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For peer review only

Default Options in Advance Directives: Study Protocol for a

Randomized Clinical Trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-010628

Article Type: Protocol

Date Submitted by the Author: 23-Nov-2015

Complete List of Authors: Gabler, Nicole Cooney, Elizabeth; University of Pennsylvania Small, Dylan; University of Pennsylvania Troxel, Andrea; University of Pennsylvania Arnold, Robert; University of Pittsburgh School of Medicine White, Douglas; University of Pittsburgh School of Medicine Angus, Derek; University of Pittsburgh School of Medicine Loewenstein, George; Carnegie Mellon University , Center for Behavioral

Decision Research Volpp, Kevin; University of Pennsylvania Bryce, Cindy; University of Pittsburgh School of Medicine Halpern, Scott; University of Pennsylvania

<b>Primary Subject Heading</b>:

Palliative care

Secondary Subject Heading: Patient-centred medicine

Keywords: Randomized clinical trial, Default option, Advance directive

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Default Options in Advance Directives: Study Protocol for a Randomized Clinical Trial

Nicole B. Gabler, PhD, MHA 1, 2

Elizabeth Cooney, MPH 1, 2

Dylan S. Small, PhD 3

Andrea B. Troxel, ScD 2

Robert M. Arnold, MD 4

Douglas B. White, MD, MAS 4

Derek C. Angus, MD, MPH 4

George Loewenstein, PhD 5

Kevin G. Volpp, MD, PhD 1,2,6,7,8

Cindy L. Bryce, PhD 4

Scott D. Halpern, MD, PhD 1,2,6,7,8

1 Fostering Improvement in End-of-Life Decision Science (FIELDS) Program, Perelman School

of Medicine, University of Pennsylvania, Philadelphia, PA

2 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of

Pennsylvania, Philadelphia, PA

3 Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA

4 University of Pittsburgh School of Medicine, Pittsburgh, PA

5 Center for Behavioral Decision Research, Carnegie Mellon University, Pittsburgh, PA

6 Department of Medicine, Perelman School of Medicine, University of Pennsylvania,

Philadelphia, PA

7 Center for Health Incentives and Behavioral Economics at the Leonard Davis Institute of

Health Economics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

8 Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of


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Principal Investigator and Corresponding Author:

Scott D. Halpern, MD, PhD

Perelman School of Medicine, Division of Pulmonary, Allergy and Critical Care

University of Pennsylvania

723 Blockley Hall, 423 Guardian Drive

Philadelphia, PA 19104

Phone: 215-898-1462 Fax: 215-573-5325

[email protected]

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Abstract

Introduction: Although most seriously ill Americans wish to avoid burdensome and aggressive

care at the end of life, such care is often provided unless patients or family members specifically

request otherwise. Advance directives (ADs) were created to provide opportunities to set limits

on aggressive care near life’s end. This study tests the hypothesis that redesigning ADs such

that comfort-oriented care is provided as the default, rather than forcing patients to actively

choose it, will promote better patient-centered outcomes.

Methods and Analysis: This multicenter trial randomizes seriously ill adults to receive one of

three different ADs: (1) a traditional AD that requires patients to actively choose their goals of

care or preferences for specific interventions (e.g., feeding tube insertion), or otherwise have

their care guided by their surrogates and the prevailing societal default toward aggressive care;

(2) an AD that defaults to life-extending care and receipt of life-sustaining interventions,

enabling patients to opt out from such care; or (3) an AD that defaults to comfort care, enabling

patients to opt into life-extending care. We seek to enroll 270 patients who return complete,

legally valid ADs so as to generate sufficient power to detect differences in the primary outcome

of hospital-free days (days alive and not in an acute care facility). Secondary outcomes include

hospital and ICU admissions, costs of care, hospice utilization, decision conflict and satisfaction,

quality of life, concordance of preferences with care received, and bereavement outcomes for

surrogates of patients who die.

Ethics and Dissemination: This study has been approved by the Institutional Review Boards

at all trial centers, and is guided by a data safety and monitoring board and an ethics advisory

board. Study results will be disseminated utilizing methods that describe the results in ways that

key stakeholders can best understand and implement.

Trial Registration: NCT02017548, first registered on December 16, 2013.

Strengths and limitations of this study:

- Utilizes a unique study design and employs principles of behavioral economics to assess the impact of default options in advance directives - Leverages changes in treatment goals and preferences to assess the impact on clinical, economic, and patient- and surrogate-reported outcomes - Many randomized patients will not complete their assigned ADs

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Background

Most seriously ill Americans wish to die at home and to avoid aggressive and burdensome care

near the end of life.1,2 However, roughly one half of deaths in the US occur in the hospital,3 20%

of Americans die in or shortly following a stay in the intensive care unit (ICU),4 one in three

elderly patients undergo an inpatient surgical procedure during their last year of life,5 one in two

elderly Americans visits an emergency department in their last month of life,6 and more than one

quarter of Medicare dollars are spent on patients in their final year.4,7 Aggressive treatments at

the end of life are also associated with reduced quality8,9 and quantity of life,10-13 and may

produce long-lasting pathological bereavement among family members making decisions about

loved ones’ end of life care.8,9,14-17

Written advance directives (ADs) have the potential to reduce the discrepancy between the care

a patient desires and the care a patient receives. Currently, critical healthcare decisions must

be made for 43% of older Americans near the end of life, but 70% of these patients are unable

to participate in making these decisions.18 ADs, which include living wills and durable power of

attorney designation, can help improve the quality of advance care planning. Observational

studies show that elderly patients who complete ADs are more likely to die outside of a hospital,

receive less costly care, and receive care consistent with their preferences.18-21 However, ADs

have known shortcomings,22-26 and finding a scalable solution for a diverse patient population is

challenging.

The use of default options has been shown to have large effects in a variety of areas,27-32 and

defaults are considered a powerful approach to help overcome a variety of problems in

healthcare without limiting choice.33-35 In a pilot randomized clinical trial (RCT),36 we showed that

default options in ADs may influence patients’ care choices while preserving patients’

satisfaction with the decision-making process, and that patients rarely changed their plan of

care after being alerted to the intervention and their responses. However, before advocating

default options in ADs for broader clinical use, it is necessary to determine whether changing

such choices leads to improved patient- and family-centered outcomes over the long term in a

larger, more diverse population of seriously ill patients.

Methods/Design

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This study is a RCT examining whether structuring advance directives to request comfort-

oriented care or life-extending care by default influences the number of days that patients are

alive and living outside of an acute-care hospital, as well as several secondary outcomes.

Study Hypothesis

The primary study hypothesis is that ADs with pre-selected comfort care measures, compared

with those defaulting to life-extension or standard ADs, will produce an increase in hospital-free

days (HFDs), a measure that represents the number of days alive and not in an acute care

facility. Secondary hypotheses are: compared to standard ADs or ADs defaulting to life-

extension, ADs defaulting to comfort care will (1) produce no change in survival; (2) reduce

hospital and ICU admissions; (3) increase hospice utilization; (4) reduce costs of inpatient plus

hospice care; (5) improve patients’ quality of life; (6) improve patients’ satisfaction with care; (7)

improve surrogates’ perceptions of the quality of dying and death; and (8) decrease the

incidence of symptoms of post-traumatic stress among surrogates following their loved ones’

deaths.

Study setting

Recruitment for the trial is occurring at several clinics associated with the University of

Pennsylvania Health System in Philadelphia, PA, and the University of Pittsburgh Medical

Center in Pittsburgh, PA. We plan to recruit 270 patients who complete ADs. Recruitment

commenced in February 2014.

Eligibility Criteria

English-speaking patients 18 years or older are being recruited from the thoracic, gynecological,

gastrointestinal, genitourinary, liver, and breast oncology, pulmonary, nephrology, movement

disorder, and heart failure clinics across the two Pennsylvania health systems. In order to be

included in our study, patients must have specific diagnostic criteria (Table 1) documented in

their electronic health records. Criteria were selected in consultation with providers in the clinics

listed above. We asked providers to help develop criteria that would define cohorts of patients

for whom predicted survival is less than two years (median survival ≤ 24 months).

Patients eligible for transplant are excluded because transplant would alter disease prognosis.

Patients are selected based on prognosis and not age because patients’ goals tend to

correspond more closely with time horizons related to prognosis than with age.37,38 We are

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limiting our patient population to residents of Pennsylvania and New Jersey to facilitate follow-

up in state-wide databases. Patients with prior living wills are excluded because one’s choices

in completing a prior living will may influence selections in subsequent ADs. Cognitively

impaired patients are excluded from the study as they will not have capacity to consent or to

make the required healthcare decisions on their AD forms. Because our intervention is

embedded in the actual AD forms, we are excluding patients who are unable to read English.

Participant Screening

Each week, trained study personnel screen electronic medical records to identify eligible

patients scheduled for outpatient follow-up visits the following week. A patient’s eligibility status

is entered into the eligibility database along with ICD9 and ICD10 codes, staging information,

provider name, clinic location, and upcoming appointments. Once an eligible patient is

identified, a research coordinator emails the patient’s provider to (1) inform the provider that the

patient is eligible for recruitment and (2) provide an opportunity for the provider to decline or

defer any patient’s enrollment by responding to the email. Patients who meet eligibility criteria

but are new patients (i.e., not follow-up visits) are tracked in the eligibility database so they may

be re-screened at a later date. If eligible, they will be approached for consent. Patients are only

eligible for inclusion once. Once they consent or decline, patients are not approached again if

they meet eligibility criteria in a different clinic.

Recruitment and retention

Patients who screen eligible are approached by a research coordinator during routine clinic

visits. The research coordinators seek patients’ consent to participate in a study about

healthcare decision-making. The consent forms contain HIPAA statements of authorization of

release of medical records and include clear explanations that they are being asked to complete

an AD, participate in several follow-up interviews, and permit the research team to follow their

health outcomes. Patients are also told that different types of ADs are assigned by chance, but

that patients in all groups may select or decline any intervention or treatment goal, and may

revise their choices at any time. All patients are encouraged to involve their family members

and/or physicians in completing their ADs. All consenting patients are provided with: (1) their

assigned AD; (2) an informational brochure about ADs; (3) contact information for study

personnel; (4) a copy of the Decisional Conflict Scale (DCS) and (5) instructions for returning

the completed AD and DCS and a stamped envelope addressed to study staff. Demographics,

including age, race, ethnicity, sex, religion, income, marital status, and health insurance type are

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collected at the time of consent, as well as data about previous experience with life sustaining

therapies and critical care medicine via the Prior Experience Questionnaire. If a participant

does not return an AD within ten days, study personnel call every ten days to encourage AD

return or meet with the participant in person at his or her next clinic appointment.

Finally, we seek consent from patients’ surrogates by phone or during clinic visits. Recruited

surrogates are those identified in patients’ ADs, or if none, according to states’ legal hierarchies.

We tell surrogates that their roles are to (1) be a point of contact in the event that we are unable

to reach the patient for follow-up; (2) participate in an interview related to surrogate outcomes;

and (3) complete the 9-item Healthcare System Distrust Scale. Patients who wish to participate,

but lack a surrogate or do not want their surrogate to be contacted, are still eligible.

Patients who do not wish to complete an AD and decline consent are asked to sign a limited

consent form providing authorization to access long term health outcomes via electronic medical

records and state-wide databases, along with providing basic demographic information (age,

race, ethnicity, and gender). No further contact with these patients is made.

Subjects will be contacted for participation in follow-up interviews two, six, and twelve months

after AD completion. In order to maximize participation in follow-up interviews, participants are

asked if they would prefer to be contacted by phone or email. For participants who wish to be

contacted by phone, phone interviews will be conducted by a research assistant who is blinded

to the participant’s study arm and using a standardized script. Participants who prefer email

contact will be sent a link to complete surveys online using the REDCap electronic data capture

tool.39 This survey will include information and questions that are identical to the phone surveys.

Surrogates will be interviewed if patients are unable to participate due to illness.

All consenting patients are compensated $20 for each follow-up interview. Surrogates are given

$20 at the time of consent to encourage them to report patient deaths and complete follow-up

interviews with study staff.

Randomization and allocation concealment

Consenting participants are randomized individually with a 33.3% probability to each trial arm

(comfort-oriented defaults, life-extension defaults, or standard AD) using electronic

randomization managed by the Data Management Unit (DMU) at the University of Pennsylvania

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(see Figure 1). Randomization is stratified by center using variable block sizes of 3, 6, and 9

patients to promote patient balance within center. Research coordinators remain blinded to

patients’ AD group until after consent is provided.

Intervention

The three AD forms used in this study are versions modified slightly from the professionally

endorsed AD published by the Allegheny County Medical Society (Appendix A).40 Patients are

asked to select between an overall plan of care focused on extending life or on relieving pain

and suffering if these two goals are to come into conflict. The language used to describe these

overall goals is taken directly from the SUPPORT trial.41 Additionally, patients are asked to

choose whether or not they desire four specific life-sustaining interventions if they were to

become sick and unable to make decision for themselves. These four interventions represent

validated markers of end-of-life intensity42 and are: cardiopulmonary resuscitation, mechanical

ventilation, dialysis, and feeding tube insertion for artificial nutrition and hydration. Finally,

patients are asked to indicate the type of care they would want following hospital discharge

(comfort-oriented without return visits to the hospital or life-extension including return visits to

the hospital). For all questions, patients may select that they do not wish to specify, deferring

the decision-making to their surrogate.

In the standard AD, patients are asked to make active choices for each of these decisions.

Patients not selecting a choice defer that decision to their surrogate. The life-extension and

comfort default ADs are identical except that in these, the life-extension (or comfort-oriented)

plan of care is pre-selected, as are choices to receive (or not) the 4 life-sustaining interventions,

and the decision to continue (or forgo) intensive care following hospital discharge including

future hospitalizations. Patients are clearly instructed that other preferences can be chosen by

crossing out the pre-selected options and choosing alternatives or choosing that they do not

wish to specify.

Debriefing

Debriefing has long been used in “deception research.” Although our study does not qualify as

deceptive because we do not provide participants with untrue information, we believe debriefing

remains an essential element of this RCT in which certain details are necessarily withheld

during the consent process. As Wendler and colleagues note,43 debriefing “should be

understood as a tool of moral accountability,” and that “debriefing makes amends by

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retrospectively providing the disclosure about the research that standardly should have been

offered prospectively.” In our study, a thorough debriefing session will ensure that patients (1)

understand their selections; (2) do not simply go with the default options because they failed to

recognize that a choice was to be made or that a default was being used; (3) have multiple

opportunities to withdraw their participation or data; and (4) are actively engaged in the research

and comfortable with the research process.

After receiving a patient’s completed AD form, a research coordinator contacts the patient for a

debriefing session. During the debriefing, the research coordinator uses an IRB-approved script

(Appendix B) that carefully explains the nature of the intervention, including the use of different

default options in ADs. Patients are reminded that they received, by chance, one of three forms

used in the study. The specific differences between all three versions are described, including

explanations that choices were pre-selected, when appropriate. The research coordinator then

reviews each AD choice with the patient and makes sure patients are satisfied with the

selections before proceeding. Patients are specifically asked if they wish to change their

selections on their AD forms, and are reminded that should their choices change in the future,

they should contact the study team, their clinician, or both. If the patient decides to make

changes to his/her AD, changes can be made immediately by the research coordinator and a

new copy forwarded to the patient, or the patient may choose to receive a blank copy of the AD

and make new selections. Any changes will be incorporated and the completed AD will be

scanned into the patient’s medical record, and mailed to the patient, identified health care

agents / surrogates, and any other requested family members.

Once patients confirm that they are comfortable with their selections, the research coordinator

informs patients that their ADs will be scanned into their medical records and sent to their home

address as well as to their surrogates. Patients are given the opportunity to decline one or both

of these efforts to promote AD accessibility. ADs will not be considered “complete” until the

debriefing session has occurred.

Outcomes (Primary and Secondary)

The primary outcome is hospital-free days (HFDs) (Table 2). This metric represents the number

of days alive and not in an acute care facility following the date of consent. We choose the date

of consent as day 0 so that all enrolled participants, including those who do not return ADs, are

eligible for intention-to-treat analyses. However, to minimize immortal-time bias, we will also

conduct a secondary analysis in which day 0 is defined as the date on which ADs are returned.

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Two additional variations on this metric will also be evaluated: (1) healthcare facility-free days,

which represent the number of days alive where a patient is in neither an acute care facility, a

chronic care facility, or a nursing home; and (2) HFDs within the first six months of follow-up.

Secondary outcomes include several clinical, economic, and patient-reported measures.

Specifically, we capture patient deaths via medical records and, if necessary, we verify deaths

in the Social Security Death Index, performing linkages via social security numbers, which are

collected at the time of consent. We assess hospitalizations, ICU admissions, costs of inpatient

care, and utilization of life-sustaining therapies by querying state-run databases that capture all

admissions and in-patient procedures in Pennsylvania and New Jersey. These databases are

also utilized to assess concordance between patients’ choices to receive 4 potentially life-

sustaining therapies and whether those interventions are actually received. Data on hospice

utilization and costs are collected via data use agreements with organizations that provide care

for 80% of patients at Penn and Pitt.

In patient interviews conducted 2, 6, and 12 months following AD completion, we are assessing

patients’ satisfaction with their advance care planning, quality of life, and desires to make any

changes to their ADs. Satisfaction is measured with the CANHELP44,45 instrument’s global

satisfaction and end-of-life care question. Quality of life is measured using the McGill Quality of

Life,46,47 which can be completed by family members on behalf of patients who are unable to

complete it themselves. Additionally, we are assessing decision conflict, using the validated

Decision Conflict Scale,48 to assess patients’ certainty in making healthcare decisions. This

measure is collected immediately following AD completion and is not assessed during follow-up.

We are assessing surrogates’ perceptions of the quality of death and dying using Prigerson’s

Quality of Death measures.8,9,49 The Impact of Events Scale50 is used to assess the risk of post-

traumatic stress disorder in surrogates of deceased patients. Finally, healthcare system distrust

is measured among the surrogates using the Health System Distrust Scale.51

Data collection methods

The Data Management Unit (DMU) at the University of Pennsylvania manages all study data,

and ensures secure multi-site data integration, accurate merging of trial data with hospice and

state claims databases, and processes scanning of report forms for demographics collection

and all follow-up data to minimize errors. The database automatically tracks patients and

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notifies study personnel when follow-up interviews are due. Only authorized project personnel

have access to the data, which is stored behind firewalls and not on stand-alone PCs or laptops.

All study participants are assigned a study identification number and any personally identifying

information is removed from analytic datasets.

Analytic plan

We will use intention-to-treat (ITT) analyses to assess the impact of group assignment on all

outcomes. However, an equally important aim of this trial is to assess the influence of the

choices patients make in ADs on long-term patient- and family-reported outcomes, respectively.

Secondarily, we also wish to estimate the impact of completing an advance directive at all,

regardless of the choices made. Using an intervention (default options) that alters choices, and

modern methods of causal inference, we will be able to estimate the effects of choices in ADs

on long-term outcomes with great precision and accuracy even though some randomized

patients will not return completed ADs.

To show how we will accomplish this, consider the three analyses described in Figure 2. First,

we will conduct ITT analyses using linear regression, adjusting for center,52 to compare the

effects of assignment to complete ADs with different default options on the outcomes of interest.

This approach uses data from all randomized participants, and provides the truest test of the

overall effectiveness of the intervention (Figure 2, diagram A). However, the ITT analysis does

not provide a specific test of the effects of choices made in ADs, because these effects will be

diluted by the fact that many randomized patients will not complete their assigned ADs.

Furthermore, among patients who do return completed ADs, not all will stick with their assigned

default choice. To surmount this problem, researchers sometimes conduct per-protocol

analyses, which in this case would compare patients who complete ADs and stay with their

assigned defaults in one arm with those who do the same in the other arms (Figure 2, diagram

B). However, per-protocol analyses are likely to be biased by selection effects: patients who

complete ADs and choose comfort care are likely different from those who do not complete ADs

or make other choices in completed ADs, and these underlying differences may influence

outcomes such as quality of life.53

To surmount the limitations of ITT analyses in estimating the specific efficacy of choices in ADs,

and of per-protocol analyses in providing biased estimates of such efficacy, we will conduct two-

stage least squares regression in which the randomization arm is modeled as an instrumental

variable54,55 in complier average treatment effect analyses.56-59 Because the randomization is

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stratified on center, the analysis will also adjust for center.52 Such analyses, also used in our

recent randomized trial of behavioral economic interventions for smoking cessation,60 use data

on all randomized participants to estimate the effects of specifying any treatment choice in ADs,

regardless of group assignment, and after accounting for the possibility that AD completion

rates may differ among the three arms (Figure 2, diagram C) by using the randomization arm

(i.e., initial treatment assignment) as the instrumental variable. Thus, the estimated effect of the

choices patients make is adjusted for the percentage of assigned patients who complete an AD

at all, and the percentage who opt out from their assigned default option. Unlike a per-protocol

analysis, this IV approach uses data on all randomized patients, and then adjusts for AD

completion rates, thereby attenuating the selection effects.

This approach requires the use of principal stratification methods61 to formulate the causal

quantities of interest and determine the proportions of patients in each arm who would choose

comfort care if they were assigned to complete each version of the AD. The analysis assumes

that all patients who would choose comfort care in a standard AD would also choose it in an AD

that defaults to comfort care, and that all patients who would choose comfort care in an AD that

defaults to aggressive care would also choose it in a standard AD or an AD that defaults to

comfort care. Coupled with the possibilities that some participants would never return an AD,

and that others would return an AD but not choose comfort care regardless of group

assignment, this creates five compliance classes (principal strata) of subjects (Table 3).19,62

Each patient has three potential outcomes, listed below. Only one of the potential outcomes can

be observed, the outcome corresponding to the actual intervention the patient received. For

simplicity, we illustrate this with a binary endpoint – whether or not patients would have a high

quality of life in the future:

YiA

= whether patient i would have high quality of life if assigned to complete an aggressive-default AD

YiS

= whether patient i would have high quality of life if assigned to complete a standard AD

YiC

= whether patient i would have high quality of life if assigned to complete a comfort-default AD

Our analytic approach will assume the exclusion restriction that AD assignment only influences

the potential outcomes through the causal pathway of determining which type of care the patient

chooses through the AD.55 However, this assumption is likely to hold in this case, because the

randomly assigned instrumental variable – which of three versions of an AD is offered – would

not influence outcomes unless it modified the probability of AD completion or the choices made

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in the ADs. Further, we will do a sensitivity analysis to examine how violations of the exclusion

restriction would influence our results.59

In all models, clinic will be entered as a random effect to adjust for potential clustering within

clinics and to mitigate confounding by clinic.63 Gender, race, and diagnosis category will be

included in all multivariable models based on pre-specified hypotheses, and others will be

added if their inclusion – singly or jointly – modifies the coefficient for the randomized exposure

by ≥ 15%.64 Planned subgroup analyses will be conducted across groups defined by age, race,

ethnicity, religion, and diagnostic category.

Secondary outcomes will be analyzed using logistic, linear or quantile regression, as

appropriate. The number of hospital and ICU admissions will be analyzed as count data. Costs

will be inflated to the date on which analyses are performed using the U.S. gross domestic

product deflator.65 Hospice utilization will be analyzed as both the time from AD completion to

hospice enrollment, and the duration of hospice utilization prior to death.

Sample size

We calculate our sample size as that required to rule out a significant reduction in HFDs

attributable to random assignment to any AD default. This approach entails non-inferiority tests

of data from a Poisson distribution, such that we seek to reject the hypothesis of a rate ratio

(RR) for HFDs that is significantly greater than 1.0. By enrolling 270 patients who complete ADs

– 90 in each of the 3 arms – we will obtain at least 80% power to demonstrate non-inferiority up

to a margin of an RR for HFDs ≥ 1.18 associated with use of one AD type. This calculation is

based on: (a) a one-sided alpha of 0.05, yielding an upper confidence limit on the observed RR

that falls entirely below an RR of 1.18; (b) a mean number of HFDs in the control group of 100,

such that a rate ratio of 1.18 would correspond to 15 (15%) fewer HFDs in a given AD group

(100/85 = 1.18); (c) an allowance for considerable dispersion in the distribution of HFDs; (d) no

loss to follow-up because all deaths and hospitalizations will be checked against the Social

Security Death Index and PHC4, respectively; (e) an allowance for two primary hypothesis tests

(comparing both the comfort-default and life-extension default arms to the control arm); and (f) a

true RR of 1.0. This final choice reflects our hypothesis that assignment to all three ADs will

produce equivalent numbers of HFDs. If the true RR is below 1.0 (e.g., the comfort default

increases HFDs), power would increase considerably. Further, because simulations used to

generate these sample size estimates included scenarios with extreme assumptions of data

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dispersion, and the proposed sample sizes incorporate this conservative assumption, our

observed power is likely to be higher than stated.

Ethics and Dissemination

Ethics

This study has been approved by the University of Pennsylvania Institutional Review Board

(Protocol #819325) and the IRB at the University of Pittsburgh (PRO14020311). This study is

also guided by a Data Safety and Monitoring Board (DSMB) consisting of individuals with

expertise in human subjects research, vulnerable populations, bioethics, clinical trials, decision

making, palliative care, and biostatistics. The DSMB reviewed and approved the research

protocol and plans for data and safety prior to the start of recruitment. Additionally, Board

members are evaluating the progress of the trial and making recommendations to ensure that

any and all issues are addressed, including decisions about the termination of individual study

arms or the study itself.

The potential risks to human subjects in this project include: (1) risks of breach of confidentiality

of personal health information; (2) risks of emotional distress from being asked to contemplate

or discuss end-of-life care; and (3) potential untoward impacts on patients or family members,

including changes in quality of life, duration of life, satisfaction with end-of-life care, surrogate

bereavement perceptions of the quality of dying, or an undesired change in intervention

utilization at the end-of-life. To minimize these risks, our study employs numerous safeguards

to protect human subjects. These include an experienced and well-trained study team, a robust

informed consent process, state-of-the-art data security, and the DSMB. Finally, an External

Advisory Board comprising noted scholars in health law, palliative care, and research ethics

meets as needed to advise the investigators on any unforeseen challenges related to the ethical

conduct of the trial.

Dissemination

In addition to presentation at scientific meetings and publication in scholarly journals, we plan to

leverage resources at Penn and Pitt to place our results in the public domain where they can be

openly discussed before any policy changes are recommended. This includes developing and

implementing strategies to describe results in ways that key stakeholders can understand and

implement.

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Discussion

Although most seriously ill Americans wish to avoid burdensome and invasive therapies at the

end of life, aggressive care is provided by default – that is, unless otherwise requested. This

randomized trial seeks to confirm our prior findings that using different default options in

advance directives affects patients’ stated treatment goals and preferences. In addition, the

current trial seeks to leverage presumed changes in these treatment goals and preferences to

assess the impact of such choices on a series of clinical, economic, and patient- and surrogate-

reported outcomes. Ultimately, we aim to establish whether a simple and readily scalable

intervention – changing default options in ADs – can meaningfully improve patients’ quality of

life and reduce resource utilization without reducing the number of days that patients are alive

and living outside of an acute-care hospital.

Trial Status

At the time of manuscript submission, 288 patients from the University of Pennsylvania clinics

and 168 patients from clinics at the University of Pittsburgh have consented to participate and

been randomized, and 208 have returned advance directives and been debriefed.

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Acknowledgements

Contributorship statement: All authors contributed to the study design and protocol. NBG drafted

the protocol manuscript and all authors provided critical feedback and revisions. All authors

have provided final approval of the study protocol.

Competing Interests: None

Funding: This work was supported by the Gordon & Betty Moore Foundation

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References

1. Fields MJ, Cassel CK. Approaching Death, Improving Care at the End of Life. Washington, D.C.: National Academy Press; 1997. 2. Fried TR, Bradley EH, Towle VR, Allore H. Understanding the treatment preferences of seriously ill patients. The New England journal of medicine 2002;346:1061-6. 3. Facts on dying. 2001. (Accessed at https://nts122.chcr.brown.edu/dying/2001DATA.HTM.) 4. Angus DC, Barnato AE, Linde-Zwirble WT, et al. Use of intensive care at the end of life in the United States: an epidemiologic study. Critical care medicine 2004;32:638-43. 5. Kwok AC, Semel ME, Lipsitz SR, et al. The intensity and variation of surgical care at the end of life: a retrospective cohort study. Lancet 2011;378:1408-13. 6. Smith AK, McCarthy E, Weber E, et al. Half of older Americans seen in emergency department in last month of life; most admitted to hospital, and many die there. Health Aff (Millwood) 2012;31:1277-85. 7. Riley GF, Lubitz JD. Long-term trends in Medicare payments in the last year of life. Health services research 2010;45:565-76. 8. Wright AA, Keating NL, Balboni TA, Matulonis UA, Block SD, Prigerson HG. Place of death: correlations with quality of life of patients with cancer and predictors of bereaved caregivers' mental health. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:4457-64. 9. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. Jama 2008;300:1665-73. 10. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. The New England journal of medicine 2010;363:733-42. 11. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. Jama 2009;302:741-9. 12. Connor SR, Pyenson B, Fitch K, Spence C, Iwasaki K. Comparing hospice and nonhospice patient survival among patients who die within a three-year window. Journal of pain and symptom management 2007;33:238-46. 13. Bakitas MA, Tosteson TD, Li Z, et al. Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015;33:1438-45. 14. Azoulay E, Pochard F, Kentish-Barnes N, et al. Risk of post-traumatic stress symptoms in family members of intensive care unit patients. American journal of respiratory and critical care medicine 2005;171:987-94. 15. Detering KM, Hancock AD, Reade MC, Silvester W. The impact of advance care planning on end of life care in elderly patients: randomised controlled trial. BMJ 2010;340:c1345. 16. Wendler D, Rid A. Systematic review: the effect on surrogates of making treatment decisions for others. Annals of internal medicine 2011;154:336-46. 17. Siegel MD, Hayes E, Vanderwerker LC, Loseth DB, Prigerson HG. Psychiatric illness in the next of kin of patients who die in the intensive care unit. Critical care medicine 2008;36:1722-8. 18. Silveira MJ, Kim SY, Langa KM. Advance directives and outcomes of surrogate decision making before death. The New England journal of medicine 2010;362:1211-8. 19. Degenholtz HB, Rhee Y, Arnold RM. Brief communication: the relationship between having a living will and dying in place. Annals of internal medicine 2004;141:113-7.

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20. Nicholas LH, Langa KM, Iwashyna TJ, Weir DR. Regional variation in the association between advance directives and end-of-life Medicare expenditures. Jama 2011;306:1447-53. 21. Teno JM, Gruneir A, Schwartz Z, Nanda A, Wetle T. Association between advance directives and quality of end-of-life care: a national study. Journal of the American Geriatrics Society 2007;55:189-94. 22. Fagerlin A, Schneider CE. Enough. The failure of the living will. The Hastings Center report 2004;34:30-42. 23. Kirschner KL. When written advance directives are not enough. Clinics in geriatric medicine 2005;21:193-209, x. 24. Perkins HS. Controlling death: the false promise of advance directives. Annals of internal medicine 2007;147:51-7. 25. Tonelli MR. Pulling the plug on living wills. A critical analysis of advance directives. Chest 1996;110:816-22. 26. Tulsky JA. Beyond advance directives: importance of communication skills at the end of life. Jama 2005;294:359-65. 27. Chapman GB, Li M, Colby H, Yoon H. Opting in vs opting out of influenza vaccination. Jama 2010;304:43-4. 28. Choi JJ, Laibson D, Madrian BC, Metrick A. Defined contribution pensions: Plan rules, participant decisions, and the path of least resistance. In: Poterba JM, ed. Tax Policy and the Economy. Cambridge, MA: MIT Press; 2002:67-113. 29. Horvat LD, Cuerden MS, Kim SJ, Koval JJ, Young A, Garg AX. Informing the debate: rates of kidney transplantation in nations with presumed consent. Annals of internal medicine 2010;153:641-9. 30. Johnson EJ, Goldstein D. Medicine. Do defaults save lives? Science 2003;302:1338-9. 31. Johnson EJ, Hershey JC, Meszaros J, Kunreuther H. Framing, probability distortions, and insurance decisions. J Risk Uncertain 1993;7:35-51. 32. Madrian BC, Shea DF. The power of suggestion: Intertia in 401(k) participation and savings behavior. Quarterly Journal of Economics 2001;116:1149-87. 33. Halpern SD, Ubel PA, Asch DA. Harnessing the power of default options to improve health care. The New England journal of medicine 2007;357:1340-4. 34. Loewenstein G, Brennan T, Volpp KG. Asymmetric paternalism to improve health behaviors. Jama 2007;298:2415-7. 35. Quill CM, Halpern S. Deciphering the appropriateness of defaults: the need for domain-specific evidence. Journal of medical ethics 2012;38:721-2. 36. Halpern SD, Loewenstein G, Volpp KG, et al. Default options in advance directives influence how patients set goals for end-of-life care. Health Aff (Millwood) 2013;32:408-17. 37. Carstensen LL. The influence of a sense of time on human development. Science 2006;312:1913-5. 38. Carstensen LL, Isaacowitz DM, Charles ST. Taking time seriously. A theory of socioemotional selectivity. The American psychologist 1999;54:165-81. 39. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of biomedical informatics 2009;42:377-81. 40. Living Will and Healthcare Power of Attorney. 2007. (Accessed at www.acms.org/lw/index.html.) 41. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. Jama 1995;274:1591-8. 42. Barnato AE, Farrell MH, Chang CC, Lave JR, Roberts MS, Angus DC. Development and validation of hospital "end-of-life" treatment intensity measures. Medical care 2009;47:1098-105.

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43. Miller FG, Gluck JP, Jr., Wendler D. Debriefing and accountability in deceptive research. Kennedy Institute of Ethics journal 2008;18:235-51. 44. Heyland DK, Cook DJ, Rocker GM, et al. The development and validation of a novel questionnaire to measure patient and family satisfaction with end-of-life care: the Canadian Health Care Evaluation Project (CANHELP) Questionnaire. Palliative medicine 2010;24:682-95. 45. Heyland DK, Frank C, Tranmer J, et al. Satisfaction with end-of-life care: a longitudinal study of patients and their family caregivers in the last months of life. Journal of palliative care 2009;25:245-56. 46. Cohen SR, Mount BM, Bruera E, Provost M, Rowe J, Tong K. Validity of the McGill Quality of Life Questionnaire in the palliative care setting: a multi-centre Canadian study demonstrating the importance of the existential domain. Palliative medicine 1997;11:3-20. 47. Cohen SR, Mount BM, Strobel MG, Bui F. The McGill Quality of Life Questionnaire: a measure of quality of life appropriate for people with advanced disease. A preliminary study of validity and acceptability. Palliative medicine 1995;9:207-19. 48. O'Connor AM. Validation of a decisional conflict scale. Medical decision making : an international journal of the Society for Medical Decision Making 1995;15:25-30. 49. Zhang B, Nilsson ME, Prigerson HG. Factors important to patients' quality of life at the end of life. Archives of internal medicine 2012;172:1133-42. 50. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. Psychosomatic medicine 1979;41:209-18. 51. Shea JA, Micco E, Dean LT, McMurphy S, Schwartz JS, Armstrong K. Development of a revised Health Care System Distrust scale. Journal of general internal medicine 2008;23:727-32. 52. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Statistics in medicine 2012;31:328-40. 53. Sommer A, Zeger SL. On estimating efficacy from clinical trials. Statistics in medicine 1991;10:45-52. 54. Newhouse JP, McClellan M. Econometrics in outcomes research: the use of instrumental variables. Annual review of public health 1998;19:17-34. 55. Angrist JD, Imbens GW, Rubin DW. Identification of causal effects using instrumental variables. Journal of the American Statistical Association 1996;91:444-55. 56. Cheng J, Small D. Bounds on causal effects in three-arm trials with noncompliance. Journal of the Royal Statistical Society 2006;68:815-36. 57. Cheng J, Small D, Tan Z, Ten Have TR. Efficient nonparametric estimation of causal effcts in randomized trials with noncompliance. Biometrika 2009;96:19-36. 58. Sussman JB, Hayward RA. An IV for the RCT: using instrumental variables to adjust for treatment contamination in randomised controlled trials. BMJ 2010;340:c2073. 59. Baiocchi M, Cheng J, Small DS. Instrumental variable methods for causal inference. Statistics in medicine 2014;33:2297-340. 60. Halpern SD, French B, Small DS, et al. Randomized trial of four financial-incentive programs for smoking cessation. The New England journal of medicine 2015;372:2108-17. 61. Frangakis CE, Rubin DB. Principal stratification in causal inference. Biometrics 2002;58:21-9. 62. Sudore RL, Fried TR. Redefining the "planning" in advance care planning: preparing for end-of-life decision making. Annals of internal medicine 2010;153:256-61. 63. Localio AR, Berlin JA, Ten Have TR, Kimmel SE. Adjustments for center in multicenter studies: an overview. Annals of internal medicine 2001;135:112-23. 64. Hosmer DW, Lemeshow S, Sturdivant RX. Applied Logistic Regression. 2nd ed: John Wiley & Sons; 2000. 65. U.S. Department of Commerce Bureau of Economic Analysis. (Accessed April 16, 2015, at www.bea.gov/national/.)

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Table 1. Inclusion and Exclusion Criteria

Inclusion Exclusion

- Age 18 or older - Speaks and reads fluent English - Has seen current physician at least once prior to current visit - Resident of PA or NJ - One or more of the following diagnoses:

(a) Amyotrophic lateral sclerosis (b) Stage IIIB or IV non-small cell lung cancer or

cholangiocarcinoma (c) Stage IV colorectal, espophageal, gastric, pancreatic,

prostate, uterine, cervical, ovarian or urothelial cancer; paraganglioma, or pheochromocytoma

(d) Stage C or D hepatocellular carcinoma (e) Stave IV renal cell carcinoma (f) Stage IV or V chronic kidney disease (g) Mesothelioma or any malignancy metastatic to the pleura (h) Other insurable interstitial lung diseases with at least

severe restriction on most recent pulmonary function tests or eligible for long-term oxygen therapy

(i) Chronic obstructive pulmonary disease with at least severe airflow obstruction on most recent spirometry or eligible for long-term oxygen therapy

(j) Congestive heart failure with NYHA Class IV status or Class III plus 1 heart failure-related hospitalization in the past 12 months or ACC stage D or C classification with 1 heart-failure hospitalization in the past 12 months

(k) Stage IV breast cancer except patients whose only metastases are to the bones or who are receiving endocrine therapy without receiving concomitant traditional chemotherapy

- Currently listed for or being considered for solid organ transplant - Previously signed advance directive or living will - Cognitive impairment

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Table 2. Outcomes

Outcome Measurement

Hospital-free days (primary outcome) Number of days alive and not in an acute care facility

Hospital and ICU Admissions Number of admissions analyzed as count data Costs of Care Combination of all costs of inpatient and

outpatient hospice, hospital stays, and life-sustaining procedures

Hospice Utilization Analyzed as time from AD completion to hospice enrollment and as duration of hospice utilization prior to death

Choices to receive 4 potentially life-sustaining interventions

Concordance of these choices with whether the interventions were actually received

Choices regarding post-hospitalization care Concordance of these choices with the care actually received

Decision conflict and satisfaction Decision Conflict Scale CANHELP

Quality of life McGill Quality of Life Surrogates’ perception of the quality of death and dying

Prigerson’s Qualtiy of Death

Bereavement outcomes Impact of Events Scale Healthcare system distrust Healthcare System Distrust Scale

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Table 3. Compliance classes to estimate the effects of choices made in advance

directives

I. Patients would not complete an AD regardless of group assignment

II. Patients would complete an AD but not choose comfort care regardless of group

assignment

III. Patients would complete an AD and only choose comfort care if assigned to the comfort-

default AD

IV. Patients would complete an AD and choose comfort care if assigned to the comfort-

default AD or standard AD

V. Patients would complete an AD and choose comfort care regardless of group assignment

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Study scheme

254x190mm (300 x 300 DPI)

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Methods of inferring the causal effects of choices made in advance directives (ADs) 254x190mm (300 x 300 DPI)

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Appendix A – Advance Directive Forms

STANDARD FORM

Part I – Durable Healthcare Power of Attorney

I, _____________________________ of ___________________ County, (State),

appoint the person named below to be my agent to make health decisions for me when and only when I

lack sufficient capacity to make or communicate a choice regarding a healthcare decision as

verified by my attending physician. My agent may not delegate the authority to make decisions.

Appointment of Healthcare Agent (“Agent”)

I appoint the following agent:

Name: _____________________________ Relationship: ______________________________

Address: _____________________________________________________________________

_____________________________________________________________________

Telephone Number: Home ________________________ Work _________________________

Email:

Alternate agent (to be contacted if the appointed agent is unable to serve):



Email:

I understand that if I do not name an agent, my healthcare providers will ask my family or others

who may know my preferences and values for help in determining my wishes for treatment.

(initial) I do not wish to appoint an agent.

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Part II - Healthcare Treatment Instructions (Living Will) The following healthcare treatment instructions exercise my right to make my own healthcare decisions. These

instructions are intended to provide clear and convincing evidence of my wishes, and are to be followed only when I

lack the ability to understand, make or communicate healthcare decisions for myself. Further, these wishes are only

intended to apply if I am in a state of permanent unconsciousness or have an end-stage medical condition as

verified by my attending physician.

In general, I wish to both live as long as possible and avoid pain and suffering. However, I understand that in some

situations, choosing between these two goals may be necessary. If I am in a situation where such a choice is needed:

Overall Goals of Care

_______ I want my healthcare providers to treat me by helping to relieve my pain and

suffering, even if that means that I may not live as long.

OR

_______ I want my healthcare providers to treat me by helping me to live as long as

possible, even if that means that I may have more pain or suffering.

OR

_______ I do not want to specify one of the above goals. My agent, with consultation from my

healthcare provider, may direct the overall goals of my care based on his or her assessment of

my preferences and values or best interests.

In addition, I want my healthcare providers and agent to focus on the following goals (optional):

____________________________________________________________________________________

____________________________________________________________________________________

Specific Procedures

These are my specific requests regarding life- prolonging procedures, in addition to requests I may write

in at the end of this section.

1. Cardiopulmonary resuscitation (CPR)

_______ I do not want cardiopulmonary resuscitation (CPR) to be performed on me if my

heart stops beating, even if performing CPR might prolong my life.

OR

_______ I request cardiopulmonary resuscitation (CPR) if my heart stops beating, even if

performing CPR may increase my pain or suffering.

OR

_______ I do not wish to specify one of these options. My agent, with consultation from my

healthcare provider, may make any decisions about cardiopulmonary resuscitation

(CPR) for me based on his or her assessment of my preferences and values or best

interests.

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2. Mechanical ventilator (breathing machine) use

_______ I do not want to be placed on a mechanical ventilator even if it might prolong my

life. If I am unable to breathe on my own, I would prefer care directed towards

relief of pain and suffering.

OR

_______ I wish to be placed on a mechanical ventilator (breathing machine) if it may

prolong my life, even if it may also increase my pain or suffering.

OR


healthcare provider, may make any decisions about mechanical ventilator use for me

based on his or her assessment of my preferences and values or best interests.

3. Dialysis (kidney filtration by machine)

_______ I do not want dialysis to be performed on me, even if dialysis might prolong my

life. If I was on dialysis before I became permanently unconscious or developed an end-

stage medical condition, I want dialysis to be stopped.

OR

_______ I request dialysis if it may prolong my life, even if it may also increase my pain or

suffering. This includes continuing dialysis if I was on it before I became permanently

unconscious or developed an end-stage medical condition.

OR


healthcare provider, may make decisions about the use of dialysis for me based on his

or her assessment of my preferences and values or best interests.

4. Feeding tube insertion for artificial nutrition and hydration

_______ I do not want to have a feeding tube inserted or used for artificial nutrition and

hydration.

OR

_______ I request feeding tube insertion and use for artificial nutrition and hydration if I

cannot eat or drink.

OR

_______ I do not wish to specify one of these options. I understand that if I do not clearly

express my preferences, my agent will presume that I want artificial nutrition and

hydration.

In addition, I make the following requests regarding whether or not to use specific therapies:

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

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Care on hospital discharge if I am in an end-stage medical condition These are my requests about how I wish to be cared for if I am in a hospital, my doctors say I no longer

need to be in the hospital, but I cannot communicate and my doctors do not expect that to change.

______ I want to be sent to my home if possible, or otherwise to a facility near my home, to

receive care focused on keeping me as comfortable as possible rather than on prolonging

my life. If my condition worsens, I do not want to return to a hospital again.

If you prefer to choose a different option, cross out the lines above and place your

initials by one of the other options below:


receive care focused on keeping me alive as long as possible. If my condition worsens,

I want to return to the hospital if that may prolong my life.

OR

______ I do not wish to specify one of these options. I understand that if I do not express my

preferences, my agent, with consultation from my health care provider, will make this

decision for me based on his or her assessment of my preferences and values or best

interests.

Agent’s Use of Instructions (Initial one option only)

_______ I want the preferences I have expressed in this Living Will to be strictly followed by my

agent.

OR

_______ I want the preferences I have expressed in this Living Will to serve as a general guide

for my agent. My agent will have final say about all decisions, and may override these

instructions.

Please indicate any exceptions to the above – that is, instructions that may not be

overrriden:___________________________________________________________________________

If I did not appoint an agent, these instructions shall be followed.

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Legal Protection

Pennsylvania law protects my healthcare agent and healthcare providers from any legal liability for their

good faith actions in following my wishes as expressed in this form or in complying with my healthcare

agent's direction. On behalf of myself, my executors and heirs, I further hold my healthcare agent and

my healthcare providers harmless and indemnify them against any claim for their good faith actions in

recognizing my healthcare agent's authority or in following my treatment instructions.

Having carefully read this document, I have signed it this _____ day of_______________, 20__,

revoking all previous healthcare powers of attorney and healthcare treatment instructions.

SIGNED: ____________________________________________________

(SIGN FULL NAME HERE)

Two witnesses at least 18 years of age are required by Pennsylvania law and should witness your

signature in each other's presence. A person who signs this document on behalf of and at the direction

of a principal may not be a witness. (It is preferable if the witnesses are not your heirs, nor your

creditors, nor employed by any of your healthcare providers.)

WITNESS: ___________________________________________

WITNESS: ___________________________________________

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COMFORT DEFAULT FORM


I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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______ I want my healthcare providers to treat me by helping to relieve my pain and suffering, even

if that means that I may not live as long.

If you prefer to choose a different overall goal of care, cross out the lines above and place

your initials by one of the other options below:



OR





____________________________________________________________________________________

____________________________________________________________________________________

Specific Procedures These are my specific requests regarding life-prolonging procedures, in addition to requests I may write









OR




interests.

X

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OR













OR






hydration.





OR



hydration.

X

X

X

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____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________











OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


X

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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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LIFE EXTENSION DEFAULT FORM


I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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_______ I want my healthcare providers to treat me by helping me to live as long as possible,

even if that means that I may have more pain or suffering





OR





____________________________________________________________________________________

____________________________________________________________________________________

Specific Procedures These are my specific requests regarding life- prolonging procedures, in addition to requests I may write









OR




interests.

X

X

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OR













OR










hydration.

OR



hydration.

X

X

X

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____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________



______ I want to be sent to my home, if possible, or otherwise to a facility near my home, to








OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


X

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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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APPENDIX B – DEBRIEFING SCRIPTS

STANDARD AD DEBRIEFING SCRIPT

UNIVERSITY OF PENNSYLVANIA

DEBRIEFING FORM

Protocol Title: Default Options in Advance Directives

Principal

Investigator:

Scott Halpern, M.D., Ph.D.


215.573.9461

To be read to all patients who return a completed an advance

directive:

Thank you for participating in this study. In addition to potentially helping other patients

in the future, by participating in this study you have also completed an advance directive

that is intended to guide your clinicians and care-givers regarding what types of medical

care you do or do not want in the event that you are unable to make such decisions

yourself.

I would like to spend just a couple minutes to explain this study a bit more and discuss

your advance directive form. I have your form in front of me and I can see you

appointed your [relationship], [name] as your agent.

[If no agent appointed say:] I can see you did not select an agent. This means that in

the event that you are unable to make decisions for yourself, your doctors will consult

your family to help determine your wishes.

You received one of three different versions of advance directives used in this study. As

I believe the research coordinator told you when he or she met with you in clinic, the

version of the form you received was determined by chance, like by flipping a coin. All 3

advance directives are the same in some respects. For example, in all 3 versions,

patients are completely free to indicate

• their goals of care near the end of life and

• their preferences for receiving specific treatments or interventions such as a

breathing machine or a feeding tube and

• their appointed health care agent

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However, what makes these 3 versions different is how the information was presented.

In some versions the ordering of options was different than on the version you received.

In others, some of the choices were pre-selected. It’s very important to realize that no

matter which version of the advance directive people in this study received, everyone

was free to choose the options that best fit their values and preferences. Our study was

designed to see if the way in which this information was presented influences peoples’

selections.

Before we go on, do you have any questions about the study itself?

[Discuss with research manager]

Now I’d like to review the choices you made on your advance directive form. Please let

me know if you hear anything that you’d like to change or if you have any questions. We

want to be sure that your choices on this form are consistent with your values and

preferences.

READ EACH OF SELECTED CHOICES IN FULL; IF PATIENTS WISHES TO MAKE

SIMPLE WORDING CHANGES, NOTE THESE IN REVISED AD AND PROCEED TO

SECTION BELOW BEGINNING: “OK. Then, if agreeable to you, we will make5”;

FOR ANYTHING MORE THAN SIMPLE WORDING CHANGES, SAY:

OK, I want to be sure your advance directive says exactly what you want it to say. I can

either make the changes you indicate DIRECTLY on your advance directive form and

send it back to you, OR I can send you another copy of the Advance Directive form. In

this case, you’d make your selections again, and then send it back to us. If you wish to

speak with the research coordinator you met with in clinic again, I can also ask [him or

her] to call you or help you schedule a time to see her when you are in clinic.

[After review, if patient says he or she is comfortable with his or her choices,

say]:

OK, we are going to scan this advance directive and make it a part of your medical

record if that is ok with you. We will send you a copy of this advance directive so that

you can have it for your records. We will also send a copy to your appointed agent, your

[relationship, name]. If at any time you change your mind about the choices you’ve

made, please contact your physician or you can speak with me, Elizabeth Cooney, the

project manager for this study. My telephone number, mailing address, and email

address will be on a letter that we’ll send you with your advance directive.

In about 6-8 weeks you’ll be receiving a call from Kristen Caldarella, a research

coordinator onour team, about this study. It will be another 5 – 10 minute phone

conversation to discuss your satisfaction with your participation in this study and your

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experience completing an advance directive. Once you speak to this team member,

your participation in this study will be complete.

If you later have questions or concerns regarding your participation in this research

study or about your rights as a research subject, you should call me at 215-573-9461. If

a member of the research team cannot be reached or you want to talk to someone other

than those working on the study, you may contact the Office of Regulatory Affairs with

any question, concerns or complaints at the University of Pennsylvania by calling

(215) 898-2614.

Thank you for your time today.

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COMFORT DEFAULT DEBRIEFING SCRIPT


DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.

















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In others, some of the choices were pre-selected. For example, in your advance

directive, the standard goal of care, which was pre-selected for you, was that you want

treatment focused on the relief of pain and suffering, even if that means you may not

live as long.

Some other people in this study received advance directives in which the standard goal

of care was that they want their healthcare providers to treat them by helping them to

live as long as possible, even if that means possibly more pain and suffering.

It’s very important to realize that no matter which version of the advance directive

people in this study received, everyone was free to choose the options that best fit their

values and preferences. Our study was designed to see if the way in which this

information was presented influences peoples’ selections.






preferences.

READ EACH OF SELECTED CHOICES IN FULL; IF PATIENT WISHES TO MAKE

ANY CHANGES: :








say]:








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In about 6-8 weeks you’ll be receiving a call from Kirsten Caldarella, a research

coordinator on our team, about this study. It will be another 5 – 10 minute phone









(215) 898-2614.


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LIFE EXTENSION DEFAULT DEBRIEFING SCRIPT


DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.

















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your healthcare providers to treat you by helping you to live as long as possible, even if

that means possibly more pain and suffering.


of care was treatment focused on the relief of pain and suffering, even if that meant they

may not live as long.










preferences.


ANY CHANGES:








say]:




[relationship,name]. If at any time you change your mind about the choices you’ve




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study or about your rights as a research subject, you should call me at 215-573-9461 If




(215) 898-2614.


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Journal: BMJ Open

Manuscript ID bmjopen-2015-010628.R1


Date Submitted by the Author: 05-Feb-2016




Palliative care




BMJ Open on A


http://bmjopen.bm

j.com/

BM


jopen-2015-010628 on 6 June 2016. Dow

nloaded from



1





















Philadelphia, PA





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2







Phone: 215-898-1462 Fax: 215-573-5325

[email protected]

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3

Abstract





that comfort-oriented care is provided as the default, rather than requiring patients to actively





















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4

Background













to participate in making these decisions18 and must have decisions made for them. ADs, which

include living wills and durable power of attorney designation, can help improve the quality of

advance care planning. Observational studies show that elderly patients who complete ADs are

more likely to die outside of a hospital, receive less costly care, and receive care consistent with

their preferences.18-21 However, ADs have known shortcomings,22-26 and finding a scalable

solution for a diverse patient population is challenging.

The use of default options has been shown to have large effects in a variety of areas, including

the use of opt-out vs. opt-in framing to increase organ donation and vaccination rates.27-32

Defaults are considered a powerful approach to help overcome a variety of problems in







larger, more diverse population of seriously ill patients.

Methods/Design

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5




Study Hypothesis










deaths.

Study setting
















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6





make the required healthcare decisions on their AD forms. Cognitive impairment is primarily

determined by physicians prior to research staff approaching the patient. Because our

intervention is embedded in the actual AD forms, we are excluding patients who are unable to

read English.
















healthcare decision-making. The consent forms (Appendix A) contain HIPAA statements of

authorization of release of medical records and include clear explanations that they are being

asked to complete an AD, participate in several follow-up interviews, and permit the research

team to follow their health outcomes. Patients are also told that different types of ADs are

assigned by chance, but that patients in all groups may select or decline any intervention or

treatment goal, and may revise their choices at any time. All patients are encouraged to involve

their family members and/or physicians in completing their ADs. All consenting patients are

provided with: (1) their assigned AD; (2) an informational brochure about ADs; (3) contact

information for study personnel; (4) a copy of the Decisional Conflict Scale (DCS) and (5)

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7

instructions for returning the completed AD and DCS and a stamped envelope addressed to

study staff. Demographics, including age, race, ethnicity, sex, religion, income, education,

marital status, and health insurance type are collected at the time of consent, as well as data

about previous experience with life sustaining therapies and critical care medicine. If a

participant does not return an AD within ten days, study personnel call every ten days for one

month, and again at 2 months and at 3 months, to encourage AD return or meet with the

participant in person at his or her next clinic appointment.





and (3) complete the 9-item Healthcare System Distrust Scale.40 Patients who wish to

participate, but lack a surrogate or do not want their surrogate to be contacted, are still eligible.

Surrogates are not approached for consent if a patient has not completed an AD.




race, ethnicity, and gender). This information is essential to complete the proposed Complier

Average Treatment Effect (or instrumental variable) analysis. No further contact with these

patients is made.









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8











Intervention


endorsed AD published by the Allegheny County Medical Society (Appendix B).42 Patients are



















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9

wish to specify. The order of responses (comfort care vs. life extension) is randomized for those

patients assigned to the standard AD arm to mitigate any potential ordering effects. Patients

randomized to the comfort care or life extension arms will see the life extension or comfort care

default options first, respectively.

Debriefing














(Appendix C) that carefully explains the nature of the intervention, including the use of different













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10






















sustaining therapies (CPR, mechanical ventilation, dialysis, feeding tube) and whether those

interventions are actually received. Data on hospice utilization and costs are collected via data

use agreements with organizations that provide care for 80% of patients at the University of

Pennsylvania Health System and the University of Pittsburgh Medical Center.




satisfaction and end-of-life care question. Quality of life is measured using the McGill Quality of

Life,48,49 which can be completed by family members on behalf of patients who are unable to

complete it themselves. Additionally, we are assessing decision conflict, using the validated

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11

Decision Conflict Scale,50 to assess patients’ certainty in making healthcare decisions. This

measure is collected immediately following AD completion and is not assessed during follow-up.


Quality of Death measures.8,9,51 The Impact of Events Scale52 is used to assess the risk of post-

traumatic stress disorder in surrogates of deceased patients. Finally, healthcare system distrust

is measured among the surrogates using the Health System Distrust Scale.40










Analytic plan

First, we will use intention-to-treat (ITT) analyses to assess the impact of group assignment on

all outcomes. Second, we will use Complier Average Treatment Effect (CATE) analyses to

assess the influence of the choices patients make in ADs on long-term patient- and family-

reported outcomes, and to estimate the impact of completing an advance directive at all,

regardless of the choices made. These methods are made feasible because, based on our pilot

trial, the intervention (default options) is expected to alter choices without altering the odds of

completing an AD at all. To show how we will accomplish this, consider the three analyses

described in Figure 2. First, we will conduct ITT analyses using linear regression, adjusting for

center,53 to compare the effects of assignment to complete ADs with different default options on

the outcomes of interest. This approach uses data from all randomized participants, and

provides the truest test of the overall effectiveness of the intervention (Figure 2, diagram A).

However, the ITT analysis does not provide a specific test of the effects of choices made in

ADs, because these effects will be diluted by the fact that many randomized patients will not

complete their assigned ADs. Furthermore, among patients who do return completed ADs, not

all will stick with their assigned default choice. To surmount this problem, researchers

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12

sometimes conduct per-protocol analyses, which in this case would compare patients who

complete ADs and stay with their assigned defaults in one arm with those who do the same in

the other arms (Figure 2, diagram B). However, per-protocol analyses are likely to be biased

by selection effects: patients who complete ADs and choose comfort care are likely different

from those who do not complete ADs or make other choices in completed ADs, and these

underlying differences may influence outcomes such as quality of life.54


























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13



YiA


YiS


YiC




















Sample size







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14















Ethics



also guided by a Data Safety and Monitoring Board (DSMB) consisting of individuals with

expertise in human subjects research, vulnerable populations, bioethics, clinical trials, decision

making, palliative care, and biostatistics. The DSMB reviewed and approved the research

protocol and plans for data and safety prior to the start of recruitment. Additionally, Board

members are evaluating the progress of the trial and making recommendations to ensure that

any and all issues are addressed, including decisions about the termination of individual study

arms or the study itself.








informed consent process, state-of-the-art data security, and the DSMB. Finally, an External

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15

Advisory Board comprising noted scholars in health law, palliative care, and research ethics

meets as needed to advise the investigators on any unforeseen challenges related to the ethical

conduct of the trial.

Dissemination





implement.

Discussion











Trial Status




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16

Acknowledgements

Contributorship statement: NBG, EC, DSS, ABT, RMA, DBW, DCA, GL, KGV, CLB, and SDH

contributed to the study design and protocol. NBG, EC, and SDH drafted the protocol

manuscript and DSS, ABT, RMA, DBW, DCA, GL, KGV, and CLB provided critical feedback and

revisions. All authors have provided final approval of the study protocol.


Funding: This work was supported by the Gordon & Betty Moore Foundation. The funding

source has no role in the study design, data collection, analytic plans, or manuscript

preparation.

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References

1. Fields MJ, Cassel CK. Approaching Death, Improving Care at the End of Life. Washington, D.C.: National Academy Press; 1997. 2. Fried TR, Bradley EH, Towle VR, Allore H. Understanding the treatment preferences of seriously ill patients. The New England journal of medicine 2002;346:1061-6. 3. Facts on dying. 2001. at https://nts122.chcr.brown.edu/dying/2001DATA.HTM.) 4. Angus DC, Barnato AE, Linde-Zwirble WT, et al. Use of intensive care at the end of life in the United States: an epidemiologic study. Critical care medicine 2004;32:638-43. 5. Kwok AC, Semel ME, Lipsitz SR, et al. The intensity and variation of surgical care at the end of life: a retrospective cohort study. Lancet 2011;378:1408-13. 6. Smith AK, McCarthy E, Weber E, et al. Half of older Americans seen in emergency department in last month of life; most admitted to hospital, and many die there. Health Aff (Millwood) 2012;31:1277-85. 7. Riley GF, Lubitz JD. Long-term trends in Medicare payments in the last year of life. Health services research 2010;45:565-76. 8. Wright AA, Keating NL, Balboni TA, Matulonis UA, Block SD, Prigerson HG. Place of death: correlations with quality of life of patients with cancer and predictors of bereaved caregivers' mental health. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:4457-64. 9. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. Jama 2008;300:1665-73. 10. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. The New England journal of medicine 2010;363:733-42. 11. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. Jama 2009;302:741-9. 12. Connor SR, Pyenson B, Fitch K, Spence C, Iwasaki K. Comparing hospice and nonhospice patient survival among patients who die within a three-year window. Journal of pain and symptom management 2007;33:238-46. 13. Bakitas MA, Tosteson TD, Li Z, et al. Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015;33:1438-45. 14. Azoulay E, Pochard F, Kentish-Barnes N, et al. Risk of post-traumatic stress symptoms in family members of intensive care unit patients. American journal of respiratory and critical care medicine 2005;171:987-94. 15. Detering KM, Hancock AD, Reade MC, Silvester W. The impact of advance care planning on end of life care in elderly patients: randomised controlled trial. BMJ 2010;340:c1345. 16. Wendler D, Rid A. Systematic review: the effect on surrogates of making treatment decisions for others. Annals of internal medicine 2011;154:336-46. 17. Siegel MD, Hayes E, Vanderwerker LC, Loseth DB, Prigerson HG. Psychiatric illness in the next of kin of patients who die in the intensive care unit. Critical care medicine 2008;36:1722-8. 18. Silveira MJ, Kim SY, Langa KM. Advance directives and outcomes of surrogate decision making before death. The New England journal of medicine 2010;362:1211-8. 19. Degenholtz HB, Rhee Y, Arnold RM. Brief communication: the relationship between having a living will and dying in place. Annals of internal medicine 2004;141:113-7.

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20. Nicholas LH, Langa KM, Iwashyna TJ, Weir DR. Regional variation in the association between advance directives and end-of-life Medicare expenditures. Jama 2011;306:1447-53. 21. Teno JM, Gruneir A, Schwartz Z, Nanda A, Wetle T. Association between advance directives and quality of end-of-life care: a national study. Journal of the American Geriatrics Society 2007;55:189-94. 22. Fagerlin A, Schneider CE. Enough. The failure of the living will. The Hastings Center report 2004;34:30-42. 23. Kirschner KL. When written advance directives are not enough. Clinics in geriatric medicine 2005;21:193-209, x. 24. Perkins HS. Controlling death: the false promise of advance directives. Annals of internal medicine 2007;147:51-7. 25. Tonelli MR. Pulling the plug on living wills. A critical analysis of advance directives. Chest 1996;110:816-22. 26. Tulsky JA. Beyond advance directives: importance of communication skills at the end of life. Jama 2005;294:359-65. 27. Chapman GB, Li M, Colby H, Yoon H. Opting in vs opting out of influenza vaccination. Jama 2010;304:43-4. 28. Choi JJ, Laibson D, Madrian BC, Metrick A. Defined contribution pensions: Plan rules, participant decisions, and the path of least resistance. In: Poterba JM, ed. Tax Policy and the Economy. Cambridge, MA: MIT Press; 2002:67-113. 29. Horvat LD, Cuerden MS, Kim SJ, Koval JJ, Young A, Garg AX. Informing the debate: rates of kidney transplantation in nations with presumed consent. Annals of internal medicine 2010;153:641-9. 30. Johnson EJ, Goldstein D. Medicine. Do defaults save lives? Science 2003;302:1338-9. 31. Johnson EJ, Hershey JC, Meszaros J, Kunreuther H. Framing, probability distortions, and insurance decisions. J Risk Uncertain 1993;7:35-51. 32. Madrian BC, Shea DF. The power of suggestion: Intertia in 401(k) participation and savings behavior. Quarterly Journal of Economics 2001;116:1149-87. 33. Halpern SD, Ubel PA, Asch DA. Harnessing the power of default options to improve health care. The New England journal of medicine 2007;357:1340-4. 34. Loewenstein G, Brennan T, Volpp KG. Asymmetric paternalism to improve health behaviors. Jama 2007;298:2415-7. 35. Quill CM, Halpern S. Deciphering the appropriateness of defaults: the need for domain-specific evidence. Journal of medical ethics 2012;38:721-2. 36. Hart J, Halpern SD. Default options in the ICU: widely used but insufficiently understood. Current opinion in critical care 2014;20:662-7. 37. Halpern SD, Loewenstein G, Volpp KG, et al. Default options in advance directives influence how patients set goals for end-of-life care. Health Aff (Millwood) 2013;32:408-17. 38. Carstensen LL. The influence of a sense of time on human development. Science 2006;312:1913-5. 39. Carstensen LL, Isaacowitz DM, Charles ST. Taking time seriously. A theory of socioemotional selectivity. The American psychologist 1999;54:165-81. 40. Shea JA, Micco E, Dean LT, McMurphy S, Schwartz JS, Armstrong K. Development of a revised Health Care System Distrust scale. Journal of general internal medicine 2008;23:727-32. 41. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of biomedical informatics 2009;42:377-81. 42. Living Will and Healthcare Power of Attorney. 2007. at www.acms.org/lw/index.html.)

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43. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. Jama 1995;274:1591-8. 44. Barnato AE, Farrell MH, Chang CC, Lave JR, Roberts MS, Angus DC. Development and validation of hospital "end-of-life" treatment intensity measures. Medical care 2009;47:1098-105. 45. Miller FG, Gluck JP, Jr., Wendler D. Debriefing and accountability in deceptive research. Kennedy Institute of Ethics journal 2008;18:235-51. 46. Heyland DK, Cook DJ, Rocker GM, et al. The development and validation of a novel questionnaire to measure patient and family satisfaction with end-of-life care: the Canadian Health Care Evaluation Project (CANHELP) Questionnaire. Palliative medicine 2010;24:682-95. 47. Heyland DK, Frank C, Tranmer J, et al. Satisfaction with end-of-life care: a longitudinal study of patients and their family caregivers in the last months of life. Journal of palliative care 2009;25:245-56. 48. Cohen SR, Mount BM, Bruera E, Provost M, Rowe J, Tong K. Validity of the McGill Quality of Life Questionnaire in the palliative care setting: a multi-centre Canadian study demonstrating the importance of the existential domain. Palliative medicine 1997;11:3-20. 49. Cohen SR, Mount BM, Strobel MG, Bui F. The McGill Quality of Life Questionnaire: a measure of quality of life appropriate for people with advanced disease. A preliminary study of validity and acceptability. Palliative medicine 1995;9:207-19. 50. O'Connor AM. Validation of a decisional conflict scale. Medical decision making : an international journal of the Society for Medical Decision Making 1995;15:25-30. 51. Zhang B, Nilsson ME, Prigerson HG. Factors important to patients' quality of life at the end of life. Archives of internal medicine 2012;172:1133-42. 52. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. Psychosomatic medicine 1979;41:209-18. 53. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Statistics in medicine 2012;31:328-40. 54. Sommer A, Zeger SL. On estimating efficacy from clinical trials. Statistics in medicine 1991;10:45-52. 55. Newhouse JP, McClellan M. Econometrics in outcomes research: the use of instrumental variables. Annual review of public health 1998;19:17-34. 56. Angrist JD, Imbens GW, Rubin DW. Identification of causal effects using instrumental variables. Journal of the American Statistical Association 1996;91:444-55. 57. Cheng J, Small D. Bounds on causal effects in three-arm trials with noncompliance. Journal of the Royal Statistical Society 2006;68:815-36. 58. Cheng J, Small D, Tan Z, Ten Have TR. Efficient nonparametric estimation of causal effcts in randomized trials with noncompliance. Biometrika 2009;96:19-36. 59. Sussman JB, Hayward RA. An IV for the RCT: using instrumental variables to adjust for treatment contamination in randomised controlled trials. BMJ 2010;340:c2073. 60. Baiocchi M, Cheng J, Small DS. Instrumental variable methods for causal inference. Statistics in medicine 2014;33:2297-340. 61. Halpern SD, French B, Small DS, et al. Randomized trial of four financial-incentive programs for smoking cessation. The New England journal of medicine 2015;372:2108-17. 62. Frangakis CE, Rubin DB. Principal stratification in causal inference. Biometrics 2002;58:21-9. 63. Sudore RL, Fried TR. Redefining the "planning" in advance care planning: preparing for end-of-life decision making. Annals of internal medicine 2010;153:256-61. 64. Localio AR, Berlin JA, Ten Have TR, Kimmel SE. Adjustments for center in multicenter studies: an overview. Annals of internal medicine 2001;135:112-23. 65. Hosmer DW, Lemeshow S, Sturdivant RX. Applied Logistic Regression. 2nd ed: John Wiley & Sons; 2000.

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66. U.S. Department of Commerce Bureau of Economic Analysis. (Accessed April 16, 2015, at www.bea.gov/national/.)

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21


Inclusion Exclusion











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Table 2. Outcomes

Outcome Measurement





Choices to receive 4 potentially life-sustaining interventions (CPR, mechanical ventilation, dialysis, feeding tube)


Choices regarding post-hospitalization care (please see Appendix B for specific choices)

Concordance of these choices with the care actually received





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23


directives



assignment


default AD




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Study scheme

254x190mm (300 x 300 DPI)

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Appendix B – Advance Directive Forms

STANDARD FORM


I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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OR



OR





____________________________________________________________________________________

____________________________________________________________________________________

Specific Procedures






OR



OR




interests.

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OR



OR








OR




OR






hydration.

OR



OR



hydration.


____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

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OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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OR





____________________________________________________________________________________

____________________________________________________________________________________










OR




interests.

X

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OR













OR






hydration.





OR



hydration.

X

X

X

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____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________











OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


X

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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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OR





____________________________________________________________________________________

____________________________________________________________________________________










OR




interests.

X

X

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OR













OR










hydration.

OR



hydration.

X

X

X

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____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________











OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


X

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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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APPENDIX C – DEBRIEFING SCRIPTS



DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.
















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selections.






preferences.



SECTION BELOW BEGINNING: “OK. Then, if agreeable to you, we will make5”;









say]:











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(215) 898-2614.


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DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.

















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live as long.













preferences.


ANY CHANGES: :








say]:








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(215) 898-2614.


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DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.

















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preferences.


ANY CHANGES:








say]:








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(215) 898-2614.


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1

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym _1___________

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _3___________

2b All items from the World Health Organization Trial Registration Data Set _n/a _________

Protocol version 3 Date and version identifier _n/a_________

Funding 4 Sources and types of financial, material, and other support _16__________

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors _1___________

5b Name and contact information for the trial sponsor _16__________

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

_16__________

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

_n/a_________

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

_4___________

6b Explanation for choice of comparators _4___________

Objectives 7 Specific objectives or hypotheses _5___________

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

_5___________

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

_5___________

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

_5___________

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

_8___________

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

_9___________

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

_n/a_________

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _n/a_________

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

_10__________

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

_7, Figure 1___

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3

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

_13__________

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _6-8_________

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

_8___________

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

_8___________

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

_8___________

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

_7-8 _________

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

_9-10________

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

_10-11________

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

_6-8, 10-11____

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4

Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

_11__________

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

_11-13_______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _11-13_______

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

_11-13_______

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

_14-15_______

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

_14-15_______

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

_14-15________

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

_14-15________

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _14-15_______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

_14-15_______

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5

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

_6-8_________

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

_n/a_________

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

_11__________

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _16__________

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

_11__________

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

_n/a_________

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

_15__________

31b Authorship eligibility guidelines and any intended use of professional writers _n/a_________

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _n/a_________

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates _Appendix A, B, C

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

_n/a_________

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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Journal: BMJ Open

Manuscript ID bmjopen-2015-010628.R2


Date Submitted by the Author: 29-Mar-2016




Palliative care




BMJ Open on A


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Philadelphia, PA





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Phone: 215-898-1462 Fax: 215-573-5325

[email protected]

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Abstract





that comfort-oriented care is provided as the default, rather than requiring patients to actively





















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Background













to participate in making these decisions18 and must have decisions made for them. ADs, which

include living wills and durable power of attorney designation, can help improve the quality of

advance care planning. Observational studies show that elderly patients who complete ADs are

more likely to die outside of a hospital, receive less costly care, and receive care consistent with

their preferences.18-21 However, ADs have known shortcomings,22-26 and finding a scalable

solution for a diverse patient population is challenging.

The use of default options has been shown to have large effects in a variety of areas, including

the use of opt-out vs. opt-in framing to increase organ donation and vaccination rates.27-32

Defaults are considered a powerful approach to help overcome a variety of problems in







larger, more diverse population of seriously ill patients. The current association of aggressive

treatments at the end of life with poor patient- and surrogate-reported outcomes suggests that

aligning the care patients desire with the care they receive, such that aggressive care is

reduced at the end of life, will improve these outcomes.

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Methods/Design




Study Hypothesis










deaths.

Study setting













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make the required healthcare decisions on their AD forms. Cognitive impairment is primarily

determined by physicians prior to research staff approaching the patient. Because our

intervention is embedded in the actual AD forms, we are excluding patients who are unable to

read English.
















healthcare decision-making. The consent forms (Appendix A) contain HIPAA statements of

authorization of release of medical records and include clear explanations that they are being

asked to complete an AD, participate in several follow-up interviews, and permit the research

team to follow their health outcomes. Patients are also told that different types of ADs are

assigned by chance, but that patients in all groups may select or decline any intervention or

treatment goal, and may revise their choices at any time. All patients are encouraged to involve

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their family members and/or physicians in completing their ADs. All consenting patients are

provided with: (1) their assigned AD; (2) an informational brochure about ADs; (3) contact

information for study personnel; (4) a copy of the Decisional Conflict Scale (DCS) and (5)

instructions for returning the completed AD and DCS and a stamped envelope addressed to

study staff. Demographics, including age, race, ethnicity, sex, religion, income, education,

marital status, and health insurance type are collected at the time of consent, as well as data

about previous experience with life sustaining therapies and critical care medicine. If a

participant does not return an AD within ten days, study personnel call every ten days for one

month, and again at 2 months and at 3 months, to encourage AD return or meet with the

participant in person at his or her next clinic appointment. This specific contact frequency was

guided by desire to limit missing data for important patient-centered outcomes.





and (3) complete the 9-item Healthcare System Distrust Scale.40 Patients who wish to

participate, but lack a surrogate or do not want their surrogate to be contacted, are still eligible.

Surrogates are not approached for consent if a patient has not completed an AD.




race, ethnicity, and gender). This information is essential to complete the proposed Complier

Average Treatment Effect (or instrumental variable) analysis. No further contact with these

patients is made.







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Intervention


endorsed AD published by the Allegheny County Medical Society (Appendix B).42 Patients are
















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wish to specify. The order of responses (comfort care vs. life extension) is randomized for those

patients assigned to the standard AD arm to mitigate any potential ordering effects. Patients

randomized to the comfort care or life extension arms will see the life extension or comfort care

default options first, respectively.

Patients in all groups are provided with an informational brochure about advance directives that

utilizes simple language and research coordinators are trained to answer patients’ questions

about advance care planning and offer assistance to patients if necessary. Patients may also be

referred to social work resources for additional assistance if desired.

Debriefing














(Appendix C) that carefully explains the nature of the intervention, including the use of different






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Debriefing primarily occurs over the phone, although a few patients who are unavailable via

phone are debriefed in person. While we recognize that this procedure may not meet the needs

of all patients, it is the best option in a RCT such as this and provides us with the ability to

debrief all patients who complete and return an AD in a timely manner.










The use of hospital-free days as our primary outcome reflects the desire to choose a measure

that is patient-centered, readily measured and analyzed, and reflects a patient’s holistic state

rather than a specific symptom. HFDs has many attractive properties: it is continuous,

enhancing power; it can be analyzed reliably and indeed flexibly, to account for different values

patients may place on avoiding hospitalization; and in nearly all cases, it is unidirectional in the

sense that nearly all patients prefer longer lives to shorter ones, and to have more of those days

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spent outside a hospital than within. This does not automatically assume that all days spent in a

hospital are without value. Indeed, the relief of acute symptoms via a short hospital stay may

have great value to a patient, but such days will be a small percentage of total cohort days. And

while these beneficial days may not be weighed differently in our model, they also would not

reduce the number of remaining days a patient would have outside the hospital.








sustaining therapies (CPR, mechanical ventilation, dialysis, feeding tube) and whether those

interventions are actually received. Data on hospice utilization and costs are collected via data

use agreements with organizations that provide care for 80% of patients at the University of

Pennsylvania Health System and the University of Pittsburgh Medical Center.




satisfaction and end-of-life care question. This instrument asks patients “how satisfied are you

with your advance care planning overall – that is, the plans you have in place regarding your

end-of-life care.” Responses range from 1-5, with 1 indicating completely satisfied and 5

indicating not at all satisfied. Quality of life is measured using the McGill Quality of Life

(MQoL),48,49 which can be completed by family members on behalf of patients who are unable to

complete it themselves. The MQoL questionnaire has 16 questions querying both mental and

physical symptoms experienced by the patient during the past two days, and asks patients to

rate the severity of each. For example, the MQoL will prompt a patient with “over the last two

days, one troublesome symptom has beenM” and the patient will self-identify a symptom. The

patient will then be asked to rate on a 0-10 scale how problematic that symptom has been, with

0 indicating no problem and 10 indicating a tremendous problem. Patients will also be asked

about their emotional well-being (e.g., “over the past two days, I have been depressed”,) as well

as support (e.g., “over the past two days, I have felt supported”), with responses ranging from

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not at all (0) to extremely or completely (10). Additionally, we are assessing decision conflict,

using the validated Decision Conflict Scale (DCS),50 to assess patients’ certainty in making

healthcare decisions. The DCS provides patients with 16 statements (“I know the benefits of

each option”, “I am clear about which risks matter most to me”) and assesses agreement or

disagreement with each statement on a 5-point scale ranging from strongly agree to strongly

disagree. This measure is collected immediately following AD completion and is not assessed

during follow-up.


Quality of Death measures.8,9,51 This three-question measure asks surrogates to rate, on a scale

of 0-10, the level of psychological distress or physical distress in the patient’s last week of life,

as well as the overall quality of the patient’s death or last week of life. The Impact of Events

Scale52 is used to assess the risk of post-traumatic stress disorder in surrogates of deceased

patients. The surrogate is presented with 15 statements commonly made after stressful life

events (e.g. “I tried to remove it from memory” and “I had dreams about it”) and asked to

respond with the frequency of how true the comments were for them during the last seven days.

Response options include not at all, rarely, sometimes, and often. Finally, healthcare system

distrust is measured among the surrogates using the Health System Distrust Scale.40 This scale

asks surrogates to rate statements about the healthcare system on a 5-point Likert scale

ranging from strongly disagree to strongly agree. Statements include items such as “the health

care system covers up its mistakes” and “the health care system gives excellent medical care.”










Analytic plan

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First, we will use intention-to-treat (ITT) analyses to assess the impact of group assignment on

all outcomes. Second, we will use Complier Average Treatment Effect (CATE) analyses to

assess the influence of the choices patients make in ADs on long-term patient- and family-

reported outcomes, and to estimate the impact of completing an advance directive at all,

regardless of the choices made. These methods are made feasible because, based on our pilot

trial, the intervention (default options) is expected to alter choices without altering the odds of

completing an AD at all. To show how we will accomplish this, consider the three analyses

described in Figure 2. First, we will conduct ITT analyses using linear regression, adjusting for

center,53 to compare the effects of assignment to complete ADs with different default options on

the outcomes of interest. This approach uses data from all randomized participants, and

provides the truest test of the overall effectiveness of the intervention (Figure 2, diagram A).

However, the ITT analysis does not provide a specific test of the effects of choices made in

ADs, because these effects will be diluted by the fact that many randomized patients will not

complete their assigned ADs. Furthermore, among patients who do return completed ADs, not

all will stick with their assigned default choice. To surmount this problem, researchers

sometimes conduct per-protocol analyses, which in this case would compare patients who

complete ADs and stay with their assigned defaults in one arm with those who do the same in

the other arms (Figure 2, diagram B). However, per-protocol analyses are likely to be biased

by selection effects: patients who complete ADs and choose comfort care are likely different

from those who do not complete ADs or make other choices in completed ADs, and these

underlying differences may influence outcomes such as quality of life.54













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YiA


YiS


YiC















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Sample size





















Ethics



guided by both a Data Safety and Monitoring Board (DSMB) and an External Ethics Advisory

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Board. The DSMB consists of three individuals with expertise in human subjects research,

vulnerable populations, bioethics, clinical trials, decision making, palliative care, and

biostatistics. Specifically, the DSMB includes the Chair of Vulnerable Subjects Research at the

NIH, the Chair of Palliative Care at Massachusetts General Hospital, and a statistician at

Stanford University. The DSMB reviewed and approved the research protocol and plans for data

and safety prior to the start of recruitment. Additionally, DSMB members are evaluating the

progress of the trial and making recommendations to ensure that any and all issues are

addressed, including decisions about the termination of individual study arms or the study itself.

The External Advisory Board is comprised of four noted scholars in health law, palliative care,

and research ethics; the Board meets as needed to advise the investigators on any unforeseen

challenges related to the ethical conduct of the trial.








informed consent process, state-of-the-art data security, a DSMB, and an External Ethics

Advisory Board consisting of some of the leading experts in the field.

Dissemination





implement.

Discussion





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Trial Status




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Acknowledgements

Contributorship statement: NBG, EC, DSS, ABT, RMA, DBW, DCA, GL, KGV, CLB, and SDH

contributed to the study design and protocol. NBG, EC, and SDH drafted the protocol

manuscript and DSS, ABT, RMA, DBW, DCA, GL, KGV, and CLB provided critical feedback and

revisions. All authors have provided final approval of the study protocol.


Funding: This work was supported by the Gordon & Betty Moore Foundation. The funding

source has no role in the study design, data collection, analytic plans, or manuscript

preparation.

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References

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43. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. Jama 1995;274:1591-8. 44. Barnato AE, Farrell MH, Chang CC, Lave JR, Roberts MS, Angus DC. Development and validation of hospital "end-of-life" treatment intensity measures. Medical care 2009;47:1098-105. 45. Miller FG, Gluck JP, Jr., Wendler D. Debriefing and accountability in deceptive research. Kennedy Institute of Ethics journal 2008;18:235-51. 46. Heyland DK, Cook DJ, Rocker GM, et al. The development and validation of a novel questionnaire to measure patient and family satisfaction with end-of-life care: the Canadian Health Care Evaluation Project (CANHELP) Questionnaire. Palliative medicine 2010;24:682-95. 47. Heyland DK, Frank C, Tranmer J, et al. Satisfaction with end-of-life care: a longitudinal study of patients and their family caregivers in the last months of life. Journal of palliative care 2009;25:245-56. 48. Cohen SR, Mount BM, Bruera E, Provost M, Rowe J, Tong K. Validity of the McGill Quality of Life Questionnaire in the palliative care setting: a multi-centre Canadian study demonstrating the importance of the existential domain. Palliative medicine 1997;11:3-20. 49. Cohen SR, Mount BM, Strobel MG, Bui F. The McGill Quality of Life Questionnaire: a measure of quality of life appropriate for people with advanced disease. A preliminary study of validity and acceptability. Palliative medicine 1995;9:207-19. 50. O'Connor AM. Validation of a decisional conflict scale. Medical decision making : an international journal of the Society for Medical Decision Making 1995;15:25-30. 51. Zhang B, Nilsson ME, Prigerson HG. Factors important to patients' quality of life at the end of life. Archives of internal medicine 2012;172:1133-42. 52. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. Psychosomatic medicine 1979;41:209-18. 53. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Statistics in medicine 2012;31:328-40. 54. Sommer A, Zeger SL. On estimating efficacy from clinical trials. Statistics in medicine 1991;10:45-52. 55. Newhouse JP, McClellan M. Econometrics in outcomes research: the use of instrumental variables. Annual review of public health 1998;19:17-34. 56. Angrist JD, Imbens GW, Rubin DW. Identification of causal effects using instrumental variables. Journal of the American Statistical Association 1996;91:444-55. 57. Cheng J, Small D. Bounds on causal effects in three-arm trials with noncompliance. Journal of the Royal Statistical Society 2006;68:815-36. 58. Cheng J, Small D, Tan Z, Ten Have TR. Efficient nonparametric estimation of causal effcts in randomized trials with noncompliance. Biometrika 2009;96:19-36. 59. Sussman JB, Hayward RA. An IV for the RCT: using instrumental variables to adjust for treatment contamination in randomised controlled trials. BMJ 2010;340:c2073. 60. Baiocchi M, Cheng J, Small DS. Instrumental variable methods for causal inference. Statistics in medicine 2014;33:2297-340. 61. Halpern SD, French B, Small DS, et al. Randomized trial of four financial-incentive programs for smoking cessation. The New England journal of medicine 2015;372:2108-17. 62. Frangakis CE, Rubin DB. Principal stratification in causal inference. Biometrics 2002;58:21-9. 63. Sudore RL, Fried TR. Redefining the "planning" in advance care planning: preparing for end-of-life decision making. Annals of internal medicine 2010;153:256-61. 64. Localio AR, Berlin JA, Ten Have TR, Kimmel SE. Adjustments for center in multicenter studies: an overview. Annals of internal medicine 2001;135:112-23. 65. Hosmer DW, Lemeshow S, Sturdivant RX. Applied Logistic Regression. 2nd ed: John Wiley & Sons; 2000.

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66. U.S. Department of Commerce Bureau of Economic Analysis. (Accessed April 16, 2015, at www.bea.gov/national/.)

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23


Inclusion Exclusion











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24

Table 2. Outcomes

Outcome Measurement





Choices to receive 4 potentially life-sustaining interventions (CPR, mechanical ventilation, dialysis, feeding tube)


Choices regarding post-hospitalization care (please see Appendix B for specific choices)

Concordance of these choices with the care actually received





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25


directives



assignment


default AD




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Study scheme

254x190mm (300 x 300 DPI)

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Appendix B – Advance Directive Forms

STANDARD FORM


I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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OR



OR





____________________________________________________________________________________

____________________________________________________________________________________

Specific Procedures






OR



OR




interests.

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OR



OR








OR




OR






hydration.

OR


cannot eat or drink. OR



hydration.


____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

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OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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OR





____________________________________________________________________________________

____________________________________________________________________________________










OR




interests.

X

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OR













OR






hydration.




cannot eat or drink. OR



hydration.

X

X

X

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____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________











OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


X

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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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I, _____________________________ of ___________________ County, (State),







Address: _____________________________________________________________________

_____________________________________________________________________


Email:




Email:




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OR





____________________________________________________________________________________

____________________________________________________________________________________










OR




interests.

X

X

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OR













OR










hydration.

OR



hydration.

X

X

X

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____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________

____________________________________________________________________________________











OR




interests.



agent.

OR



instructions.


overrriden:___________________________________________________________________________


X

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Legal Protection








SIGNED: ____________________________________________________






WITNESS: ___________________________________________

WITNESS: ___________________________________________

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APPENDIX C – DEBRIEFING SCRIPTS



DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.












their goals of care near the end of life and

their preferences for receiving specific treatments or interventions such as a


their appointed health care agent

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selections.






preferences.



SECTION BELOW BEGINNING: “OK. Then, if agreeable to you, we will make…”;









say]:











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(215) 898-2614.


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DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.

















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live as long.













preferences.


ANY CHANGES: :








say]:








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(215) 898-2614.


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DEBRIEFING FORM


Principal

Investigator:



215.573.9461


directive:





yourself.

















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preferences.


ANY CHANGES:








say]:








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(215) 898-2614.


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1

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym _1___________

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _3___________

2b All items from the World Health Organization Trial Registration Data Set _n/a _________

Protocol version 3 Date and version identifier _n/a_________

Funding 4 Sources and types of financial, material, and other support _16__________

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors _1___________

5b Name and contact information for the trial sponsor _16__________

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

_16__________

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

_n/a_________

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

_4___________

6b Explanation for choice of comparators _4___________

Objectives 7 Specific objectives or hypotheses _5___________

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

_5___________

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

_5___________

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

_5___________

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

_8___________

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

_9___________

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

_n/a_________

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _n/a_________

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

_10__________

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

_7, Figure 1___

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3

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

_13__________

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _6-8_________

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

_8___________

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

_8___________

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

_8___________

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

_7-8 _________

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

_9-10________

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

_10-11________

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

_6-8, 10-11____

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4

Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

_11__________

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

_11-13_______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _11-13_______

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

_11-13_______

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

_14-15_______

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

_14-15_______

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

_14-15________

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

_14-15________

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _14-15_______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

_14-15_______

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5

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

_6-8_________

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

_n/a_________

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

_11__________

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _16__________

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

_11__________

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

_n/a_________

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

_15__________

31b Authorship eligibility guidelines and any intended use of professional writers _n/a_________

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _n/a_________

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates _Appendix A, B, C

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

_n/a_________

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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