Triggered Palliative Care for Advanced Dementia
Phase: NA
Conditions: Alzheimer Disease, Dementia
Sponsor: University of North Carolina, Chapel Hill

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Advanced Dementia PC NPCRC 
July 18, 2016 page   
Advanced Dementia Palliative Care Study Protocol 
Administrative Information 
 
 
Study title:   
Triggered Palliative Care for Advanced Dementia 
 
Clinicaltrials.gov: 
 
NCT02719938 
 
Protocol Version: 
 
Version 2.0 
 
Date:  
 
 
July 18, 2016 
 
Sponsor:   
 
 
National Palliative Care Research Center 
 
 
 
 
National Institute on Aging 
 
 
 
 
 
The study sponsor has no role in study design, data collection,  
                                                     analysis, or publication. 
 
Grant number: 
 
National Institute on Aging: NIA R21AG052140 
 
 
 
 
National Palliative Care Research Center: n/a 
 
 
Principal Investigator:   
Laura C. Hanson, MD, MPH (UNC-Chapel Hill) 
 
 
 
 
 
Lead Statistician: 
 
Feng-Chang Lin, PhD  
(UNC-Chapel Hill) 
 
Project Manager: 
 
Stacey Gabriel, MPH  
(UNC-Chapel Hill) 
 
Investigators:  
 
Christine Kistler, MD  
(UNC-Chapel Hill) 
 
 
 
 
Natalie Ernecoff, MPH 
(UNC-Chapel Hill) 
 
 
 
 
Susan Mitchell, MD 
 
(Hebrew SeniorLife) 
Greg Sachs, MD 
 
(Indiana University) 
 
 
 
 
Data Safety Monitors: 
Cathleen Colon-Emeric, MD  (Duke University) 
 
 
 
 
 
Study Contact: 
 
Laura C. Hanson, MD, MPH 
 
 
 
 
Professor, UNC School of Medicine, Division of Geriatric Medicine 
 
 
 
 
CB 7550 UNC,  5003 Old Clinic Bldg 
 
 
 
 
Chapel Hill, NC   27599-7550 
 
 
 
 
lhanson@med.unc.edu 
 

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Advanced Dementia PC NPCRC 
July 18, 2016 page A 
 
 
 
 
Protocol Introduction 
 
Background  
3.A.i Improving advanced dementia palliative care is a compelling public health priority. Alzheimer’s disease and 
other dementias affect more than 5 million Americans and their family caregivers.1 Societal costs were $157-215 
billion in 2010, largely due to Medicaid long-term care and family caregiving expenses.2  Dementia is associated 
with increased rates of hospitalization, care transitions, and 30-day readmissions.3  Medications may slow 
progression, but current research offer little hope of cure. 4,5 Patients live 3-9 years after diagnosis, and dementia is 
a contributing cause for 1 in 3 deaths.6,7,8 Dementia is the only leading cause of death in the U.S. with no 
meaningful preventive or curative intervention; as a result, prevalence is expected to double by 2030.9   
Approximately 1 million Americans have advanced dementia, the final and most symptomatic stage of illness.  
Using the Global Deterioration Scale (GDS) staging system, advanced dementia is characterized by profound 
memory deficits, inability to recognize family members, sparse speech, incontinence, and dependence for all 
activities of daily living.10 The cohort of persons with advanced dementia enrolled in the Choices, Attitudes, and 
Strategies for Care of Advanced Dementia at the End-of-Life (CASCADE) Study had a 6-month mortality risk of 
25% and median survival of 1.3 years.11  
3.A.ii Advanced dementia care places extraordinary demands on family caregivers.  Dementia results in a 
prolonged course of functional dependency.12  Family caregivers provide care an estimated 22 hours per week.13  
Caregiving lasts an average of 3 years, with significant loss of paid work.14 A high portion of the cost of care is 
borne by family caregivers; out-of-pocket family expenses average $66,000 in the last year of life – more than any 
other cause of death.15 
3.A.iii Current advanced dementia care is poor quality -- high symptom distress, poor communication about goals 
of care, and limited hospice access.  Current care for patients with advanced dementia rarely meets standards for 
high quality palliative care.  Distressing symptoms such as pain, shortness of breath, neuropsychiatric symptoms, 
feeding problems, and problems with incontinence and personal cleanliness are common in advanced dementia, and 
severity worsens as death approaches.11,16,17, 18, 19, 20 Cognitive impairment is a risk factor for under-treatment of 
pain, and up to 50% of dementia patients experience frequent and unrelieved pain during their last year of life. 21, 
22,23  
Compared with advanced cancer patients, persons with advanced dementia are rarely recognized as terminally ill, 
and less likely to have decisions about life-sustaining treatment.24,25 Burdensome medical treatments are common. 
In CASCADE 40.7% of patients experienced at least one hospitalization, emergency transfer, parenteral therapy or 
tube feeding during the final 3 months of life.11 Less than half of persons who die from advanced dementia access 
hospice care, due to lack of a predictable terminal phase of illness to match the 6-month prognosis criterion.26,27 
3.A.iv Hospitalization for acute illness is burdensome in advanced dementia. While as many as 67% of persons 
with advanced dementia ultimately die in a nursing home, hospitalization for acute illness is common in the final 
year of life.28  In a national study of Medicare decedents with advanced cognitive impairment, 19% experienced at 
least one burdensome transition during the final 3 months of life.29 One in ten nursing home residents with 
advanced dementia are admitted to intensive care in the final 30 days of life, and this practice is becoming more 
common over time.30 In hospital, persons with dementia experience other treatments that may be more burdensome 
than beneficial, such as percutaneous feeding tubes, central lines, or physical restraints.31,32  
3.A v Hospitalization for acute illness signals high risk of death in the coming months for persons with advanced 
dementia.  Infections and nutritional decline typically precede death in advanced dementia.32,33,34 In CASCADE, 
the primary causes of hospitalization in advanced dementia were pneumonia, other infections, heart failure, hip 
fracture and dehydration.11,35 Six-month mortality risk for persons with advanced dementia who are hospitalized 
with pneumonia, septicemia, or hip fracture is 50%, and 20-40% for those who develop persistent feeding problems 
or dehydration.11,32,36,37  Thus, hospital admission for pneumonia, infection with septicemia, hip fracture, or 

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Advanced Dementia PC NPCRC 
July 18, 2016 page B 
complications of feeding problems such as weight loss and dehydration are sentinel events identifying persons with 
advanced dementia and high risk of death in the next year.   
3.A.vi Hospitalization for acute illness is a unique opportunity for patients with advanced dementia to access 
specialty palliative care. Current workforce projections make it unfeasible to propose a nursing home model of 
specialty palliative care for persons with advanced dementia.  First, demand for palliative care greatly exceeds the 
specialty workforce, estimated to include fewer than 4000 physicians and 17,000 nurses.38,39 Second, geographic 
variation magnifies these workforce shortages -- Southeastern retirement in-migration states with large African-
American populations lag other regions in palliative care.40  
Hospitalization may be burdensome, but it is also an opportunity to access specialty palliative care for this patient 
population.  While only 27% of US nursing homes report any type of special services for palliative or end-of-life 
care, 63% of hospitals, and 85% of large hospitals have specialty palliative care services.41,42 Access to specialty 
palliative care is thus likely to remain rare in long-term care settings, but readily available in acute care hospitals.  
3.A.vii Triggered consultation is effective to improve palliative care access in other diseases.  The growing practice 
of triggered consultation has been shown to improve access to specialty palliative care for high need patient 
populations, including patients with advanced cancer or critical illness. 43,44 First, attending physicians and specialty 
palliative care teams agree on clinical indicators of a need for palliative care consultation such as advanced stage 
incurable diagnoses and uncontrolled symptom distress.  Next, patient electronic records are screened for these 
indicators.  When a patient screens positive on the chosen indicators, the attending physician affirms the need and 
writes a consultation order. Triggers for palliative care consultation in advanced dementia, such as hip fracture, 
have been proposed but never tested.45 
3.A.viii The trajectory of dementia results in a prolonged phase of advanced stage illness and unique palliative care 
needs.  The long trajectory of functional decline in dementia is unlike any other life-limiting illness.46  In a 
thoughtful narrative review, Sachs summarized the unique aspects of dementia palliative care, all of which must be 
addressed in any palliative care intervention.  First, dementia has a slow trajectory without a distinct terminal phase, 
making it difficult for clinicians and family caregivers to time transitions in goals of care.  Second, symptom 
management is challenging due to loss of verbal communication for assessment, and concerns about medication 
side effects in frail patients.  Third, the most common and important decisions involve treatments considered 
ordinary -- feeding options, antibiotics, or hospitalization.47 The unique needs of this patient population demand a 
dementia-specific model of palliative care.  
3.A.ix Specialty palliative care improves outcomes, but is unproven for advanced dementia. 
High quality clinical trials and observational studies demonstrate the benefits of specialty palliative care for patients 
with advanced cancer and critical illness.  Systematic access to palliative care teams results in improved treatment 
decision-making and quality of life for seriously ill patients and their families, while reducing costs.48,49,50,51,52 
However, these studies do not generalize to the advanced dementia population, given the unique symptom 
management concerns and treatment decisions relevant to this disease.   
No major clinical trial has tested a model of palliative care for advanced dementia.  Only two small studies have 
been published. Ahronheim conducted a small randomized trial of geriatric palliative care consultation at a single 
hospital, enrolling n=99 patients with advanced stage dementia.  The intervention resulted in increased use of 
palliative care plans (23% vs 4%, p=0.008) and a reduction in intravenous therapies (66% vs 81%, p=0.025), but 
had no effects on other invasive procedures, physical restraint use, or life-sustaining treatment decisions.53  In a 
small pre-post study (n=52), Campbell tested proactive case-finding of patients with advanced dementia for 
palliative care in intensive care.  Intervention patients experienced fewer hospital days (7.4 vs 12.1, p<0.007) and 
ICU days (3.5 vs 6.8, p<0.004), with no difference in mortality or overall treatment intensity.54 
3.A.x Conceptual Framework:  Donebedian model applied to Palliative Care Domains.  The design of this 
innovative approach to improve advanced dementia palliative care is grounded in the Donebedian model to analyze 
and explain the quality of healthcare, in order to measure the effects of health services innovations on patient-
centered outcomes.  This model is widely used to evaluate the quality of healthcare, and to design health services 

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Advanced Dementia PC NPCRC 
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research to test hypotheses about how changes in health care access and delivery will affect patient outcomes. The 
Donebedian model proposes causal relationships between the structural elements of healthcare (e.g. hospital 
staffing with specialty palliative care), care processes (e.g. palliative care consultations, family meetings to discuss 
goals of care) and desired patient outcomes (e.g. reduced 30-day hospital admissions, increased documentation of 
treatment preferences using POLST).55,56  
Since the overarching goal is to improve the quality of advanced dementia palliative care, the design of the 
intervention is mapped to the National Consensus Project (NCP) for Quality Palliative Care framework of 
guidelines and preferred practices.57 Updated in 2013, the NCP defines best practices in 8 key palliative care 
domains: (1) structure and process (2) physical, (3) psychiatric, (4) social, (5) spiritual, religious, and existential (6) 
cultural, (7) care of the imminently dying patient, and (8) ethical and legal.  The intervention design addresses the 
first domain (the structure and process of advanced dementia palliative care), by increasing access to specialty 
palliative care teams during hospitalization. Consultation content and resulting post-discharge care plans will 
address the remaining domains: physical symptoms, psychiatric symptoms, social support, spiritual support, 
cultural concerns, care of the imminently dying (when appropriate to prognosis), and ethical and legal dimensions 
of goals of care and treatment preference documentation.   
 
SUMMARY OF SIGNIFICANCE AND INNOVATION  
The proposed research is significant in seeking to ameliorate the extraordinary individual and public health impact 
of advanced dementia.  Alzheimer’s disease and other dementias affect millions of Americans and their family 
caregivers, extracting the highest family and societal costs of any leading cause of death. Prior research, much of it 
done by these investigators, demonstrates the extraordinary suffering caused by advanced dementia.  Patients and 
families have extensive unmet palliative care needs, and current models of hospice and palliative care are poorly 
designed for advanced dementia.  This pilot study, if successfully executed, matches a clear national research 
priority as demonstrated by the NIA Program Announcement (PA-13-354 Advancing the Science of Geriatric 
Palliative Care) and the National Alzheimer’s Project Act. 
The proposed research is innovative, as it will provide the first clinical trial of an advanced dementia palliative 
care model matched to the unique characteristics of this disease, in a novel setting, with components of 
collaborative care. Specialty palliative care has proven benefits for patients with advanced cancer; however, 
specialty palliative care has never been tested to improve outcomes for advanced dementia. Dementia’s long 
trajectory of functional dependency, challenges in symptom assessment and management, and ethical demands for 
shared decision-making about “ordinary” treatments such as nutrition and antibiotics requires new approaches in 
palliative care consultation. The proposed intervention is innovative in moving research on dementia palliative 
care out of the nursing home -- where most research has focused -- and into the acute care hospital setting.  
Further, the approach is innovative as it explores the potential for collaborative palliative care, connecting 
hospital-based specialty palliative care clinicians with post-acute primary healthcare providers. 
 
  
 
 

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Advanced Dementia PC NPCRC 
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Study Aims 
Alzheimer’s disease and related dementias affect 5 million Americans at an annual cost of $215 billion. Dementia 
is a contributing cause for 1 in 3 deaths, and is the only major cause of death with no effective prevention or 
treatment.  
One million Americans have advanced dementia, characterized by inability to recognize family, sparse speech, and 
dependency for all activities of daily living. Median survival is 1.3 years, and 6-month mortality is 25%.  Family 
care averages 22 unpaid hours per week for 3 years. Family expenses average $66,000 in the last year of life – 
greater than any other cause of death.  
The final year of life with dementia is characterized by hospitalizations for acute complications -- pneumonia and 
other infections, dehydration, malnutrition, falls and fractures. Acute illnesses cause symptom distress for patients, 
with emotional and financial strain for family caregivers. These illnesses are also associated with a high risk of 
death in the next year and raise ethical questions about goals of medical treatment.  
Palliative care consultation improves outcomes for patients with advanced cancer and critical illness, but has never 
been rigorously tested for advanced dementia. Dementia-specific palliative care is needed to address the unique 
symptoms and treatment decisions relevant to this disease. Hospital admissions provide an opportunity to access 
specialty palliative care teams for patients with advanced dementia, at a time when acute illness signals worsening 
prognosis. Collaboration with primary providers is essential, since dementia’s prolonged trajectory means most 
clinical care for dementia is provided at home and in nursing facilities.  
We therefore propose to develop and pilot test a model of palliative care consultation for advanced dementia 
patients, triggered by hospitalization for a serious acute illness.  After systematic refinement of operational 
protocols and tools with stakeholders, we will enroll persons with advanced dementia plus an acute illness 
associated with high risk of death in the coming year.  Patients will be enrolled with their family decision-makers 
(N=60 dyads) in a randomized feasibility trial. Intervention dyads will receive specialty palliative care consultation 
during hospital admission, plus post-discharge collaborative care by their outpatient primary care provider and a 
palliative care nurse practitioner. Control dyads will receive usual care. 
Our research objective is to generate preliminary data for a large multi-site randomized controlled trial (RCT) of a 
model of palliative care consultation for advanced dementia in an application to NIA (PA-13-354 Advancing the 
Science of Geriatric Palliative Care).   
Our specific aims for this application are: 
Aim 1:  To develop a best-practice model of palliative care consultation for advanced dementia triggered by 
hospital admission for serious acute illness. 
Aim 2:  To conduct a pilot randomized trial of triggered palliative care consultation for advanced dementia (versus 
usual care) to demonstrate the feasibility of conducting a larger RCT and to estimate effect sizes to inform the 
larger RCT. The primary outcome will be number of hospital transfers (emergency room or hospital 
admission) in the 30 days post discharge. Secondary outcomes, measured at hospital discharge and 30 days 
follow-up, will include number of palliative care domains in the care plan, hospice referral, POLST 
(Physician Orders for Life-Sustaining Treatment) form completion, decision not to re-hospitalize, and 60 day 
hospital transfers and burdensome treatments. 
H1:  The dementia palliative care model will be feasible as demonstrated by full enrollment and 80% completion of 
intervention key components and outcomes data collection. 
H2:  Compared to usual care, intervention dyads will demonstrate trends in outcome measures -- fewer 30-day 
hospital transfers; increased number of palliative care domains in the care plan; increased hospice referral; 
increased POLST completion; increased decisions not to re-hospitalize and fewer burdensome treatments. 
 
 
 

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Methods 
3.D.i  Overview:  The proposed 2-year study will develop a model for palliative care consultation for hospitalized 
patients with advanced dementia (Aim 1) and conduct a pilot study of an RCT to test the efficacy of this model 
(Aim 2).  During the first 3 months investigators will work with an advisory group of stakeholders to refine 
intervention protocols.  The study population will consist of N=60 dyads of persons with advanced dementia who 
are hospitalized with serious acute illness and their family decision-makers.  Eligible patients will have baseline 
advanced dementia, corresponding to moderately severe to severe dementia using GDS staging of 5-7) and an acute 
illness associated with increased mortality risk (pneumonia, septicemia, hip fracture, malnutrition or dehydration 
complicating persistent feeding problems, or other similar condition).  Each dyad will be randomized to specialty 
palliative care consultation followed by collaborative care with outpatient primary providers vs. usual care. The 
dyad will be the unit of analysis.  The primary outcome will be number of hospital transfers in the 30 days post-
discharge, defined as visits to an emergency department or acute care hospitalization. Secondary outcomes, 
measured at hospital discharge and 30 days, will include number of palliative care domains in the care plan, 
hospice referral, POLST  (Physician Orders for Life-Sustaining Treatment) form completion, decision not to 
re-hospitalize, 60-day hospital transfers and burdensome treatments.  
3.D.ii  Methods to meet Aim 1:  To develop a best-practice model of palliative care consultation for advanced 
dementia triggered by hospital admission for serious acute illness. 
During Year 1 (months 1-3) investigators will complete developmental steps to refine the model of palliative care 
consultation for advanced dementia with input from key stakeholders who address practical aspects of 
implementation. Investigators will convene a Stakeholder Advisory Group (SAG) composed of hospital-based 
attending physicians from services that commonly take care of advanced dementia patients (N=3), nursing home or 
community based primary physicians, nurse practitioners or physician assistants (N=3), and family caregivers for 
persons with advanced dementia (N=3).  Stakeholders will be asked to meet 3 times to provide recommendations 
on 1) identification of eligible patients for advanced dementia palliative care consultation, 2) meaningful use of 
educational tools for family caregivers, and 3) collaborative care in transitions from hospital to primary care 
settings. 
Step 1: Identification of eligible patients for advanced dementia palliative care consultation.  Investigators will 
develop a method to screen hospital admissions for rapid identification of eligible patients.  This will require 
electronic screening for dementia diagnosis plus selected serious illness diagnoses, followed by confirmation of 
dementia stage using descriptions of baseline function based on the GDS.  Investigators will review the most recent 
12 months of data from the UNC Hospital discharge database for service location of patients admitted with paired 
diagnoses of dementia plus one of the serious acute illnesses -- pneumonia, septicemia, hip fracture, or 
complications of feeding problems such as dehydration, protein malnutrition or failure to thrive. In 2014, 567 
patients were discharged with dementia plus one of these acute illnesses, indicative of adequate population for this 
screening approach.  
Attending physicians for services with high admission rates for these patients will be asked to approve daily census 
screening in the electronic health record for these paired diagnoses, and for evidence suggestive of advanced 
dementia stage. Admission census screens will be completed by a Palliative Care Nurse Practitioner, who will then 
contact the attending physician for permission to approach the patient’s family caregiver about the study.  Family 
caregivers will be asked to confirm dementia stage using functional descriptions of GDS 5, 6 or 7, and to give 
consent for study participation.  The attending physician will also authorize consultation should the patient-family 
dyad enroll and be randomized to intervention. The SAG will assist investigators to ensure this approach fits 
hospital physician practice and meets patient and family caregiver needs.  
Addressing a potential threat to validity:  Consultation can be ineffective if implemented without attention to 
patients’ right to refuse services and respect for the professionalism of the attending physician. From our experience 
with triggered consultations, currently used at UNC Hospital for patients with Stage IV gynecologic cancers and 
with advanced systolic heart failure, the UNC Palliative Care physicians and nurse practitioners have developed an 
effective approach to gain entrée with referring teams, patients and family caregivers.  Attending physicians will be 

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Advanced Dementia PC NPCRC 
July 18, 2016 page F 
permitted to refuse triggered consultations, as will patients and families; acceptance of consultation will allow 
billing for professional time but not for other research activities. 
 
Table 1:  Evidence-based Educational Tools 
Tool 
Content 
Planned Use  
BOOKLET 
 
Advanced 
Dementia:  A 
Guide for Families  
1) What is Advanced Dementia   
2) Determining the Primary Goal of Care  
3) Approach to Decision-making   
4) Approach to Eating problems   
5) Decisions about Hospitalization  
6) Treatment decisions for infections  
7) How Advanced Dementia affects Family  
8) Hospice and Palliative Care 
UNIVERSAL USE: 
Booklet will be given to and 
reviewed with all intervention 
family decision-makers.  
NURSE-GUIDED 
FAMILY 
EDUCATION  
 
IN-PEACE 
Caregiver Manual 
Over 20 print educational summaries on key topics 
for family caregivers; examples include: 
• 
Caregiver stress 
• 
Communicating with the person with dementia 
• 
Bathing techniques 
• 
Feeding techniques 
• 
Responding to pain 
• 
Responding to sundowning 
• 
Dental care 
• 
Help with sleeping  
• 
Depression in dementia 
SELECTIVE USE: 
Consultants will select and 
provide materials targeted to the 
needs of each family caregiver.  
DECISION AID 
 
Making Choices:  
Feeding Options 
for Patients with 
Dementia 
Video decision aid defining the pros and cons of 
the treatment choice between tube feeding and 
assisted feeding in advanced dementia. 
SELECTIVE USE:   
Consultants will view the 
decision aid with family 
caregivers when treatment 
options for eating problems are 
being considered. 
 
Step 2:  Meaningful use of educational tools for advanced dementia family caregivers.  Drs. Hanson, Mitchell and 
Sachs have developed evidence-based tools to educate family decision-makers and support meaningful shared 
decision-making related to advanced dementia.  (Table 1)  These tools include the educational booklet developed 
by Dr. Mitchell and used the pilot test of hospital consultation (3.C.vi); a video decision aid developed by Drs. 
Hanson and Mitchell for the decision between assisted feeding and tube feeding (3.C.iv); and dementia care 
protocols used by nurse practitioners to support family caregivers developed by Dr. Sachs for the PEACE study 
(3.C.v).  The SAG will review tools and discuss ways to make them meaningful for families. 
Step 3: Collaborative care in transitions from hospital to primary care settings.  Care transitions are critical 
junctures for all patients; however most transitional care studies have excluded dementia patients. To be effective, 
hospital-based palliative care teams must collaborate with primary providers since most dementia care is provided 
in long-term care and community settings.58 Therefore, at the time of hospital discharge, the specialty Palliative 
Care team will complete a structured care plan addressing domains of palliative care.  When supported by 
communication with the family decision-maker, they will also complete and sign a Medical Orders for Scope of 
Treatment (MOST) form.  MOST is the North Carolina version of the POLST paradigm, a multi-state portable 
order set proven effective to enhance treatment consistent with patient preferences across healthcare transitions.59,60 
The Palliative Care Plan and the MOST will be provided in print and fax format to the patient’s primary provider, 
followed by a post-discharge telephone call from the Palliative Care Nurse Practitioner to ensure receipt and answer 
questions.  Working with the SAG, investigators will develop a practical and flexible procedure for collaborative 

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July 18, 2016 page G 
care to ensure effective hand-off to the primary provider and ways to address post-discharge palliative care 
concerns.   
3.D.iii  Methods to meet Aim 2:  To conduct a pilot randomized trial of triggered palliative care consultation for 
advanced dementia (versus usual care) to demonstrate the feasibility of conducting such a trial and to generate 
data to estimate effect sizes to inform a larger RCT. 
During Year 1 (months 4-12) through Year 2 investigators will conduct the pilot RCT and measure outcomes using 
hospital chart review at discharge and family decision-maker interviews at enrollment and 30 and 60 days post 
hospital discharge.  Specific aspects of the pilot RCT will be informed by results from Aim 1. 
3.D.iv  Study Site:  All study participants will be recruited at the University of North Carolina Hospital during 
admission for acute illnesses.  UNC Hospital is a public academic healthcare complex of 5 hospitals -- Medical-
Surgical, Women’s Health, Neurosciences, Cancer, and Pediatrics -- with 783 licensed beds serving over 37,000 
admitted patients annually.  Faculty physicians appointed in the UNC School of Medicine provide all medical 
services. 
3.D.v Study Participants and Recruitment:  Study participants will be n=60 dyads of patients with GDS Stage 5-7 
dementia from any underlying cause who are hospitalized with a serious acute illness and their family decision-
maker.  Inclusion Criteria:  The Palliative Care Nurse Practitioner (PCNP) and Project Manager will screen target 
inpatient census lists every day for patients with a diagnosis of dementia and a qualifying acute illness, under a 
HIPAA waiver. The PCNP or Palliative Care physician will contact the attending physician to confirm the 
qualifying diagnoses and probable stage of dementia, as well as to obtain permission to approach the family 
decision-maker about study participation, including consultation if randomized to intervention. Patients will be 
eligible if they are aged 65 or older and have a physician-confirmed a) diagnosis of dementia, b) advanced dementia 
scored as 5, 6 or 7 on the Global Deterioration Scale (GDS), and c) hospital admission for pneumonia, septicemia, 
hip fracture, protein malnutrition, dehydration or similarly serious acute illness. Dementia stage will be confirmed 
for eligibility with family decision-makers by showing them the GDS Stage descriptions and asking them to select 
the description most consistent with the patient’s pre-admission functioning.  If family decision-makers are 
uncertain, the Palliative Care Nurse Practitioner will request permission to contact the primary provider for this 
information. 
Eligible family decision-makers will be defined as the family caregiver with the greatest involvement in decision-
making. If two family caregivers share this role the legally authorized representative will be eligible, but may 
include input from others.61 Exclusion Criteria:  Patients will be excluded if they do not have a family surrogate 
decision-maker. Family decision-makers will not be eligible if they cannot complete interviews in English, or if the 
treating physician believes participation would cause undue stress.  
Addressing a potential threat to validity:  During the pilot study by Mitchell (3.C.vi) barriers to identification of 
eligible patients and to consultation were discovered.  In addition, during the development phase of this trial, 
precise staging was confounded by acute illness symptoms.  These barriers are addressed in this design by using 
more sensitive screening criteria, broadening eligibility to GDS stages 5, 6 and 7, and use of clinician-to-clinician 
communication to affirm consultation orders.   
3.D.vi  Human Subjects:  Once an eligible patient-family decision-maker dyad is identified and attending physician 
approval is obtained, the Project Manager / Data Collector will obtain informed consent from the family decision-
maker; consent will be obtained prior to randomization. All study procedures will be subject to IRB review at the 
University of North Carolina, which will serve as the sole study site. Study risks include emotional distress and 
confidentiality; protections will include strict training of study staff, data security, and strategies to address family 
emotional distress with compassion, flexibility and appropriate referrals to supportive resources.  Treatment plans 
will be controlled throughout the study by attending physicians providing direct care to patients who are enrolled, 
regardless of group assignment. 
3.D.vii Training for Intervention Protocols:  In Year 1, investigators developed a templated, structured approach to 
intervention protocols to ensure consistent delivery of the intervention.  All Palliative Care consultation will 

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Advanced Dementia PC NPCRC 
July 18, 2016 page H 
initially be provided by a small group of 3 members of the Palliative Care specialty team to promote consistent 
quality -- Kyle Terrell, NP, Laura Hanson, MD and Chrissy Kistler MD -- who are trained in the intervention 
protocol. Their training includes knowledge of clinical evidence for advanced dementia palliative care, educational 
tools and their use in consultations, completion of advanced dementia Palliative Care Plans, MOST form 
completion, and principles of shared decision-making and the VALUE (Value family comments, Address family 
concerns, Listen, Understand the patient as a person, Elicit family questions) framework to guide family meetings 
and discussion of goals of care.62,63,64,65 Physicians and nurse practitioners will gain access to an electronic health 
record template for consultation.  Dr. Hanson will provide this training, and be available for follow-up questions as 
consultations are completed. 
3.D.viii Randomization:  The dyad will be the unit of randomization and analysis. Decision-makers who provide 
informed consent for participation will then be randomized by the study statistician in a 1:1 ratio to intervention vs. 
control.  Allocation will be revealed to the specialty Palliative Care team, but will be concealed from the Project 
Manager / Data Collector who will collect outcome measures during follow-up interviews. 
3.D. ix Intervention Condition:  Patient-family dyads randomized to the intervention group will receive specialty 
inter-disciplinary Palliative Care consultation during hospitalization with post-discharge collaborative care by a 
Palliative Care Nurse Practitioner and outpatient primary care physician. The consultation will consist of at least 
one visit with the patient and their family decision-maker, with additional visits consistent with clinical needs.  
Consultation will address a) prognosis and trajectory of advanced stage dementia, b) assessment and treatment of 
pain and other physical symptoms, c) assessment and management of neuropsychiatric symptoms, c) social support 
including caregiver stressors, d) spiritual support needs for patient or caregivers, e) cultural concerns framing care, 
and f) goals of care and g) key clinical decisions such as feeding options, antibiotic use, invasive procedures, or re-
hospitalization. All intervention families will receive and review a copy of the booklet on Advanced Dementia 
(Table 1).  Access to other evidence-based educational and decision aid tools for family decision-makers will be 
selective, based on needs discovered during consultation.   
For the collaborative care component of the intervention, the Palliative Care physician or nurse practitioner will 
prepare a Palliative Care plan in printed form, as well as a copy of the MOST form if discussed and signed during 
consultation. Copies of the Palliative Care Plan and the MOST form will be given to the primary family decision-
maker prior to discharge.  These documents will be mailed and faxed to the patient’s primary provider.  The 
Palliative Care Nurse Practitioner will then make follow-up calls to the family decision-maker and the primary 
provider within 72 hours and again contact the family caregiver within 2 weeks after discharge to discuss concerns 
or questions related to the Palliative Care plan, and to facilitate access to post-acute services if needed.  Calls to 
family caregivers will follow a semi-structured script [see attached], but calls to primary providers will not, and will 
be modified to e-mail or electronic health record communication at the preference of the provider.  Up to 3 call 
attempts will be made for each contact. 
3.D.x Control Condition:  Patient-family decision-maker dyads randomized to the control group will receive usual 
hospital and post-acute care.  To encourage participation, they will also be offered a copy of the Alzheimer’s 
Association free booklet Tips for Late-Stage Caregivers, which addresses common problems but does not duplicate 
any of the intervention tools. 
Addressing a potential threat to validity: Palliative care services cannot be ethically withheld from patients in the 
control group.  Palliative care consultation will be permitted for controls, but these consultations will not use 
intervention protocols and tools, and will not include post-discharge collaboration with primary providers.  Training 
to palliative care clinicians may dilute the measurement of differences between groups.  However, advanced 
dementia is currently rare as a palliative consultation diagnosis at UNC Hospitals, accounting for only 20 of 685 
patients in 2013.   
3.D.xi Baseline and Follow-up Data Collection:  Data collection will be identical for intervention and control 
groups. Study measures will be obtained from Hospital Chart Reviews covering the enrollment admission AND 
from family decision-maker interviews at enrollment (Family Baseline Interview) and at 30 days post-discharge 
(Family Follow-up Interview) 60 days post-discharge (60 Day Family Follow-Up Interview).  Family decision-

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Advanced Dementia PC NPCRC 
July 18, 2016 page I 
makers will be offered flexibility in timing of interviews. Our team has extensive experience with after death 
interviews; an After-Death version of the 30 and 60-day Interview will be designed to be sensitive to bereaved 
family.  
3.D.xii Measures for Feasibility and Fidelity to the Intervention (Aim 2, Hypothesis 1) 
H1:  The dementia palliative care model will be feasible as demonstrated by full enrollment and 80% completion of 
intervention key components and outcomes data collection. 
Measures of feasibility will include enrollment and data completion rates (intervention and control) and fidelity to 
key components of the advanced dementia palliative care consultation (intervention). Measures will be obtained 
from research enrollment tracking forms, hospital chart reviews, and call sheets kept by the Palliative Care Nurse 
Practitioner for communication post-discharge. Investigators will track enrollment and data completion rates, with 
targets of full enrollment and 80% data completion.  For fidelity, investigators will measure completion of 5 key 
components of the intervention:  initial consultation, transmission of Palliative Care Plan to family, transmission of 
Palliative Care Plan to primary care provider, completion of 2 follow-up calls to family decision-maker, and 
completion of 1 follow-up call to primary provider.  Fidelity to the intervention will be met when there is 
completion of 4 of 5 (80%) key components.   
3.D.xiii Outcome Measures for the Intervention (Aim2, Hypothesis 2):   
H2:  Compared to usual care, intervention dyads will demonstrate trends in outcome measures -- reduced hospital 
transfers; increased number of palliative care domains in the care plan; increased hospice referral; increased 
POLST completion; increased decisions not to re-hospitalize and fewer burdensome treatments. 
Analyses to examine effects of the intervention vs. usual care will focus on outcomes with the greatest impact on 
patient and family experience during and up to 60 days after hospitalization.  (Table 2) 
Table 2:  Aim 2 Primary and Secondary Outcomes and Sources of Data 
Outcome 
1 Measure 
Source 
PRIMARY OUTCOME Aim 2:  
30-day hospital transfers  
Number of hospital transfers (ED visits + 
hospital admissions) within 30 days after 
discharge.   
Family Follow-up Interview  
SECONDARY OUTCOME Aim 2:  
Patient Comfort 
Comfort at the End of Life in Dementia (C-
EOLD) 
Family Follow-up Interview 
SECONDARY OUTOCME Aim 2:  
Family Distress 
Family Distress in Advanced Dementia 
Scale 
Family Follow-up Interview 
SECONDARY OUTCOME Aim 2:  30-
day referral to hospice or palliative care 
post-discharge 
% of patients with referral to hospice or 
outpatient palliative care from discharge to 
60 days follow-up 
Hospital Chart Review 
Family Follow-up Interview 
SECONDARY OUTCOME Aim 2:  
POLST (MOST) completed 
% of patients with MOST form completed  
Hospital Chart Review 
Family Follow-up Interview 
SECONDARY OUTCOME Aim 2:  
Palliative Care Domain Index 
Number of palliative care domains 
addressed in the plan of care at hospital 
discharge (range 0-10) 
Hospital Chart Review 
 
SECONDARY OUTCOME Aim 2: 
Decision not to re-hospitalize 
% of patients with do-not-hospitalize 
decisions 
Hospital Chart Review 
Family Follow-up Interview 
SECONDARY OUTCOME Aim 2: 
Use of burdensome treatments 
Total number of the following treatments 
used: feeding tube, central intravenous line, 
surgical procedure, ICU transfer, ventilator 
use, CPR use 
Hospital Chart Review 
Family Follow-up Interview 
SECONDARY  OUTCOME Aim 2:  
60-day hospital transfers  
Number of hospital transfers (ED visits + 
hospital admissions) within 60 days after 
discharge.   
Family Follow-up Interview  
 
• 
PRIMARY OUTCOME-- 30-day hospital transfers will be measured during Family Follow-up Interviews by 
asking how many times the patient with advanced dementia has been to an emergency room and how many times 

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Advanced Dementia PC NPCRC 
July 18, 2016 page J 
he / she has been admitted to a hospital within the time frame of interest; chart review is not feasible for this data as 
patients come from a wide geographic area with many hospitals. 
• 
SECONDARY OUTCOME -- Patient Comfort will be measured in Enrollment and Family Follow-up 
Interviews, using the reliable and valid Comfort at the End of Life in Dementia (C-EOLD) which includes 1 week 
recall of patient comfort with multiple symptom items; 10 items are rated 1-4 and summed, for a range of 10-40.  It 
has good internal consistency (Cronbach’s alpha 0.83-0.90) and convergent validity (r=0.81 with the Decision 
Satisfaction Inventory).66,67  
• 
SECONDARY OUTCOME –Family Distress will be measured in Enrollment and Family Follow-up Interviews, 
using the Family Distress in Advanced Dementia 
• 
SECONDARY OUTCOME -- 30-day referral to hospice or outpatient palliative care will be measured using 
Hospital Chart Review for referrals at discharge AND Family Follow-up Interviews for data on subsequent 
referrals. 
• 
SECONDARY OUTCOME -- POLST (MOST) completion will be measured in Hospital Chart Review by 
tracking the presence or absence of a completed POLST paradigm form (MOST) in the discharge packet; to detect 
new POLST form completion post-discharge we will ask this as a single item in the Family Follow-up Interview. 
• 
SECONDARY OUTCOME -- Palliative Care Domain Index is a Hospital Chart Review count of the presence 
or absence of information addressing10 domains of palliative care in a patient’s treatment plan -- prognosis, overall 
goals of care, physical symptoms, psychiatric symptoms, spiritual needs, and 5 treatment preferences:  
resuscitation, artificial feeding, intravenous fluids, antibiotics, and hospitalization. Each domain is scored as present 
or absent for a range of 0-10.  Domains are scored based on whether or not they are addressed, not on choices for or 
against specific treatments. This measure is developed and currently in use for Dr. Hanson’s Goals of Care clinical 
trial (3.C.iii) and has good inter-rater reliability (kappa =0.90). 
• 
SECONDARY OUTCOME -- Decision not to re-hospitalize will be measured in Hospital Chart Review as the 
percent of patients with a decision against re-hospitalization documented at the time of discharge; to detect new 
decisions post-discharge we will ask this as a single item in the Family 30-day Interview and 60-day Interviews. 
• 
SECONDARY OUTCOME -- Burdensome treatments will be measured in Hospital Chart Review for the 
enrollment admission AND Family 60-day Interviews for the post-discharge period to generate a count per patient 
of use of the following treatments: feeding tube, central intravenous line, surgical procedure, ICU transfer, 
ventilator use, CPR use at any time during the time frame of interest. 
• 
SECONDARY OUTCOME-- 60-day hospital transfers will be measured during Family Follow-up Interviews 
by asking how many times the patient with advanced dementia has been to an emergency room and how many 
times he / she has been admitted to a hospital within the time frame of interest; chart review is not feasible for this 
data as patients come from a wide geographic area with many hospitals. 
• 
 
3.D.xiv Measures of Covariates 
• 
Patient demographics – age, gender, race and ethnicity, religious affiliation (Family Enrollment Interview) 
• 
Family Decision-maker Demographics – age, gender, race and ethnicity, religious affiliation, relationship to 
patient (Family Enrollment Interview) 
• 
Pre-admission residence -- as private home, assisted living facility, nursing home or other (Hospital Chart 
Review) 
• 
Major co-morbid diagnoses -- (Hospital Chart Review) 
• 
Functional status – measured using the Bedford Alzheimer Nursing Severity scale for function in advanced 
dementia; this scale ranges from 0-28 with higher scores indicating worse function (alpha=0.80, Pearson’s r 0.62-
0.79)68 (Family Enrollment Interview) 
• 
Dementia stage – measured using the valid and reliable Global Deterioration Scale (GDS) (Family Enrollment 
Interview AND Family Follow-up Interview) 
• 
Advance directives – measured by recording presence or absence of a living will or Health Care Power of 
Attorney (Family Enrollment Interview) 

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Advanced Dementia PC NPCRC 
July 18, 2016 page K 
• 
Discharge location -- measured as private home, assisted living facility, nursing home or other (Hospital Chart 
Review) 
• 
Survival will be measured for each patient as days from study enrollment to death up to and including 60 days 
follow-up (Hospital Chart Review and Family Follow-up Interview)  
• 
Family Decision-maker knowledge of advanced dementia will be measured using an 18-item true / false 
Knowledge Index with content on advanced dementia, treatment options and their outcomes. These items have been 
previously developed by Dr. Hanson and used in prior studies.  (Family Enrollment) 
• 
Family Decision-maker perception of prognosis will be measured using a single item asking what they expect 
will happen to the patient during the next 6 months, with response options of “get better,” “stay about the same,” 
“get worse” or “likely to die.” (Family Enrollment, 30-day Interview, and 60-day Interview) 
 
3.D.xv  Analysis 
Analyses to meet Aim 2, Hypothesis 1 will be purely descriptive.  We will calculate and report the percent of 
eligible dyads approached who enrolled, and the percent who were retained to study completion with data 
collection on outcome measures.  We will describe fidelity to the 5 key components of the intervention.  We will 
summarize any barriers to study enrollment and retention, or fidelity, in order to enhance protocols for a future 
clinical trial.   
Analyses to meet Aim 2, Hypothesis 2 will begin by examining the validity of randomization by comparing 
intervention and control participants on baseline measures. Any variables that are not equally distributed between 
groups could potentially bias results. An adjusted analysis that includes these variables as covariates will be 
implemented.  
Descriptive analyses of all major variables will be carried out to examine their distributions, influential data points, 
and missing data. If the amount of missing data on any individual independent variable is small and the pattern of 
missing data both within and among variables is reasonably random, we will exclude subjects in analyses with 
missing data. However, we will use the method of multiple imputation for sensitivity analysis to ensure the 
robustness of the analysis results.69  Categorical variables will be collapsed into meaningful groups.  Continuous 
variables that are poorly distributed may be transformed, categorized or analyzed using non-parametric tests. Two-
sample t-tests or Fisher exact tests will be used when appropriate for the comparison between intervention and 
control groups, with adjustments for multiple comparisons. Generalized estimating equations (GEE) with an 
exchangeable dependence structure will be used to test the overall intervention effect. All statistical tests will be 2-
tailed with an overall 0.05 significance level for pre-specified analyses.  The secondary outcomes will be analyzed 
similarly and alphas will also be adjusted for multiple comparisons.70  
For a dichotomous primary outcome (hospital transfer), the sample size of 60 patients with 30 patients per group 
gives 81% power to detect a relative risk of 2.7, assuming that 25% of the patients in the control group would have 
a positive/presence outcome. The power is calculated based on Fisher’s exact tests with a significance level 
α=0.05/2=0.025. For a normally distributed continuous outcome (Palliative Care Domain Index), our current 
sample size gives 79% power to detect an effect size of 0.8 in Cohen’s d based on a 2-sample t-test with equal 
variation in two groups. The effect size is large according to general guidelines using Cohen’s d. We anticipate 
collecting sufficient data to determine the true effect size for future clinical trials.   
 
Research Ethics 
Data Management and Storage 
The study database complies with current data security standards, and provides real-time data entry validation, and 
provides audit trails documenting any changes or corrections of the study data.  Data entry or review requires 
logging into a secure portal with a username and password.  The database is hosted by the Cecil Sheps Center for 
Health Services Research at the University of North Carolina-Chapel Hill, and is HIPAA-compliant. Explicit 

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July 18, 2016 page L 
identifying information will be recorded on separate forms and will NOT be sent to the database; these forms will 
be maintained in a secure location.   
Human Subjects 
Protection of Human Subjects 
Participants and Eligibility:  The target population is n = 60 persons with advanced dementia paired with n=60 
family decision-makers (30 dyads in control, 30 in intervention group).  Persons with dementia are participants, but 
family surrogate consent and participation is required for all of them, as the severity of their dementia will make 
them incapable of informed consent. If two family caregivers share this role the legally authorized representative 
will be eligible for study enrollment. Surrogate decision-makers identified for each eligible nursing home resident 
are defined as a)  their guardian, b) Health Care Power of Attorney, or if no HCPOA is available, c)  the usual 
family surrogate decision-maker identified by the primary physician. 
Enrollment and Informed Consent:  The Palliative Care Nurse Practitioner or Project Manager will screen target 
inpatient census lists every day for patients with a diagnosis of dementia and a qualifying acute illness, under a 
HIPAA waiver. She will contact the attending physician to confirm the qualifying diagnoses and probable stage of 
dementia, as well as to obtain permission to approach the family decision-maker about study participation, 
including sharing basic information about the study.  The Project Manager will speak with the surrogate decision-
maker in a private area to discuss the study and obtain informed consent.  Once enrolled, study participants in both 
the control and intervention groups will be followed up to2 months.  Due to change in funding, Investigators 
decided to add an additional follow-up interview (60-day interview). The Project Manager will attempt to reconsent 
all participants to date all to allow for a 60-day follow-up call. The Project Manager will do this by mailing 
participants an addendum consent, and have them return a response card. The card will indicate “yes, please contact 
me” or “no, please do not contact me”. For all participants who sends the card back saying “yes”, we’ll re-consent. 
For everyone who mails it backing saying no, we will not contact them. For all those who don’t mail any card back, 
we will call them to see if they are interested in the additional 60-day interview. 
 
Potential Risks:  The primary risk of this study for family surrogates is emotional distress related to learning more 
about dementia prognosis and goals of care decisions for a frail and cognitively impaired family 
member.  Participation in the study, particularly in the intervention group, may draw family members’ attention to 
serious illness, and may result in anxiety or sadness over the health consequences of these problems. 
A potential risk is breach of confidentiality, given that investigators will collect personal health information about 
the person with advanced dementia. 
Adequacy of Protection Against Risks:  All study procedures, informed consent forms, and recruitment procedures 
will undergo review by the Institutional Review Board at the University of North Carolina-Chapel Hill prior to 
initiating research, and will be subject to annual and other required reviews. 
All family decision-makers will provide written informed consent for their participation, and surrogate informed 
consent for the participation of the person with advanced dementia for chart review data collection.  Through the 
informed consent process, we will address the risks of emotional distress for family surrogates, or breach of 
confidentiality for the person with dementia.   
To address the risks of emotional distress:  Investigators will include attention to emotional distress during training 
on the intervention protocol for Palliative Care team members, and for the Project Manager / Data 
Collector.  Subjects will be informed that they do not have to respond to questions if they feel uncomfortable and 
they may stop the interview at any time. Distressed surrogates will be provided with a referral source including on-
site social workers at each facility for emotional distress and hospice for bereavement support. The likelihood the 
family subject may need a referral source for dealing with emotional distress will be less than 1%.  
To address the protection of confidential medical information: All health status and health care utilization data will 
be recorded without personal identifiers.  Data will be entered in a password protected secure database, and all 
documentation will be maintained in locked files.  All identifying information will be destroyed once all analysis 
and reporting is complete. At no time will personal identifying information be stored with the interviews, and no 

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Advanced Dementia PC NPCRC 
July 18, 2016 page M 
identifying information will be stored on portable laptop computer devices used in field interviews. Participants 
will not be identified in any report or publication about this study. The procedures to minimize risks will help 
ensure a breach of confidentiality is rare occurring less than 1%.  
Potential Benefits of the Proposed Research to Subjects and Society:  Study participants may benefit from the 
palliative care consultation in the intervention group.  All participants may benefit from the increased opportunity 
to communicate about the experience of family caregiving for advanced dementia. Societal benefits include 
enhanced understanding of interventions to improve the quality of palliative care for advanced dementia. If this trial 
has positive effects, the methodology has broad potential application and will be proposed for testing in a larger, 
and more definitive, randomized controlled trial design.   
 
Data Safety Monitoring 
 
This study poses minimal risks. Any unanticipated problems or adverse events will be reported to the PI 
immediately. The study does not have any stopping rules.  The PI will review and unanticipated problems or 
adverse events and decide of subject withdrawal is in the best interest of the subject.  A Data Safety Monitor, Dr. 
Cathleen Colon-Emeric, will meet every 6 months during data collection and data analysis with Dr. Hanson, Dr. 
Lin and Project Manager Stacey Gabriel.  Dr. Colon-Emeric will review study protocols and preliminary data to 
ensure safe procedures are followed for this relatively vulnerable population.   
 
Dissemination Plan 
 
Dr. Hanson will present and discuss results from this pilot randomized controlled trial at the Kathleen Foley 
Palliative Care Retreat & Research Symposium. The research team will work together to submit pilot trial methods 
and results to a national peer-reviewed clinical journal in at least one publication.   
Study results will be used to demonstrate the feasibility of a palliative care consult intervention tailored to meet the 
needs of patients and families facing advanced dementia. Our research analyses will provide preliminary evidence 
for the potential of this intervention to improve outcomes for patients with advanced dementia and their families.  
Investigators will use data from Aim 2 to establish the potential effect sizes of this intervention on important 
clinical outcomes, and to estimate the necessary sample size for a definitive efficacy clinical trial of this 
intervention. Given the long trajectory of even the most advanced stages of dementia care, we anticipate extending 
the collaborative care component in a larger efficacy trial. 
During Year 2, this investigative team will submit a grant application for a multi-site randomized controlled trial 
(RCT) of a model of triggered palliative care consultation with enhanced collaborative care for advanced dementia, 
in an application to NIA (PA-13-354 Advancing the Science of Geriatric Palliative Care).   
Protocol References 
1. Schulz KF, Altman DG, Moher D for the CONSORT Group.  CONSORT 2010 Statement:  Updated Guidelines for 
Reporting Parallel Group Randomized Trials.  Ann Intern Med 2010; 152:726-732. 
2. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P for the CONSORT Group.  Extending the CONSORT 
Statement to Randomized Trials of Nonpharacologic Treatment:  Explanation and Elaboration.  Ann Intern 
Med 2008; 148:295-309. 
3. Chan AW, Tatzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, Hrobjartsson A, Mann H, Dickerson 
K, Berlin JA, Dore CJ, Parulekar WR, Summerskill WSM, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, 
Moher D.  SPIRIT 2013 Statement:  defining standard protocol items for clinical trials.  Ann Intern Med 2013;  
158:200-207. 
 

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