when treatment is not 
clinically indicated).  To enhance sustainability, TRAIN-AD site champions will be trained to 
conduct the seminar enabling him/her to co-lead on-going sessions and be an on-site resource to 
reinforce the intervention principles. Providers that are unable to attend the on-site training will 
be offered a condensed 1:1 training session at their convenience.  

TRAIN-AD protocol June 30, 2017 
19 
8.1.1.1 
Targeted attendees 
All providers with primary care responsibilities for residents with advanced dementia (e.g., 
medical providers (physicians, NPs, PAs, nurses) and other key individuals (e.g., Director of 
Nursing (DON), infection control monitor) will be targeted to attend the seminars. See section 
7.1.3 for description of provider eligibility criteria.  
8.1.1.2 
Materials 
Invited providers will be sent a training seminar packet prior to the seminar which includes items 
presented in the seminar and will serve as an ongoing resource for participants, and for those 
unable to attend, the in-person training. 
8.1.2 On-line course 
The “Infection Management in Advanced Dementia" on-line course is being offered through the 
Harvard Medical School Department of Continuing Education (HMS DCE) and has been 
approved for CME credit. The PIs created this peer-reviewed course through an iterative process 
with experts in infectious diseases, palliative care, and geriatrics. The self-directed course 
consists of 4 virtual patient cases, 2 for UTIs and 2 for LRIs, with 3-4 multiple choice 
questions/case, and 3 communication training videos embedded within the course. Participants 
receive response-specific, evidence-based feedback, and complete a 12-item multiple-choice 
pre/post knowledge test. Providers including RNs, LPNs, NPs, PAs and MDs with direct care 
responsibilities for advanced dementia residents will be targeted to complete the course. 
Instructions on how to access the course will be in the orientation package and reviewed at the 
initial training. Participating providers will receive $50 from the research team 1 CME credit for 
completing the course for which the usual $50 will be waived. 
Providers are encouraged to complete the course by the end of the first month following 
invitation.  The course website provides the research team with provider participation data, to 
inform ongoing engagement efforts directed toward providers.  Several strategies will be used to 
promote timely completion.  Weekly reminders will be sent by the PD to non-participants for up 
to 1 month (mail/email) and the site champion will also be given the names of providers that 
have not completed the course to encourage their participation.  
8.1.3 Algorithms 
Algorithms guiding appropriate antimicrobial initiation for suspected UTIs and LRIs that 
integrate palliative care principles and patient preferences are used throughout the training 
program and displayed throughout intervention NHs to reinforce provider learning.  Laminated 
5” X 7” pocket reference cards with the algorithms, will be given to providers in their orientation 
material packet and made available throughout the study. 
8.1.4 Prescribing Feedback Reports 
A key component of the intervention is the provision of infection management feedback to 
prescribing providers within intervention NHs.  This, prescribing feedback reports will be sent to 
all prescribing providers and the site champions  based on data abstracted from the charts, 
including: 1. Proportion of residents given antimicrobials for suspected LRIs and UTIs when 
minimal criteria were absent in prior 2 months, and which criteria were absent, 2. Benchmarking 

TRAIN-AD protocol June 30, 2017 
20 
of inappropriately treated episodes for individual prescriber with other prescribers in the facility 
and in other intervention NHs, and 3. Time trends for these parameters.   
8.2 
Proxy Education: 
The goal for proxy education is to promote informed decision-making for resident care that it is 
concordant with preferences, which is also desired goal for high quality nursing home care. At 
the time of resident enrollment, English-speaking proxies of enrolled residents will be sent a 
booklet written by the co-PIs, professionally reviewed and translated into 6th grade reading level 
that explains in a lay fashion:  i. the nature of urinary and respiratory tract infections in advanced 
dementia, ii. Treatment options (antimicrobials vs. only comfort care), iii. Concerns about 
antimicrobial overuse, and iv. Features of appropriate antimicrobial use. Proxies will be sent the 
booklet following resident screening and encouraged to discuss infections in advanced dementia 
with their family member’s direct care providers.   
8.3 Handling of Study Interventions  
Intervention Implementation: The implementation plan aims to strike a balance between 
maximizing intervention adherence, and sustainability. While its components emphasize a 
standardized approach to UTIs and LRI management, NHs will have the opportunity to adapt 
implementation to their own environment.  To increase likely program success, the research team 
will encourage ongoing communication between providers and proxies regarding infection 
management planning, and encourage integration of aspects of the infection management 
program into NHs’ quality improvement programming.  Various supports will be put in place to 
help sustain the program and support the NH implementation team.  These supports include 
provision of information support for the site champions.  A compendium of reference and 
guidance materials is provided to each site.  Additionally, the research team will be available to 
site champions for ongoing support through monthly huddles and one on one check in calls.   
Finally, members of the research implementation team will meet with the NH implementation 
and leadership team every 3 to 6 months to review program implementation and optimize as 
necessary. 
8.4 
Facility Start-Up 
Program start up within all participating nursing homes will happen over three month periods.   
8.4.1 Control home Start-up 
Following randomization, the project director contacts the administrator to inform them of the 
facility’s research assignment, facilitate a brief environmental scan questionnaire, and schedule a 
brief (30 minute) in-service for the leadership team and staff to introduce them to the study and 
data collection procedures.  At the start of data collection, flyers informing residents and family 
members about the study will be posted throughout the facility. 
8.4.2 Intervention home Start-up 
Following randomization, the project director contacts the administrator of the intervention NH 
and informs them of their study assignment.  She reminds him/her of the implications of the 
intervention assignment, asks him or her to select a site champion and facilitates completion of 

TRAIN-AD protocol June 30, 2017 
21 
the environmental scan questionnaire.  Study start-up within intervention homes will involve at 
least 3 in-person meetings and up to weekly check-in phone calls between the research team PD 
and the site champion.  During this time members of the TRAIN AD team will meet with 
members of the leadership team and site champion within the NH to review the program and 
intervention components and strategize about the best way to implement them within the NH.  
The following activities will occur during the 3 month planning period within intervention 
facilities:   
1. Identify TRAIN-AD site champion 
2. Completion of infection management questionnaire 
3. Develop implementation plan with NH leadership during 3 on-site planning meetings 
4. Identify targeted providers 
5. Schedule training seminar 
6. Provide orientation packages, conduct training seminars, and introduce on-line course to 
targeted providers 
7. Conduct final facility set-up (e.g., hang posters of algorithms and study flyers throughout 
NH).   
8.4.2.1 Identification of site champion 
At the start of the planning period, each NH will designate at least one champion. This individual 
needs to be someone engaged in infection management who understands the special concerns of 
advanced dementia residents. The site champion will most likely be either the DON, individual 
responsible for infection control, or nurse directing dementia care. The site champion will work 
with the research team throughout the planning and intervention period to facilitate successful 
program implementation.  He or she serves as a primary contact for both providers within the 
NH and for the research team.  Site champions are provided with a compendium of references 
and support tools at the start of the program and in encouraged to contact the project director 
with questions or concerns.  Monthly phone conference huddles will be held when site 
champions from all intervention sites have the opportunity to discuss the program and provide 
suggestions/support to one another.  The champion is an on-site leader and resource, working 
with both facility and research team to increase likelihood of program success.  Site champions 
will: 
• Help tailor TRAIN-AD to NH culture 
• Identify and motivate providers  
• Facilitate training seminars 
• Review prescribing feedback reports 
• Encourage infection management discussions in care planning  
• Integrate program into quality improvement activities 
8.4.2.2 
Development of implementation plan with NH leadership 
Successful program planning and implementation depends on teamwork between members of the 
facility team and the research team.  This starts with the 3 month planning period wherein the 
research team and NH team meet at least monthly to review and optimize plan for program roll-
out.  Throughout the program, the research team will work with members of the facility team to 
optimize the program within the facility and to support program activities within the facility.   

TRAIN-AD protocol June 30, 2017 
22 
8.4.2.3 
Identify targeted providers 
See section 7.1.3 for description of provider eligibility criteria. Prior to the program’s initial 
provider training seminar and every 6 months throughout the program (months 6,12, 18), the site 
champion will generate a list of providers with primary care responsibilities for residents with 
advanced dementia who will be targeted to complete the training seminar and on-line course 
8.4.2.4 
Provide orientation packets, conduct training seminars, and introduce on-line course to targeted 
providers 
Two weeks prior to all training seminars, the project director will send orientation packets to 
targeted providers.  Each provider will be invited to attend one of the seminars where the 
TRAIN-AD program and components will be reviewed in detail.  Providers will be asked to 
utilize reference materials and participate in the online course within one month of receiving the 
course invitation. Group seminars will be conducted at the NH twice the same day to reach 
various shifts.  One on one sessions will be arranged for providers unable to attend the group 
training.  The first training seminar marks the official start of the intervention period within each 
facility. 
8.4.2.5 
Conduct final facility set-up (e.g., hang posters of algorithms and study flyers throughout NH).   
Immediately following initial training seminar, intervention materials will be posted and made 
available throughout the facility.  The site champion will be asked to contact the research team 
for more materials as necessary throughout the intervention period.  
8.5 
On-going implementation 
Ongoing implementation will involve a number of procedures and strategies to support efforts 
within participating NHs and to encourage program success.   
1. The research team and a trained physician will meet with the NH leadership every 6 
months to review the overall project status, prescribing feedback, provider training and 
course completion, and proxy reaction to booklets. They will strategize about ways to 
further improve implementation.  
2. On-site training seminars will be conducted by our team every 6 months to train newly 
hired providers, reinforce learning for on-going providers, and review cases to illustrate 
key points, and problem-solve ongoing concerns. (With time, the site champion will co-
lead these sessions).  
3. Prescribing feedback reports will be sent to the TRAIN-AD site champion and 
prescribing providers every 2 months.    
4. The research team will facilitate huddles every quarter for site champions at multiple 
intervention facilities.   
5. Study materials will be available and on display and resident charts will be reviewed 
every other month throughout the intervention period. 
The chart below reflects the schedule of activities which occur during the 24-month 
implementation period at each NH:  
 

TRAIN-AD protocol June 30, 2017 
23 
 
 
8.5.1 Materials distributed/displayed throughout NH 
Study materials will be posted and available throughout the intervention period.  Research notice 
flyers and algorithm posters will remain posted throughout the intervention period.  All other 
study materials will be available through the study site champion and research team upon request 
including:  booklets, algorithms and communication guidance cards 
8.5.2 Integration into care planning practices 
During the provider training seminar and throughout the intervention period, direct care 
providers are encouraged to include infection management in quarterly care planning meetings.  
In the letter accompanying the booklet at the time of mailing, proxies are encouraged to discuss 
the booklet with their providers.   
8.5.3 Program Evaluation 
Throughout the intervention period, program implementation success will be monitored.  By the 
following metrics: i. the proportion of targeted providers who attended an initial training session, 
ii. the proportion of targeted providers who completed the online course, and iii. rate of 
suspected UTIs and LRIs treated when minimal criteria not present as measured by the q2month 
prescribing provider feedback reports. The project director will also regularly (see section 8.5.4) 
with the site champion to review the project’s status, problem solve any issues, and adapt the 
program as needed. The research team encourages the NH leadership team and site champion to 
include the TRAIN-AD program in their quality improvement initiatives. 
8.5.4 Team check-in meetings  
Throughout the intervention period, the research PD will engage the champion in periodic check-
in meetings to address questions or issues that arise.  The PD will make monthly phone calls and 
schedule on-site meetings with champion and members of the leadership team every 6 months or 
as desired to review program progress, and address questions and concerns as they arise 
throughout the trial. 
8.5.5 Provider recruitment and training  
Provider identification and recruitment efforts will be ongoing throughout the intervention 
Month
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Material distribution/display
Integrate into care planning
Program evaluation
Team check-in meetings
X
X
X
X
X
X
X
X
Champion huddles
X
X
X
X
X
X
X
X
Provider Recruitment and Training 
X
X
X
X
Provider Feedback reports 
X
X
X
X
X
X
X
X
X
X
X
Resident screening/enrollment 
X
X
X
X
X
X
X
Mail booklets to proxies 
X
X
X
X
X
X
X
Resident Follow-up 
X
X
X
X
X
X
X
X
X
X
X
X
X
Program Implementation

TRAIN-AD protocol June 30, 2017 
24 
period.  Training seminars and invitations to the online course will be conducted at the start of 
the intervention and again at months 6, 12 and 18.   
8.5.6 Provider feedback reports  
Every 2months, starting in month 3, site champions and providers will be sent (mail/email) 
reports with aggregated facility data. Each provider will receive their own data.  
8.5.7 Resident screening and enrollment  
Bi-screening eligibility screening and enrollment of new residents will be ongoing for the first 12 
months in each participating facility. 
8.5.8 Mail booklet to proxies 
Within one week of every bimonthly resident eligibility screening, the project director facilitates 
the mailing of study information and the infection management booklets to the proxies of eligible 
residents.  The mailing includes research team contact information for the proxy to use to request 
exclusion from the study and is accompanied by a letter from the site champion explaining the 
contents and reason for the mailing.  Following the 12 month enrollment period, proxies and 
providers can still obtain a copy of the booklets from the site champion or by request to the 
research team. 
8.5.9 Resident follow-up 
Bimonthly chart reviews will be conducted for 12 months or until death for all enrolled residents. 
8.5.10 Quarterly site champion “huddles” 
The research project director will facilitate monthly “huddles” via conference call for all active 
site champions.  The huddles provide an opportunity for the champions to exchange ideas and 
experiences in their role and provide an opportunity for them to support and problem solve with 
other site champions 
8.6 Concomitant Interventions 
Following randomization, but prior to initiation of intervention period, the PD conducts a 
structured survey with senior administrators in all control and intervention facilities to ascertain 
information the facility’s infection management activities, advance care planning practices, and 
palliative care/hospice services. Regardless of whether or not participating facilities engage in a 
separate antimicrobial stewardship programs during our intervention period, all randomized NHs 
will be retained in the analyses in accordance with intention-to-treat principles.  
8.7 
Intervention fidelity 
Our approach fidelity monitoring reflects an attempt to balance intervention adherence with a 
pragmatic approach to implementation. All targeted providers will be sent the orientation 
package (printed training material, laminated cards with algorithms), and be exposed to the 
algorithms posters strategically place in the NH. We will aim for >90% attendance of providers 
at either an initial group training group or 1:1 session and 70% completion of the on-line course. 

TRAIN-AD protocol June 30, 2017 
25 
Prescribing feedback reports will provide an on-going measure of adherence to the management 
algorithms.  
9 
DATA COLLECTION ELEMENTS AND PROTOCOL  
9.1 
Facility Data 
Nursing home data are collected prior to the start of the study for descriptive purposes and to 
inform the development of a list of eligible nursing homes for recruitment. Prior to recruitment 
efforts, NH characteristics that may be relevant to advanced dementia care, were abstracted from 
the Medicare Nursing Home Compare, including: the number of beds, hospital-based, special 
care dementia unit, nursing and nursing assistant hours/resident/day, and number of deficiencies 
on state inspections. Long-term Care: Facts on Care in the US (http://www.ltcfocus.org/) is also 
used to gather information about potentially eligible NHs that will help balance factors for the 
randomization procedures (see SAP), including number of beds, number of residents with 
advanced cognitive impairment, and number of Black residents.  Administrators of participating 
facilities are also asked whether NPs/PAs are on staff and whether there is an open or closed 
medical staff.  At the time of initial enrollment and every 12 months during the implementation 
period, following randomization, but prior to initiation of intervention period, the PD conducts a 
structured written survey with senior administrators in all control and intervention facilities to 
ascertain information the facility’s infection management activities, advance care planning 
practices, and palliative care/hospice services.  
9.2 
Resident assessments 
Resident data will be collected by RAs masked to the study arms. All data will be obtained from 
the residents’ charts except for functional status and proxy ability to communicate in English, 
which will be ascertained in a 1-minute nurse interview. Data is collected from the medical 
records of enrolled residents every 2 months for up to 12 months, unless the resident passes or 
the proxy requests to opt out during that time.  Their charts are abstracted at baseline, q2months, 
and within 30 days of death to determine whether antimicrobials were prescribed. If a treated 
episode was a suspected LRI or UTI, documented signs/symptoms will be ascertained to assess 
whether minimal criteria to start antimicrobials were present. Procedures used to evaluate these 
episodes (chest x-rays, bladder catheterization, blood draws, hospital transfer), and documented 
advance care planning about infection management (provider/proxy discussions and advance 
directives to withhold antimicrobials) will also be collected. A 1-minute nurse interview at 
baseline will also be done to assess the resident’s functional status. 
Demographic: (baseline) age, gender, race, ethnicity, length of NH stay, residing in a special care 
dementia unit, and proxy contact information (for mailing booklet) and relationship to resident.  
 
Medical co-morbidity: (baseline) All active medical diagnoses.  
Functional status: (baseline; nurse) Bedford Alzheimer’s Nursing Severity-Subscale (BANS 
range, 7-28; higher score worse disability) 
 
Antimicrobial exposure: (q2months, death) While analyses focus on treatment of suspected LRIs 
and UTIs, details about all antimicrobial courses will be ascertained from the medication 
administration records, including; suspected diagnoses, administration dates, agent, dose, route, 

TRAIN-AD protocol June 30, 2017 
26 
and prescribing provider. There are many ways to quantify antimicrobial exposure. We chose 
number of courses/person-years as our primary outcome as it best captures the intent of the 
intervention which is to reduce antimicrobial initiation. A course will be defined as starting an 
antimicrobial after a > 3-day treatment-free interval. Multiple antimicrobials given 
simultaneously for an episode will be considered single course for analytic purposes. For 
descriptive purposes, we will also quantify antimicrobial exposure as days of therapy 
(DOT)/person-days. 
Treated suspected UTIs and LRIs: (q2months, death): Documented details will be collected for 
treated suspected UTIs and LRIs, including: i. vital signs, mental status changes, localized signs 
and symptoms (e.g., lung sounds, cough, hematuria), ii. procedures used to evaluate including 
bladder catheterizations, chest x-rays, blood draws, iii. hospital transfer (admission or emergency 
room (ER), and vi. treatment discussions between providers and proxies. Signs and symptoms 
will be used to determine whether minimal criteria to initiate antimicrobials were met as 
operationalized in SPREAD and the pilot study. 
Advance care planning: (baseline, q2months, death). The occurrence and date of advance care 
planning events will be ascertained from all available documentation (e.g., progress notes 
physician orders, POLST forms) and will include: discussions between providers and proxies 
about infection management and new directives to withhold antimicrobials (intravenous, 
intramuscular and/or oral) will be ascertained. Do-not-resuscitate and do-not-hospitalize orders 
will also be collected for descriptive purposes.  
Devices: (baseline, q2months, death) feeding tubes, foley catheters  
Health services: (q2months, death) hospitalizations, emergency room visits, hospice enrollment. 
3.C.vii.1.i.  
Other major new acute illnesses: (q2months, death), e.g. fracture, stroke, seizures. Death: RAs 
will phone the NH (nursing units) q2month.  
Death date will be obtained from the chart. 
 
 

TRAIN-AD protocol June 30, 2017 
27 
 
 
Data Collection Elements and Protocol 
Data Collected 
Purpose 
From 
When 
Eligibility Screen 
Age, length of NH stay, available proxy 
Eligibility 
Chart 
Screen 
Advanced dementia 
Eligibility 
Nurse, Chart 
Screen 
IF ELIGIBLE 
Resident Characteristics 
Demographic, medical comorbidity, functional status 
Descriptive 
Chart 
Baseline 
Antimicrobial exposure 
Total courses for LRIs and UTIs2 
10 Outcome (Aim 1) 
Chart, MAR1 
q2months, death 
Total courses for LRIs and UTIs2 not meeting minimal criteria 
20 Outcome (Aim 2) 
Chart, MAR1 
q2months, death 
Burdensome procedures to evaluate suspected LRIs and UTIs 
20 Outcome (Aim 3) 
Chart 
q2months, death 
Advance care planning 
20 Outcome (Aim 3) 
Chart 
Baseline, q2months, death 
Devices 
Descriptive 
Chart 
Baseline, q2months, death 
Health services utilization, new acute illnesses 
Descriptive 
Chart 
q2months, death 
Death 
Descriptive 
Nurse, chart 
Death 
Facility Characteristics 
Descriptive 
NH Compare 
Administrator 
Baseline 
Baseline, q12 months 
1MAR=Medication Administration Record; 2 LRIs and UTIs= lower respiratory tract infections, urinary tract infections 
 
9.2.1 Consenting Procedure (also see sections 7 and 16.2) 
In accordance with federal guidelines, the HSL IRB granted a waiver of informed consent for the 
participation of both providers and residents (i.e., from proxies) based on: i. The determination of 
minimal risk, ii. The trial could not be practically conducted without the waiver. The NH is the 
unit of randomization and the intervention will be implemented as a new program for all 
advanced dementia residents. Including all eligible residents (versus only those consenting) 
reflects how the intervention would be used in the “real-world,” thus enhances the trial’s 
generalizability and interpretability, and iii. The trial does not adversely affect the rights and 
welfare of the subjects. Providers and proxies will have the opportunity to opt out at the start and 
throughout the implementation period, as described in Section 7.   
9.2.2 Baseline Assessments 
The charts of all eligible residents will be including in the baseline data abstraction unless the 
proxy has contacted the study team with a request for exclusion.  Baseline assessments are chart 
review and data extraction along with a 1 minutes Bedford Alzheimer’s Nursing Severity-
Subscale (BANS) interview to assess residents functional status. Baseline assessment includes 
the following:  
• Demographics 
• Health status  
• Chronic or co-morbidities 
• Advanced directives 
• Recent history of treatments or investigations 
• Healthcare utilization 
• BANS interview  
• Infection Screen 

TRAIN-AD protocol June 30, 2017 
28 
9.2.3 Follow-up Visits 
Follow up chart reviews will be completed every 2 months for up to 1 year or until the resident 
dies.  If the resident dies during the 12 month follow up period, a post-death chart review will be 
conducted. Follow-up chart reviews include the following elements: 
• Demographics 
• Advance directives 
• Treatments/Investigations 
• Healthcare utilization 
• Sentinel Events 
• Infection Screen 
9.2.4 Post death Chart review 
Post death chart reviews will be conducted within 30 days of enrolled residents passing.  The 
research nurse will access the residents chart in the same way as she did for follow up chart 
reviews and collect the following information: 
• Advance directives 
• Treatments/Investigations 
• Healthcare utilization 
• Sentinel events 
• Infection Screen 
10 
HUMAN SUBJECT PROTECTIONS 
10.1 Sources of Data 
Residents’ NH record: The residents’ medical record containing information collected for routine 
clinical care will be abstracted at the baseline, q 2month and death assessments for up to 12 
months. The following information will be obtained from the chart: demographic information, 
antimicrobial exposure and prescribing provider, lower respiratory and urinary tract episodes, 
medical comorbidity, advance care planning, devices, health care utilization, acute medical 
illnesses, and death date.  
Nurse interviews: During screening procedures, nurses will be asked to identify subjects who 
meet criteria for Global Deterioration Stage 7. For enrolled residents, at baseline only, nurses 
will be asked to rate the functional status of the patients using the Bedford Alzheimer’s Nursing 
Severity-Subscale during a 1-minute interview.  
  
On-line course: Individual provider completion of the on-line course will be tracked.  
NH residents, proxies, and NH providers (intervention arm only) will be assigned a study 
number known only to the co-principal investigators (PIs) and research assistants (RAs). NH 
providers in the intervention arm will be given a unique username and password to access the on-
line education course known only to them, the PIs and project director. All documentation will 

TRAIN-AD protocol June 30, 2017 
29 
be stored in a locked area, accessible only to the PIs, RAs, and data manager. Data will be stored 
on computer workstations, accessible only through use of a unique password. Access to these 
data will be limited to study personnel on a “need to know” basis. 
11 POTENTIAL RISKS OF STUDY PROCEDURES 
The study meets criteria for minimal risk. All the resident data will be obtained from their 
medical record and nursing interviews, and coded at the time of data entry to protect their 
confidentiality. The residents in the control NHs will receive usual care for suspected infections. 
Residents in the intervention arm will receive care for the suspected infections at the discretion 
of their primary care providers as guided by the practice intervention. Given that the intervention 
is based on consensus, peer reviewed guidelines, the risk from the intervention with regards to 
infection management is minimal. 
11.1 Potential Medial Risk to Study Participants 
Patients with advanced dementia are very frail. In the natural course of the disease, we expect of 
40% mortality rate over one year. Thus, while deaths will be reported to the Data Safety 
Monitor, they are not considered an adverse event. The intervention does not involve any direct 
treatment of residents. Treatment of suspected infections is ultimately at the discretion of the 
nursing home primary care provider. Nonetheless, as part of this study, every 2 months, we will 
be collecting data from the residents’ charts about the rates of suspected urinary and respiratory 
infections, treatment of these infections, and appropriateness of that treatments as defined by our 
primary outcome. 
11.2 Potential psychosocial (non-medical) risks, discomforts, inconveniences of study 
procedures 
We do not anticipate any potential psycho-social risks discomforts or inconveniences of study 
procedures beyond those encountered in usual care practices.  The intervention provides 
information for proxies about infections in advanced dementia residents to promote informed 
decision-making that it is concordant with preferences, which is also desired goal for high 
quality nursing home care. The intervention was very well-received with no adverse events in the 
pilot study. Thus, we believe the intervention does not incur any greater distress than usual 
practice. Second, data collection conforms to the definition of minimal risk. No direct input from 
the residents or proxies is needed to complete any data for this study. All resident data are 
already being collected as part of routine medical care with the exception of the 1-minute nursing 
interview at baseline to quantify the resident’s functional status for descriptive purposes.  All 
resident data are entered into a password protected encrypted software system using unique study 
identifiers.  The data sheet linking residents with unique study ids is maintained in a separate 
secure system location at the discretion of the study site champion. 
 
One additional potential burden of this study is the time commitment of the NH staff to assist 
with eligible subject identification, which involves 1-minute baseline nursing interviews, and 
intervention implementation. We will make every effort to minimize staff burden. Staff at the 
~60 facilities that have participated in our prior large studies that used similar methods to recruit 
residents with advanced dementia felt the procedures were not too onerous. Based on our 
experience, the baseline nursing interview to quantify functional status is expected to take ~1 

TRAIN-AD protocol June 30, 2017 
30 
minute to complete. It is unlikely this burden will fall on a single nurse. Every effort will be 
made to conduct these interviews at times that are convenient for the nurses. Some burden will 
be experienced by the TRAIN-AD site champion and 15-20 targeted providers/NH (12-16 
nurses, 1-3 physicians, 0-3 NPs/PAs) in the 12 intervention NHs with respect to the time 
required for initial training, completion of the on-line education course, use of algorithms to 
guide antimicrobial initiation, and review of prescribing feedback reports. All training 
procedures will be done at the convenience of these providers. Their involvement is voluntary. 
Group seminars will be conducted twice the same day to reach various shifts, and 1:1 sessions 
will be arranged for providers unable to attend the group training. The on-line course can also be 
done at the providers’ convenience.  
11.3 Adverse Events and Serious Adverse Events  
The study intervention is a facility level training and educational program in line with CDC 
recommendations for infection management and antimicrobial stewardship programming.  The 
research team has no direct contact with study participants.   We do not anticipate any serious 
adverse events or adverse events to occur in this study.  
11.4 Reporting Procedures 
Although, there are no anticipated adverse events, should any unanticipated study-related event 
of concern come to the attention of any research team member (i.e., report by site champion, 
proxy or provider), it will documented on a ‘event of concern’ form by the PD and reviewed 
within 24 hours with the PI. Site champions will be trained on this procedure during the 3-month 
facility planning period.  Any unanticipated adverse event will be promptly reported in writing to 
the NIH and the HSL IRB within 48 hours by the PI. 
11.5 Follow-up for Adverse Events:  
If an adverse event was deemed to have occurred, the site champion will be instructed to check 
on the provider/family/resident who experienced the event within 24 hours of the event to see 
how he/she is managing. If deemed necessary, the individual will be referred to the appropriate 
health care professional based on the nature of the event (i.e, counseling with a NH social 
worker, medical attention by a physician). In the case of a provider or family member, if deemed 
necessary, the site champion may suggest to the proxy that he/she contact his/her own primary 
care provider. The research project director will contact the facility site champion within 48 
hours of the event to determine the status of the provider/family/resident and whether further 
follow-up was deemed necessary. The project director will report the follow-up information to 
the PI (by telephone) and to the data safety monitor (in writing) within 72 hours. 
11.6 Safety Monitoring 
As agreed upon by the NIA and overseeing project officer, Dr. Marcel Salive, safety monitoring 
will be the responsibility of a Data Safety Monitor (DSM), Dr. David Mehr of the University of 
Missiouri.  The PI will meet with Dr. Mehr during the preparation stage of the study via 
conference call, to provide input and guidance on the study evaluation and intervention 
protocols, data handling activities, and quality assurance and safety issues. Together they will 
agree on definitions of an adverse event and the content of the regular DSM reports. Once the 
study starts, the DSM will be sent a report prepared by the research team summarizing the 

TRAIN-AD protocol June 30, 2017 
31 
overall study status, recruitment, data completion rates, adverse events, protocol deviations, and 
outcomes (if desired). Data will be presented aggregated for both arms of the RCT, and in a sub-
report that the PI will not see, in a semi-blinded fashion with study arms labeled as Group 1 and 
Group 2. The DSM will be free to determine the need to stop the continuation of the study based 
on examination of these reports. 
12 
INTERVENTION DISCONTINUATION  
The study may be discontinued at any time by the IRB, the NIA, OHRP or other government 
agencies as part of their duties to ensure that research participants are protected. Individual NHs 
in the intervention arm may withdraw from study participation at any time at the discretion of 
their senior management or corporate supervisors. Providers can opt out of any part of 
intervention participation at any time, and while not being asked to provide informed consent for 
this research, resident proxies can opt out of reading the infection management booklet and 
contact the research team at any time to request exclusion of their resident from ongoing data 
collection efforts.  Program being adopted into the clinical practice of participating intervention 
NHs. Such refusals are expected as part of this pragmatic trial. 
13 
STATISTICAL CONSIDERATIONS (SEE SAP) 
 DATA COLLECTION AND QUALITY ASSURANCE 
13.1 Data Use Agreements 
There are no Data Use Agreement (DUA) for this study.  All facility level data comes from 
public data sources and all resident data is obtained from residents’ medical charts, with the 
exception of a 1-minute nurse interview at baseline to assess the resident’s functional status. 
13.1.1 Residents:  
Data will be collected by a trained RAs masked to the aims, outcomes, and that there are 2 arms. 
All data will be obtained from the residents’ charts except for functional status and proxy ability 
to communicate in English, which will be ascertained in a 1-minute nurse interview at baseline. 
Charts will be abstracted (~20 minutes) when residents are first enrolled (baseline), q2months, 
and within 30 days of death, for up to 12 months. REDcap will be used for collecting data 
electronically and tracking protocol elements. 
All resident data will be entered and managed in HSL data systems under a confidential study 
ID. The code sheet linking study ID to individual resident will be kept in a secure location within 
the NH. HSL data bases will maintain data under subject study ID related to nursing home name, 
age, and gender. Access to this code sheet will be limited to the RA assigning the codes, the 
study site champion and the project manager as needed to facilitate mailing of booklets to 
proxies of enrolled residents.   
13.1.2 Proxies 
Proxy information is collected to facilitate mailing of the infection management booklet and 
study information. Information collected is limited to name and mailing address which is 
abstracted from the resident’s chart, and the proxy’s ability to communicate in English, which is 
obtained from the unit nurses.  All proxy information will be maintained in the secure study 

TRAIN-AD protocol June 30, 2017 
32 
subject code sheet maintained within the NHs. 
13.2 Identifiers to be stored separately from resident data 
13.2.1 Key or link to the codes 
A code sheet linking individual residents and proxy information with the assigned study IDs will 
be kept in hard copy and/or electronic format on a password protected flash drive in a secure 
location within the participating NH. The location and means of securing this data will be 
decided in collaboration with the NH leadership team and study champion. 
13.2.1.1 Individuals (or study roles) who will have access to identifiable data, or key/link to codes 
Research assistants who will be conducting eligibility screenings and subsequent chart reviews, 
study site champions, and project directors who will be sending the proxy materials from within 
the nursing home have access to the study ID code sheet. 
13.3 Data security measures 
All access to data is restricted to those in the research group who have been authorized by the PI 
to utilize this information.  Because HSL is a licensed hospital, the information technology group 
adheres to all the policies and practices under the HIPAA regulations.  Although not required, 
HSL treats all lines of business as HIPAA locations and hold them accountable to these security 
standards therefore, creating a very tight computing environment.   In order to preserve 
confidentiality, subjects will be assigned a study number known only to the co-PIs, PDs, RAs 
and data manager. A code sheet linking individual residents and proxy information with the 
assigned study IDs will be kept in hard copy and/or electronic format on a password protected 
flash drive in a secure location within the participating NH. 
All data collected electronically by RAs on laptop computer using internet-based electronic data 
capture programs (i.e., REDcap) accessible only to research personnel through the use of unique 
password. All written documentation with subject information will be stored in a locked area 
within the nursing home, accessible only to the RAs, PDs, and site champion. All data will be 
stored on computer workstations, accessible only through use of a unique password. Access to 
these data will be limited to study personnel on a “need to know” basis. If a NH resident is 
deemed ineligible for the study, all personal health information obtained for screening purposes 
will be destroyed as soon as possible.  
13.3.1 Timing of destruction of materials containing identifiers and keys/links to codes 
Once the study has ended and all subjects have been followed for safety and study outcomes. 
13.3.2 Method for destroying materials with identifiers and keys/links to codes 
Paper documents will be shredded and electronic files will be deleted. 
13.4 Data Collection Forms 
There are three levels of data collection.  Data are collected at the start of the study and annually 
thereafter from NH leadership related to the site’s independent infection management initiatives 
and readiness for infection management program implementation.  Resident level data are 

TRAIN-AD protocol June 30, 2017 
33 
collected at baseline and every 2 months for 12 months or until the resident deceases.  Provider 
level data are collected via site champion interaction and from their participation in the HMS 
online course.  Finally, proxy name and mailing address is obtained from the resident’s chart 
during eligibility screening. 
13.4.1 Facility level data collection 
General facility information including its size, address, for-profit status, acuity status and 
demographic data is obtained from public data sources including Medicare Nursing Home 
Compare and LTCfocus.  Facility level data collection will be conducted by the research team in 
an effort to ascertain potential concomitant initiatives and to assess readiness for new program 
implementation.  This questionnaire has been built into the Redcap data project and conducted 
prior to program planning efforts within the facility and annually thereafter. 
13.4.2 Resident Data collection forms  
The following data collection forms, programed into redcap are used for resident-level data 
collection: 
• Resident eligibility screening 
• Baseline resident chart review 
• Resident bimonthly chart reviews 
• Post Death Chart review 
• Infection Screening (occurs at baseline and bimonthly chart reviews) 
• UTI and LRI infection modules (used when either UTI or LRI are recorded during an 
• infection screening) 
13.4.3 Provider level data collection 
Provider names and contact information will be obtained by the research project director from 
the site champion.  Data related to their participation in the online course will be obtained from 
HMS website.  This data will include the provider results on the pre and post-test and course 
completion status. Data will be uploaded and maintained in a REDap provider database 
maintained by the project manager within IFAR.  Access to this data will be limited to the 
project director and study data analyst in blinded form.  
13.5 Data Management  
Data management and analysis for the study will take place at HSL under the direction of the 
informatics and biostatistics cores at the Institute for Aging Research (IFAR). All access to data 
is restricted to those on the research team who have been authorized by the PI to use this 
information. The HSL information technology (IT) department adheres to all the policies and 
practices under HIPAA regulations and is responsible for securing IFAR's IT infrastructure 
including physical servers and application software. IFAR has established additional sensitive 
data policies and procedures in concert with the IRB to ensure safe data handling by faculty and 
staff.  

TRAIN-AD protocol June 30, 2017 
34 
13.5.1 Resident/Proxy data collection 
One to two research assistants (RAs) will be responsible for screening subjects and conducting 
chart reviews. To the extent possible, the RAs collecting outcome data through chart reviews and 
follow-up proxy interviews will be blinded to nursing home randomization. All data will be 
collected and entered electronically by the RAs using laptop computers in the field. State-of-the-
art electronic data capture software and programming (e.g., REDCap) will be used for these 
purposes. Once entered, the data will be downloaded and entered into the computer systems at 
HSL IFAR for cleaning, programming and analyses. 
13.5.2 Provider data collection and management 
The pre/post knowledge scores of providers doing the education modules in intervention NHs 
will be submitted to the research team by the staff at the HMS CME office using a password 
protected electronic computer file. Once received, HSL data management will strip the scores of 
subject identifiers and enter the data into the electronic data file.  
13.6 Quality Assurance  
13.6.1 Training 
All research staff have been trained in human subject safety and data security measures.  SOPs 
document procedural requirements for all study related activities. Each member of the research 
team is trained in their research role by the PI and PDs in accordance to the SOP.  Cross training 
among the research team ensures redundancy within the team to ensure uninterrupted procedures 
throughout the trial.   
13.6.2 Protocol Deviations 
All identified protocol procedures will be tracked in a protocol deviations database by the project 
director and included in periodic reports to the data safety monitor for review. 
13.6.3 Monitoring 
The TRAIN-AD program is designed to be adapted to optimize implementation within each 
participating NH.  A few essential elements will be monitored by the research team during 
periodic site visits and implementation check-in meetings with the site champions.  Essential 
components include the visible display of study flyers and infection management guidelines 
throughout the facility.  Additionally, the PD will ensure, through ongoing interactions with the 
site champion that all new providers are invited to participate in the on-site trainings and online 
course.  The RA conducting the periodic chart review will ensure that the procedures for 
maintaining securing around the participant code sheet are being followed within the facility. 
The PD will conduct monthly reviews of data collection to ensure that all targeted data collection 
is completed in a timely manner.  
14 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
14.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent and HIPAA waiver applications have been reviewed and 

TRAIN-AD protocol June 30, 2017 
35 
approved by Hebrew Senior Life’s IRB.  Continuation of study is contingent on annual review 
and approval by the IRB.  Any changes to study protocol or materials will be submitted to the 
IRB for review and approval prior to implementation.   
14.2 Informed Consent Forms 
A waiver of informed consent and HIPAA Waiver of Patient Authorization was approved by the 
NIH, and Hebrew Senior Life’s Institutional Review Board, based on federal guidelines 45 CFR 
46.116(d)): 
1. The research involves no more than minimal risk to the participants; 
2. The waiver or alteration will not adversely affect the rights and welfare of the participants; 
3. The research could not practicably be carried out without the waiver or alteration; and 
4. Whenever appropriate, the participants will be provided with additional pertinent information 
after participation. 
14.2.1 The study meets criteria for minimal risk as per HHS 45 CFR 45.102:  
“Minimal risk means that 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.” 
Explanation 
First, TRAIN-AD is an education and training program rolled out at the facility level which 
promotes the general recommendations of the Center for Disease Control (CDC) that NHs 
engage in antimicrobial stewardship activities as a standard of care.  The educational content of 
the program is aligned with CDC recommendations for antimicrobial prescribing based on 
national consensus guidelines, intended to improve infection management for residents with 
advanced dementia.  The program also provides information for proxies about infections in 
advanced dementia residents to promote informed decision-making that is patient-centered and 
consistent with goals for patient care.  At no point will members of the research team have direct 
contact with residents or proxies or directly affect care. 
Second, data collection conforms to the definition of minimal risk. Data collected for research 
purposes will be obtained through bimonthly review and abstraction from the charts of enrolled 
residents and a single 1-minute nursing interview at baseline to quantify the resident’s functional 
status for descriptive purposes. Research data will be maintained in an encrypted, password 
protected database which uses unique study IDs for all enrolled residents and proxies. The code 
sheet linking study subjects with study IDs will be kept in a secure location within the 
participating NH. 
14.2.2 The waiver or alteration will not adversely affect the rights and welfare of participants 
Explanation 
TRAIN-AD is a facility-wide education and training program that promotes CDC established 
best practices for infection management and CMS recommendations for antimicrobial 
stewardship within nursing homes.  The program promotes the provision of patient-centered care 
in an effort to improve care quality, but individual treatment decisions remain entirely at the 
discretion of the residents’ medical providers.  Research team members have no direct contact 

TRAIN-AD protocol June 30, 2017 
36 
with residents or proxies and all. With the exception of the 1-minute nurse interview to 
characterize functional status, all resident data will be obtained from residents’ existing s medical 
record, and recorded in the secure research database using unique study identifiers.  Study 
information is mailed to proxies of eligible residents and posted throughout the facility.  
Residents’ healthcare proxies can opt-out of allowing the research team to include resident data 
in the study at any time. 
14.2.3 The research could not practicably be carried out without the waiver or alteration 
Explanation 
Obtaining individual informed consent for this study is impractical for this facility-level 
education and training program, which involves no direct contact by our research team with 
either residents or proxies and leaves resident care decisions entirely at the discretion of the 
providers. The intervention is being rolled-out facility-wide, so all residents with advanced 
dementia within the facility are potentially affected by the program.  The waiver of consent 
enables us to assess the effect of the intervention as it is implemented in the real world. 
14.2.4 Whenever appropriate, the participants will be provided with additional pertinent 
information after participation:  
Upon the study’s conclusion, results and publications will be provided by the research team to 
the NH administrators and providers, as well as proxies of residents with advanced dementia, as 
requested.  
14.3 Participant Confidentiality  
This trial has been granted a HIPAA Waiver of Requirement for Authorization for Release of 
Protected Health Information for Research Purposes from the Hebrew Senior Life IRB.   In order 
to preserve confidentiality, subjects will be assigned a study number known only to the RAs PDs 
and site champions. All physical documentation and IT assets are stored in a locked areas within 
the participating NHs and within HSL, monitored 24-hours a day by security personnel, and 
accessible only by authorized employees. Access to the HSL cooperate computer network is 
strictly prohibited and all electronic research data will be stored on dedicated IFAR systems 
located on our private network. Access to these data will be limited to study personnel on a 
“need to know” basis. If a NH resident is deemed ineligible for the study, all personal health 
information obtained for screening purposes will be destroyed as soon as possible. 
15 STUDY DISCONTINUATION  
The study may be discontinued at any time by the IRB, the NIA, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected.  
16 
ETHICAL CONSIDERATIONS 
Ethical consideration for the PROVEN trial will be in accordance with the Federal Policy for the 
Protection of Human Subjects (HHS Human Subjects Research 45 Code of Federal Regulations 
(CFR) 46). 

TRAIN-AD protocol June 30, 2017 
37 
17 COMMITTEES 
 
Purpose 
Meeting 
Chair 
Attendees 
Frequency 
Timing 
Executive committee 
Mitchell 
Mitchell, D’Agata, Bergman, Carroll 
Q2weeks 
Months 1-52 
Data Safety Monitoring 
Mitchell 
Mitchell, Shaffer, Habtemariam, Tsai, 
Bergman and  Mehr 
Q6 Months 
 
Full team meetings 
Co-led 
Mitchell, D’Agata, Shaffer, Hanson,
 Bergman, 
Anderson (months 1-24 only), Carroll, 
Habtemariam, Tsai, Loizeau 
Quarterly 
Months 1-52 
Field operations 
Co-led 
Mitchell, D’Agata, Carroll, Bergman 
Weekly 
Q2weeks 
Months 1-20 
Months 20-38 
Intervention content and 
Implementation 
D’Agata 
D’Agata, Mitchell (only meeting that do not require 
naming of facilities), Carroll, Bergman, Loizeau, 
Anderson (ad hoc basis)son1,3 
Weekly 
Q2weeks 
Months 1-20 
Months 20-38 
Data 
management/analyses 
Mitchell 
Mitchell, Bergman, Habtemariam, Tsai, Shaffer1 
Monthly 
Weekly 
Months 7-44 
Months 45-52 
 
 
 

TRAIN-AD protocol June 30, 2017 
38 
18 PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures developed 
by the Steering Committee.  Any presentation, abstract, or manuscript will be made available for 
review by the sponsor and the NIA prior to submission. 
19 REFERENCES 
Bibliography  
1. Mitchell SL, Teno JM, Kiely DK, et al. The clinical course of advanced dementia. N Engl J 
Med 2009;361:1529-38.  
2. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US 
population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119-22.  
3. Goldfeld KS, Stevenson DG, Hamel MB, Mitchell SL. Medicare expenditures among nursing 
home residents with advanced dementia. Arch Intern Med 2011;171:824-30.  
4. Wimo A, Ljunggren G, Winblad B. Costs of dementia and dementia care: a review. Int J 
Geriatr Psychiatry 1997;12:841-56.  
5. Deaths: Leading Causes for 2011. National Vital Statistics Reports, 2015. (Accessed August 
12, 2015, at http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_07.pdf.)  
6. Givens JL, Jones RN, Shaffer ML, Kiely DK, Mitchell SL. Survival and comfort after treatment 
of pneumonia in advanced dementia. Arch Intern Med 2010;170:1102-7.  
7. Volicer L. Management of severe Alzheimer's disease and end-of-life issues. Clin Geriatr Med 
2001;17:377-91.  
8. Chen JH, Lamberg JL, Chen YC, et al. Occurrence and treatment of suspected pneumonia in 
long-term care residents dying with advanced dementia. J Am Geriatr Soc 2006;54:290-5.  
9. Mitchell SL, Shaffer ML, Loeb MB, et al. Infection management and multidrug-resistant 
organisms in nursing home residents with advanced dementia. JAMA Intern Med 
2014;174:1660-7.  
10. Mody L. Optimizing antimicrobial use in nursing homes: no longer optional. J Am Geriatr 
Soc 2007;55:1301-2.  
11. Norman DC. Management of antibiotic-resistant bacteria. J Am Geriatr Soc 2002;50:S242-6.  
12. Loeb M, Simor AE, Landry L, et al. Antibiotic use in Ontario facilities that provide chronic 
care. J Gen Intern Med 2001;16:376-83.  
13. Loeb M, Brazil K, Lohfeld L, et al. Optimizing antibiotics in residents of nursing homes: 
protocol of a randomized trial. BMC Health Serv Res 2002;2:17.  
14. Yoshikawa TT. Resistant pathogens: considerations in geriatrics and infectious disease. J 
Am Geriatr Soc 2002;50:S225.  
15. Pickering TD, Gurwitz JH, Zaleznik D, Noonan JP, Avorn J. The appropriateness of oral 
fluoroquinolone-prescribing in the long-term care setting. J Am Geriatr Soc 1994;42:28-32.  
16. Yoshikawa TT. Antimicrobial resistance and aging: beginning of the end of the antibiotic 
era? J Am Geriatr Soc 2002;50:S226-9.  
17. Pop-Vicas A, Mitchell SL, Kandel R, Schreiber R, D'Agata EM. Multidrug-resistant gram-
negative bacteria in a long-term care facility: prevalence and risk factors. J Am Geriatr Soc 
2008;56:1276-80.  
18. The Core Elements of Antibiotic Stewardship for Nursing Homes. Centers for Disease 
Control and Prevention, 2015. (Accessed September 21, 2015, at 
http://www.cdc.gov/longtermcare/prevention/antibiotic- stewardship.html.)  
19. Daneman N, Bronskill SE, Gruneir A, et al. Variability in Antibiotic Use Across Nursing 
Homes and the Risk of Antibiotic-Related Adverse Outcomes for Individual Residents. JAMA 
Intern Med 2015;175:1331-9.  

TRAIN-AD protocol June 30, 2017 
39 
20. Yates E, Mitchell SL, Habtemariam D, Dufour AB, Givens JL. Interventions Associated with 
the Management of Suspected Infections in Advanced Dementia. J Pain Symptom Manage 
2015.  
21. Dufour AB, Shaffer ML, D’Agata EMC, Habtemariam D, Mitchell SL. Survival after 
Suspected Urinary Tract Infections in Advanced Dementia. J Am Geriatr Soc 2015;doi: 
10.1111/jgs.13833.  
22. Mitchell SL, Shaffer ML, Kiely DK, Givens JL, D'Agata E. The study of pathogen resistance 
and antimicrobial use in dementia: study design and methodology. Arch Gerontol Geriatr 
2013;56:16-22.  
23. Loeb M, Bentley DW, Bradley S, et al. Development of minimum criteria for the initiation of 
antibiotics in residents of long-term-care facilities: results of a consensus conference. Infect 
Control Hosp Epidemiol 2001;22:120-4.  
24. Crnich CJ, Jump R, Trautner B, Sloane PD, Mody L. Optimizing Antibiotic Stewardship in 
Nursing Homes: A Narrative Review and Recommendations for Improvement. Drugs Aging 
2015;32:699-716.  
25. Inside NIA: A Blog for Researchers. A special budget for Alzheimer’s and relateddementias  
 
2016. (Accessed August 10, 2015, at <https://www.nia.nih.gov/research/blog/2015/08/special-
budget- alzheimers-and-related-dementias>.)  
26. Dying In America: Improving Quality and Honoring Individual Preferences Near the End-of-
Life. In: Institute of Medicine of the National Academies; 2014. 
27. Alzheimer’s Association. 2015 Alzheimer's disease facts and figures. (Accessed August 24, 
2015, at https://www.alz.org/facts/downloads/facts_figures_2015.pdf.)  
28. Mitchell SL, Teno JM, Miller SC, Mor V. A national study of the location of death for older 
persons with dementia. J Am Geriatr Soc 2005;53:299-305.  
29. Ahronheim JC, Morrison RS, Morris J, Baskin S, Meier DE. Palliative care in advanced 
dementia: a randomized controlled trial and descriptive analysis. J Palliat Med 2000;3:265-73.  
30. Mitchell SL, Kiely DK, Hamel MB. Dying with advanced dementia in the nursing home. Arch 
Intern Med 2004;164:321-6.  
31. Mitchell SL, Black BS, Ersek E, et al. Advanced dementia: State-of-the-art and priorities for 
the next decade. Ann Intern Med 2012;In press.  
32. Mitchell SL. CLINICAL PRACTICE. Advanced Dementia. N Engl J Med 2015;372:2533-40.  
33. Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for 
assessment of primary degenerative dementia. Am J Psychiatry 1982;139:1136-9.  
34. Morrison RS, Siu AL. Survival in end-stage dementia following acute illness. JAMA 
2000;284:47-52.  
35. Mehr DR, van der Steen JT, Kruse RL, Ooms ME, Rantz M, Ribbe MW. Lower respiratory 
infections in nursing home residents with dementia: a tale of two countries. Gerontologist 
2003;43 Spec No 2:85-93.  
36. van der Steen JT, Kruse RL, Ooms ME, et al. Treatment of nursing home residents with 
dementia and lower respiratory tract infection in the United States and The Netherlands: an 
ocean apart. J Am Geriatr Soc 2004;52:691-9.  
37. D'Agata E, Mitchell SL. Patterns of antimicrobial use among nursing home residents with 
advanced dementia. Arch Intern Med 2008;168:357-62.  
38. D'Agata E, Loeb MB, Mitchell SL. Challenges in assessing nursing home residents with 
advanced dementia for suspected urinary tract infections. J Am Geriatr Soc 2013;61:62-6.  
39. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus 
aureus infections in the United States. Jama 2007;298:1763-71.  
40. Campaign to Reduce Antimicrobial in Healthcare Settings. 2007. (Accessed January 7, 
2008, 2008, at http://www.cdc.gov/drugresistance/healthcare/.)  

TRAIN-AD protocol June 30, 2017 
40 
41. The Problem of Antimicrobial Resistance. 2006. (Accessed January 7, 2008, at 
http://www.niaid.nih.gov/factsheets/antimicro.htm.)  
42. Kunin CM. Resistance to antimicrobial drugs--a worldwide calamity. Ann Intern Med 
1993;118:557-61.  
43. Holmberg SD, Solomon SL, Blake PA. Health and economic impacts of antimicrobial 
resistance. Rev Infect Dis 1987;9:1065-78.  
44. Dommeti P, Wang L, Flannery EL, Symons K, Mody L. Patterns of ciprofloxacin-resistant 
gram- negative bacteria colonization in nursing home residents. Infect Control Hosp Epidemiol 
2011;32:177-80.  
45. Mody L, Gibson KE, Horcher A, et al. Prevalence of and Risk Factors for Multidrug-
Resistant Acinetobacter baumannii Colonization Among High-Risk Nursing Home Residents. 
Infect Control Hosp Epidemiol 2015:1-8.  
46. Mody L, Krein SL, Saint S, et al. A targeted infection prevention intervention in nursing home 
residents with indwelling devices: a randomized clinical trial. JAMA Intern Med 2015;175:714-
23.  
47. Cassone M, Mody L. Colonization with Multi-Drug Resistant Organisms in Nursing Homes: 
Scope, Importance, and Management. Curr Geriatr Rep 2015;4:87-95.  
48. Toubes E, Singh K, Yin D, et al. Risk factors for antibiotic-resistant infection and treatment 
outcomes among hospitalized patients transferred from long-term care facilities: does 
antimicrobial choice make a difference? Clin Infect Dis 2003;36:724-30.  
49. Trick WE, Weinstein RA, DeMarais PL, et al. Colonization of skilled-care facility residents 
with antimicrobial-resistant pathogens. J Am Geriatr Soc 2001;49:270-6.  
50. Niclaes L, Buntinx F, Banuro F, Lesaffre E, Heyrman J. Consequences of MRSA carriage in 
nursing home residents. Epidemiol Infect 1999;122:235-9.  
51. Suetens C, Niclaes L, Jans B, et al. Methicillin-resistant Staphylococcus aureus colonization 
is associated with higher mortality in nursing home residents with impaired cognitive status. J 
Am Geriatr Soc 2006;54:1854-60.  
52. Tacconelli E, Pop-Vicas AE, D'Agata EM. Increased mortality among elderly patients with 
meticillin- resistant Staphylococcus aureus bacteraemia. J Hosp Infect 2006;64:251-6.  
53. Wiener J, Quinn JP, Bradford PA, et al. Multiple antibiotic-resistant Klebsiella and 
Escherichia coli in nursing homes. JAMA 1999;281:517-23. 
54. Capitano B, Leshem OA, Nightingale CH, Nicolau DP. Cost effect of managing methicillin-
resistant Staphylococcus aureus in a long-term care facility. J Am Geriatr Soc 2003;51:10-6.  
55. Manzur A, Vidal M, Pujol M, et al. Predictive factors of meticillin resistance among patients 
with Staphylococcus aureus bloodstream infections at hospital admission. J Hosp Infect 
2007;66:135-41.  
56. Wright SW, Wrenn KD, Haynes M, Haas DW. Prevalence and risk factors for multidrug 
resistant uropathogens in ED patients. Am J Emerg Med 2000;18:143-6.  
57. Pop-Vicas AE, D'Agata EM. The rising influx of multidrug-resistant gram-negative bacilli into 
a tertiary care hospital. Clin Infect Dis 2005;40:1792-8.  
58. Mody L, Bradley SF, Strausbaugh LJ, Muder RR. Prevalence of ceftriaxone- and 
ceftazidime-resistant gram-negative bacteria in long-term-care facilities. Infect Control Hosp 
Epidemiol 2001;22:193-4.  
59. Lee DC, Barlas D, Ryan JG, Ward MF, Sama AE, Farber BF. Methicillin-resistant 
Staphylococcus aureus and vancomycin-resistant enterococci: prevalence and predictors of 
colonization in patients presenting to the emergency department from nursing homes. J Am 
Geriatr Soc 2002;50:1463-5.  
60. Suetens C, Niclaes L, Jans B, et al. Determinants of methicillin-resistant Staphylococcus 
aureus carriage in nursing homes. Age Ageing 2007;36:327-30.  
61. Loeb MB, Craven S, McGeer AJ, et al. Risk factors for resistance to antimicrobial agents 
among nursing home residents. Am J Epidemiol 2003;157:40-7.  

TRAIN-AD protocol June 30, 2017 
41 
62. Sandoval C, Walter SD, McGeer A, et al. Nursing home residents and Enterobacteriaceae 
resistant to third-generation cephalosporins. Emerg Infect Dis 2004;10:1050-5.  
63. Bonomo RA. Multiple antibiotic-resistant bacteria in long-term-care facilities: An emerging 
problem in the practice of infectious diseases. Clin Infect Dis 2000;31:1414-22.  
64. Muder RR, Brennen C, Drenning SD, Stout JE, Wagener MM. Multiply antibiotic-resistant 
gram- negative bacilli in a long-term-care facility: a case-control study of patient risk factors and 
prior antibiotic use. Infect Control Hosp Epidemiol 1997;18:809-13.  
65. Fabiszewski KJ, Volicer B, Volicer L. Effect of antibiotic treatment on outcome of fevers in 
institutionalized Alzheimer patients. JAMA 1990;263:3168-72.  
66. van der Steen JT, Ooms ME, Ader HJ, Ribbe MW, van der Wal G. Withholding antibiotic 
treatment in pneumonia patients with dementia: a quantitative observational study. Arch Intern 
Med 2002;162:1753-60.  
67. van der Steen JT, Ooms ME, van der Wal G, Ribbe MW. Pneumonia: the demented 
patient's best friend? Discomfort after starting or withholding antibiotic treatment. J Am Geriatr 
Soc2002;50:1681-8.  
68. Rozzini R, Sabatini T, Trabucchi M. Medical treatment of acute illnesses in end-stage 
dementia. Arch Intern Med 2003;163:496-7; author reply 7-8.  
69. Morrison RS, Ahronheim JC, Morrison GR, et al. Pain and discomfort associated with 
common hospital procedures and experiences. J Pain Symptom Manage 1998;15:91-101.  
70. Givens JL, Selby K, Goldfeld KS, Mitchell SL. Hospital transfers of nursing home residents 
with advanced dementia. J Am Geriatr Soc 2012;60:905-9.  
71. Fried TR, Gillick MR, Lipsitz LA. Whether to transfer? Factors associated with hospitalization 
and outcome of elderly long-term care patients with pneumonia. J Gen Intern Med 1995;10:246-
50.  
72. Loeb M, Carusone SC, Goeree R, et al. Effect of a clinical pathway to reduce 
hospitalizations in nursing home residents with pneumonia: a randomized controlled trial. JAMA 
2006;295:2503-10.  
73. Kyne L, Merry C, O'Connell B, Kelly A, Keane C, O'Neill D. Factors associated with 
prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing 1999;28:107-
13.  
74. van der Steen JT, Mehr DR, Kruse RL, et al. Predictors of mortality for lower respiratory 
infections in nursing home residents with dementia were validated transnationally. J Clin 
Epidemiol 2006;59:970-9.  
75. Faulkner CM, Cox HL, Williamson JC. Unique aspects of antimicrobial use in older adults. 
Clin Infect Dis 2005;40:997-1004.  
76. Givens JL, Kiely DK, Carey K, Mitchell SL. Healthcare proxies of nursing home residents 
with advanced dementia: decisions they confront and their satisfaction with decision-making. J 
Am Geriatr Soc 2009;57:1149- 55.  
77. Albrecht JS, McGregor JC, Fromme EK, Bearden DT, Furuno JP. A nationwide analysis of 
antibiotic use in hospice care in the final week of life. J Pain Symptom Manage 2013;46:483-90.  
78. Furuno JP, Noble BN, Horne KN, et al. Frequency of outpatient antibiotic prescription on 
discharge to hospice care. Antimicrob Agents Chemother 2014;58:5473-7.  
79. Rosenberg JH, Albrecht JS, Fromme EK, et al. Antimicrobial use for symptom management 
in patients receiving hospice and palliative care: a systematic review. J Palliat Med 
2013;16:1568-74. 
80. Thompson AJ, Silveira MJ, Vitale CA, Malani PN. Antimicrobial use at the end of life among 
hospitalized patients with advanced cancer. Am J Hosp Palliat Care 2012;29:599-603.  
81. Hickman SE, Nelson CA, Perrin NA, Moss AH, Hammes BJ, Tolle SW. A comparison of 
methods to communicate treatment preferences in nursing facilities: traditional practices versus 
the physician orders for life-sustaining treatment program. J Am Geriatr Soc 2010;58:1241-8.  

TRAIN-AD protocol June 30, 2017 
42 
82. Loeb M, Brazil K, Lohfeld L, et al. Effect of a multifaceted intervention on number of 
antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes: 
cluster randomised controlled trial. Bmj 2005;331:669.  
83. Monette J, Miller MA, Monette M, et al. Effect of an educational intervention on optimizing 
antibiotic prescribing in long-term care facilities. J Am Geriatr Soc 2007;55:1231-5.  
84. Naughton BJ, Mylotte JM, Ramadan F, Karuza J, Priore RL. Antibiotic use, hospital 
admissions, and mortality before and after implementing guidelines for nursing home-acquired 
pneumonia. J Am Geriatr Soc 2001;49:1020-4.  
85. Hutt E, Ruscin JM, Corbett K, et al. A multifaceted intervention to implement guidelines 
improved treatment of nursing home-acquired pneumonia in a state veterans home. J Am 
Geriatr Soc 2006;54:1694- 700.  
86. Zimmerman S, Mitchell M, Beeber AS, et al. Strategies to Reduce Potentially Inappropriate 
Antibiotic Prescribing in Assisted Living and Nursing Homes. In: Advances in the Prevention and 
Control of HAIs. Rockville, MD: Agency for Healthcare Research and Quality 2014:99-109.  
87. Zimmerman S, Sloane PD, Bertrand R, et al. Successfully reducing antibiotic prescribing in 
nursing homes. J Am Geriatr Soc 2014;62:907-12.  
88. Juthani-Mehta M, Malani PN, Mitchell SL. Antimicrobials at the End-of-Life: An Opportunity 
to Improve Palliative Care and Infection Management. Journal of the American Medical 
Association 2015;In press.  
89. Trautner BW, Grigoryan L, Petersen NJ, et al. Effectiveness of an Antimicrobial Stewardship 
Approach for Urinary Catheter-Associated Asymptomatic Bacteriuria. JAMA Intern Med 
2015;175:1120-7.  
90. Meeker D, Linder JA, Fox CR, et al. Effect of Behavioral Interventions on Inappropriate 
Antibiotic Prescribing Among Primary Care Practices: A Randomized Clinical Trial. JAMA 
2016;315:562-70.  
91. Anderson RA, Issel LM, McDaniel Jr RR. Nursing homes as complex adaptive systems: 
relationship between management practice and resident outcomes. Nurs Res 2003;52:12-21.  
92. Rantz MJ, Flesner MK, Zwygart-Stauffacher M. Improving care in nursing homes using 
quality measures/indicators and complexity science. J Nurs Care Qual 2010;25:5-12.  
93. Donabedian A. Evaluating the quality of medical care. Milbank Mem Fund 
Q1966;44:Suppl:166-206.  
94. Stewart AL, Teno J, Patrick DL, Lynn J. The concept of quality of life of dying persons in the 
context of health care. J Pain Symptom Manage 1999;17:93-108.  
95. Donner A, Birkett N, Buck C. Randomization by cluster. Sample size requirements and 
analysis. Am J Epidemiol 1981;114:906-14.  
96. Donner A, Klar N, eds. Design and Analysis of Cluster Randomization Trials in Health 
Research. . London,U.K.: Arnold Publishing Co; 2000.  
97. Grimshaw JM, Eccles MP, Lavis JN, Hill SJ, Squires JE. Knowledge translation of research 
findings. Implement Sci 2012;7:50.  
98. Mitchell SL, Miller SC, Teno JM, Kiely DK, Davis RB, Shaffer ML. Prediction of 6-month 
survival of nursing home residents with advanced dementia using ADEPT vs hospice eligibility 
guidelines. JAMA 2010;304:1929-35.  
99. Kiely DK, Givens JL, Shaffer ML, Teno JM, Mitchell SL. Hospice use and outcomes in 
nursing home residents with advanced dementia. J Am Geriatr Soc 2010;58:2284-91.  
100. Mitchell SL, Kiely DK, Jones RN, Prigerson H, Volicer L, Teno JM. Advanced dementia 
research in the nursing home: the CASCADE study. Alzheimer Dis Assoc Disord 2006;20:166-
75.  
101. Mitchell SL, Tetroe J, O'Connor AM. A decision aid for long-term tube feeding in cognitively 
impaired older persons. J Am Geriatr Soc 2001;49:313-6.  
102. Hanson LC, Carey TS, Caprio AJ, et al. Improving decision making for feeding options in 
dementia care: a randomized trial. . J Am Geriatr Soc 2011 In press.  

TRAIN-AD protocol June 30, 2017 
43 
103. Volandes AE, Paasche-Orlow MK, Barry MJ, et al. Video decision support tool for advance 
care planning in dementia: randomised controlled trial. BMJ 2009;338:b2159.  
104. Catic AG, Berg AI, Moran JA, et al. Preliminary data from an advanced dementia consult 
service: integrating research, education, and clinical expertise. J Am Geriatr Soc 2013;61:2008-
12. 
105. Fisch J, Lansing B, Wang L, et al. New acquisition of antibiotic-resistant organisms in 
skilled nursing facilities. J Clin Microbiol 2012;50:1698-703.  
106. Givens JL, Spinella S, Ankuda CK, et al. Healthcare Proxy Awareness of Suspected 
Infections in Nursing Home Residents with Advanced Dementia. J Am Geriatr Soc 
2015;63:1084-90.  
107. D'Agata EM, Habtemariam D, Mitchell S. Multidrug-Resistant Gram-Negative Bacteria: 
Inter- and Intradissemination Among Nursing Homes of Residents With Advanced Dementia. 
Infect Control Hosp Epidemiol 2015;36:930-5.  
108. Mitchell SL, Teno JM, Roy J, Kabumoto G, Mor V. Clinical and organizational factors 
associated with feeding tube use among nursing home residents with advanced cognitive 
impairment. JAMA2003;290:73-80.  
109. Engel SE, Kiely DK, Mitchell SL. Satisfaction with end-of-life care for nursing home 
residents with advanced dementia. J Am Geriatr Soc 2006;54:1567-72.  
110. Recommendations of regulatory issues in cluster studies. US Department of Health and 
Human Services, 2014. (Accessed January 12, 2016, at 
http://www.hhs.gov/ohrp/sachrp/commsec/attachmentcjul32014:recommendationsonregulatoryi
ssuesinclusters tudies.html.)  
111. D'Agata EM, Magal P, Olivier D, Ruan S, Webb GF. Modeling antibiotic resistance in 
hospitals: The impact of minimizing treatment duration. J Theor Biol 2007.  
112. Simone MJ, Roberts DH, Irish JT, et al. An educational intervention for providers to 
promote bone health in high-risk older patients. J Am Geriatr Soc 2011;59:291-6.  
113. Volicer L, Hurley AC, Lathi DC, Kowall NW. Measurement of severity in advanced 
Alzheimer's disease. J Gerontol 1994;49:M223-6.  
114. Gozalo P, Teno JM, Mitchell SL, et al. End-of-life transitions among nursing home 
residents with cognitive issues. N Engl J Med 2011;365:1212-21.  
115. Mitchell SL, Teno JM, Intrator O, Feng Z, Mor V. Decisions to forgo hospitalization in 
advanced dementia: a nationwide study. J Am Geriatr Soc 2007;55:432-8.  
116. Hilbe JMH. Negative Binomial Regression. Cambridge Cambridge University Press; 2007.  
117. Cheng SC, Fine JP, Wei LJ. Prediction of cumulative incidence function under the 
proportional hazards model. Biometrics 1998;54:219-28.  
118. Schafer JL. Analysis of Incomplete Multivariate Data. London: Chapman & Hall; 1997.  
119. Little RJA, Rubin DB. Statistical Analysis with Missing Data. Second ed. New York: John 
Wiley & Sons; 2002.  
120. Signorini D. Sample size for Poisson regression. Biometrika 1991;78:446-50. 
 
20 SUPPLEMENTS/APPENDICES