Does Outpatient Palliative Care Improve Patient-centered Outcomes in Parkinson's Disease?
Phase: NA
Conditions: Parkinson's Disease
Sponsor: University of Colorado, Denver

Does outpatient palliative care improve patient-centered outcomes in Parkinson's disease?
University of Colorado PI: Benzi Kluger, MD
COMIRB# 15-0814
Version date: 29Mar2017
SPECIFIC AIMS
Parkinson’s disease (PD) is the second most common neurodegenerative illness affecting 1-2% of adults over 
age 65.1 This incurable and relentlessly progressive disease affects approximately 1.5 million Americans and is 
the 14th leading cause of death in the United States.2 PD is traditionally described as a movement disorder with 
characteristic motor symptoms such as tremor, rigidity, bradykinesia (slowness) and postural instability. 
However, more recent research demonstrates the extremely high prevalence and impact of nonmotor 
symptoms such as pain, depression, fatigue and dementia.3 Both motor and nonmotor symptoms impact 
mortality, patient quality of life (QOL), disability, nursing home placement and caregiver distress with most 
studies suggesting that nonmotor symptoms have a greater impact than motor symptoms in these domains.4, 5 
Regarding PD care models, evidence suggests that care including a neurologist results in lower mortality, hip 
fractures and nursing home placement than care solely from a primary care physician (PCP).6 Unfortunately, 
there is also significant evidence that many of the needs most important to PD patients and their caregivers 
(e.g. depression, advance care planning) are poorly addressed under current models of care.7, 8  We also plan 
to include the closely related neurodegenerative conditions of multiple systems atrophy (MSA), corticobasal 
degeneration (CBD), progressive supranuclear palsy (PSP) and Lewy Body Dementia (LBD). These disorders 
are collectively referred to as Parkinson-plus syndromes or atypical parkinsonian disorders (APD) and are 
closely related to PD in terms of both clinical manifestations and pathology.9
Palliative care is an approach to caring for individuals with life-threatening illnesses that addresses potential 
causes of suffering including physical symptoms such as pain, psychiatric symptoms such as depression, 
psychosocial issues and spiritual needs. Palliative care approaches have been successfully applied to improve 
patient-centered outcomes in cancer as well as several chronic progressive illnesses including heart failure 
and pulmonary disease.10, 11 To date there have been minimal attempts to apply these principles to PD 
although preliminary evidence suggests that PD patients have significant unmet needs under current models of 
care which may be amenable through a palliative care model.12 Notably, there is a small but growing cadre of 
centers now providing outpatient interdisciplinary palliative care for PD patients and caregivers with some 
evidence of effectiveness. This proposal will provide critical information to forward this field including data on 
the comparative effectiveness of outpatient palliative care for PD versus current standards of care; effects of 
this intervention on cost and service utilization; and the characteristics of patients most likely to benefit from 
such an approach and the specific services most needed by PD patients and their caregivers.
Our long-term goal is to improve outcomes for persons living with PD and their family caregivers. We 
hypothesize that outpatient interdisciplinary palliative care will improve patient-centered outcomes for PD 
patients at high-risk for poor outcomes. By targeting these at-risk individuals with a focused intervention we 
intend to provide a care model that efficiently deploys resources to those who need it most,  
Aim 1: Determine whether interdisciplinary outpatient palliative care for PD and APD improves patient 
quality of life (QOL) and caregiver burden as compared to usual care including a neurologist. We will 
randomize 300 PD and APD patients from 3 sites who are at high risk for poor outcomes in a 1:1 ratio to either: 
a) Usual care or b) Usual care augmented by an outpatient interdisciplinary palliative care team. Data 
regarding patient symptoms, QOL and caregiver burden will be measured at baseline, 3, 6, 9 and 12 months. 
Our primary outcomes will be differences between groups in patient QOL and caregiver burden at 6 months. 
We will also examine patient symptom burden, spiritual wellbeing and mood as planned secondary outcomes. 
We predict that patient QOL and caregiver burden will be significantly improved in the palliative care group 
versus usual care at 6 months and that this difference will persist and widen by 12 months.
Aim 2: Describe the effects of an interdisciplinary outpatient palliative care intervention on patient and 
caregiver costs and service utilization. Data regarding health-related costs, including informal caregiver 
time, and the use of health and social services for the three months prior to each study visit will be assessed 
for all participants from Aim 1 using a standard schedule. Our primary outcome will be the difference between 
groups in total patients and caregiver costs from month 0 to month 6 of the study. Secondary analyses will 
COMIRB
APPROVED
07-Apr-2017

examine changes in healthcare utilization and cost from a systems perspective. We predict patient/caregiver 
costs will be lower for the palliative care group versus usual care at 6 months and that service utilization will 
shift towards home services and away from acute care such as emergency room visits and hospitalizations.
Aim 3: Identify opportunities to optimize palliative care for this population by: a) describing patient and 
caregiver characteristics associated with intervention benefits; and b) through direct patient and 
caregiver interviews. For Aim 3a, interactions in linear regression models using data from Aim 1 will be used 
to identify patient/caregiver features that modify treatment effects. For Aim 3b, we will augment quantitative 
data through qualitative interviews of a subset of study participants. Standard qualitative and mixed methods 
techniques will be used to better understand patient and caregiver satisfaction with the intervention and to 
identify opportunities for optimizing this intervention as well as develop future interventions. We predict 
nonmotor symptoms, caregiver burden and psychosocial factors will predict benefit from palliative services.
RESEARCH STRATEGY
SIGNIFICANCE
Parkinson’s disease (PD) is the second most common neurodegenerative illness after Alzheimer’s disease 
affecting 1-2% of people over age 65, representing over 1 million Americans.1 Although PD is traditionally 
viewed as a movement disorder with characteristic motor symptoms which affects quality of life (QOL) but not 
mortality our understanding of this illness has shifted markedly over the past 20 years. Over the course of the 
illness nonmotor symptoms have a greater impact on patient suffering, nursing home placement, and caregiver 
burden despite being under-recognized.13 These symptoms include pain, fatigue, psychosis, depression, 
anxiety, and dementia. In patients with PD surviving 20 years or longer, three fourths ultimately develop 
dementia making it the leading cause of nursing home placement in PD.5 There is also increasing recognition 
of the impact of PD on mortality with recent CDC statistics ranking PD as the 14th leading cause of death with a 
clearly rising trend and potential for this statistic to be an underestimate.2, 14 Finally, pathological studies reveal 
the effects of PD involve not only dopamine, but nearly every ascending neurotransmitter system, and include 
effects outside of the central nervous system.15, 16 Thus PD should be viewed as a multi-system chronic illness 
associated with impaired QOL, pain, disability, dementia and increased mortality. Despite these advances in 
our understanding of PD, clinical care and research continues to be driven by a chronic illness model.17 
Features of this model relevant to this proposal include an intense focus on managing and monitoring motor 
symptoms with care driven by a patient-physician dyad. Notable gaps in this model include care for caregivers, 
management of non-motor symptoms, advance care planning, and use of interdisciplinary services.17
Palliative care is an approach to improving the QOL of patients and their families that focuses on the 
relief of suffering through the assessment and treatment of physical, psychosocial and spiritual issues.18 While 
traditionally associated with cancer, palliative approaches have been successfully applied to several chronic 
illnesses including congestive heart failure, chronic pulmonary disease and multiple sclerosis.10,11, 19 Several 
lines of research, many driven by collaborators on this proposal, suggest that PD patients and their families 
have many unmet needs that may be effectively addressed through palliative models. First, PD patients are 
more likely than age-matched controls to die in hospitals supporting contentions that advance care planning 
and timely identification of patients appropriate for hospice are lacking.8 Second, studies of PD caregivers 
demonstrate high levels of strain and distress and a large proportion who feel unprepared for their role.20 Third, 
symptom burden in advanced PD is similar to patients with metastatic cancer and may be significantly 
improved through an outpatient palliative clinic.12 Notably, nonmotor symptoms, such as depression, fatigue, 
pain, and nutritional status are frequently not identified or treated in current models of care but are the focus of 
the medical component of palliative interventions.21-23 Finally, while there is a recognition by experts in the field, 
including the American Academy of Neurology, that “optimal care of such patients requires that neurologists 
understand and apply the principles of palliative medicine” there are virtually no data to guide clinicians in this 
charge with striking gaps in assessing spiritual and psychosocial needs, identifying patients in need of 
palliative services, use of advance care planning and appropriate management strategies.24, 25 Given these 
documented needs a fundamental next step in moving this field forward and developing PD-specific palliative 
services will be clinical trials of palliative care interventions for PD patients and their family caregivers.
Figure 1 provides a conceptual model of current care practices and a proposal for addressing currently 
unmet needs. Care including a neurologist reduces mortality, hip fractures and nursing home placement 
compared to care solely from a primary care physician (PCP), likely through improved medication and motor 
symptom management.6 However, as shown in Figure 1A, some medical needs, such as nonmotor symptoms 
and nutrition, are poorly met while other needs such as advance care planning, caregiver support and 

psychosocial issues are left to patients and caregivers to arrange.13, 17, 26 Figure 1B depicts an alternate model 
of care which incorporates an interdisciplinary outpatient palliative care team to address unmet needs, improve 
coordination of care and relieve patients and caregivers of the responsibility of securing resources. Notably, 
there is a small but growing cadre of centers worldwide, including this proposal’s 3 study sites, who are 
beginning to offer these types of services with some signs of efficacy.27, 28 However, as noted in recent reviews, 
there are significant gaps in the evidence needed to support widespread adoption of this care model.29 Gaps 
which will be addressed in this proposal include:
1) The first randomized controlled comparative effectiveness trial of palliative care for PD to determine 
whether such care does in fact improve patient-centered outcomes versus current standards of care.
2) Data to guide referral and selection of appropriate patients for this time and resource intensive intervention.
3) Data to standardize and optimize which services are provided and how they are delivered, optimally with 
direct input from PD patients and their caregivers.
We were approved by PCORI to modify of our research protocol to expand our inclusion criteria from 
Parkinson’s disease (PD) to also include the closely related neurodegenerative conditions of multiple systems 
atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Lewy Body 
Dementia (LBD). These disorders are collectively referred to as Parkinson-plus syndromes or atypical 
parkinsonian disorders (APD) and are related to PD in terms of both clinical manifestations and pathology.9 
Current standards of care for APD patients are very similar to PD patients, and include care from a neurologist 
and PCP as well as trials of the same medications used to treat PD. These patients suffer from many of the 
same complications as PD patients (e.g. falls, dysphagia, dementia, depression) and tend to have less 
response to motor treatments (e.g. levodopa) and faster progression.  Although these conditions are 
individually rare, collectively they account for approximately 15% of all parkinsonism and, because they are 
largely untreatable and more rapidly progressive than PD, may have a higher proportion of patients and 
caregivers with high palliative care needs.30, 31 All of the palliative care clinics involved in this study see APD 
patients which makes the question of clinical effectiveness equally important for APD patients, caregivers and 
clinicians as it is for PD.
Figure 1. Conceptual model of current (A) and palliative (B) care for PD emphasizing where needs are met,; 
coordination of care; quality of care (areas well-met = ‘+’ or variably met = ‘-‘); and relation to Specific Aims. 

From a practical standpoint, recruitment has been more challenging than initially anticipated. We have 
had higher than expected rates of refusal due to time commitment and logistical challenges among patients. 
We have also had many potential participants refuse to agree to be randomized as they feel they have high 
needs and do not want to take the 50% chance of being randomized to usual care. Although this is the first trial 
of a palliative care intervention in Parkinson’s disease (PD), similar issues have been described in palliative 
care trials for other conditions.32, 33 Expansion of our recruitment criteria to include APD patients is anticipated 
to improve our recruitment numbers and may account for one-third of our final sample. We have already had 
several potential participants excluded because of having an undiagnosed APD and have had requests from 
referring clinicians to see their APD patients in the study.
From a theoretical standpoint there are several reasons why the inclusion of APD patients is attractive. 
First, regarding palliative care services there are no significant differences in the care our palliative care clinics 
provide to APD versus PD patients in terms of symptomatic needs (e.g. dementia, depression, dysphagia), 
goals of care, caregiver support, psychosocial issues or spiritual care.31 Second, there is a paucity of clinical 
therapeutic research to guide care for patients with APD and this study will help fill this gap and encourage 
other investigators to include this patient population.34 Finally, the inclusion of APD patients is consistent with 
PCORI and palliative care principles to move towards patient-centered care based on symptoms or other 
shared challenges (e.g. elderly multiple comorbidities) as opposed to specific diagnoses and there are other 
clinical researchers in neurology and palliative care moving in this direction.35
INNOVATION
Although growing evidence supports palliative models for several chronic illnesses there is scant evidence and 
no randomized trials supporting this approach in PD.12, 19, 36, 37 This proposal will conduct the first randomized 
trial of outpatient palliative care for PD. While this trial builds on prior palliative trials our approach is innovative 
in its application of these methods to the specific needs of PD. Specifically, our Aims will be the first studies to:
1)
Test the impact of outpatient palliative care in PD on patient QOL and caregiver burden in a 
randomized controlled trial. The intervention is based on our collective experience in providing palliative care 
for PD. Our study sites represent the first clinics and longest experience with this work in North America. 
Clinical trial results for other illnesses do not directly translate to PD due to unique aspects of PD such as the 
long duration of illness (10-20 years) and variable combination of motor and nonmotor symptoms.
2)
Use the recently developed Needs Assessment Tool - Parkinson’s Disease to provide standard and 
reproducible screening of high-risk patients. This instrument was modified for PD by Drs. Miriam Johnson and 
Edward Richfield with input from Dr. Kluger (PI) from the Palliative Care Needs Assessment Tool.38 
3)
Describe the impact of outpatient palliative care on cost and service utilization from a patient and 
caregiver perspective. As opposed to traditional cost-effectiveness analyses, these analyses do not depend on 
assumptions valuing quality of life years or other complex modeling. Rather they are designed to provide 
practical data directly relevant to patients, caregivers and PD advocacy groups.
4)
Include patients with and without PD-related dementia (PDD) in a randomized clinical trial. One of the 
challenges of building a palliative care model for PD is the wide variability of clinical phenotypes, including a 
wide range of cognitive abilities and impairment. Our goal is to strive for inclusivity, specifically including PDD 
patients who are often excluded from clinical research but represent a very high-risk population for palliative 
care needs. We have specifically chosen primary outcome measures not dependent on cognitive status.
5)
Use the Quality of Life: Alzheimer’s Disease (QOL-AD)39 and recently developed Edmonton Symptom 
Assessment Scale – Parkinson’s Disease (ESAS-PD)12 to measure of QOL and symptom burden respectively. 
We chose these scales for their applicability to patients with advanced disease, ease of use with cognitive 
impairment, brevity and caregiver proxy reporting. More commonly used PD quality of life outcomes (e.g. the 
Parkinson’s Disease Questionnaire 3940) are less relevant to the needs of the population we are serving as 
they focus primarily on functional activities, many of which are beyond the abilities of our patients. 
PRELIMINARY DATA AND FEASIBILITY
1)
Effectiveness of Outpatient Palliative Care for PD: Dr. Janis Miyasaki (University of Alberta site PI) and 
colleagues published a case series of 109 PD patients who had received outpatient palliative care from her 
team.27 This study showed a significant improvement in symptom burden as measured by the Edmonton 
Symptom Assessment Scale PD (ESAS-PD) between their baseline (mean + STD = 56 + 19) and first follow-
up visit (40 + 17; paired t-test p < 0.0001). Significant improvements were seen in many individual symptoms 
including pain, anxiety, drowsiness and dysphagia. Although there was no control group, these patients were 
largely referred by their treating neurologist because of limited success with usual care. Further findings from 
an article in press by Dr. Miyasaki and Dr. Benzi Kluger (PI) showed that over 80% of PD patients participating 

in outpatient palliative clinics died at home and less than 10% died in a hospital.41 While there was no control 
group, historical data shows over 50% of PD patients typically die in hospitals and less than 10% die at home.8
2)
Patient and Caregiver-Centeredness of Intervention: Dr. Kluger (PI) obtained a Clinical Effectiveness 
and Patient Safety Grant through the University of Colorado Hospital in July 2013 to optimize our outpatient 
palliative care clinic with the non-negotiable goal of achieving high quality, patient-centered care. We collected 
data through surveys and phone interviews with patients and caregivers and made ongoing adjustments in our 
clinic based on feedback received. Specifically, we revised clinic processes by: 1) Providing written information 
about palliative care and our clinic to patients prior to their first visit; 2) Clarifying team member roles to reduce 
redundancy and ensure coverage of key issues; 3) Providing written instructions to patients in real time from 
each team member; and 4) Following up on visit recommendations with phone calls within 2 weeks. We 
tracked patient and caregiver satisfaction through the course of this project and obtained mean scores of at 
least 9 (on a 10 point scale) on all items by the end of our 1-year improvement period including overall 
satisfaction, answering their questions and likelihood of referring other patients to our program.
3)
Experience and Standardization of Intervention: Dr. Miyasaki created the first outpatient palliative care 
program in the world dedicated to PD patients and their families at the University of Toronto in 2008. From the 
time of its inception this program became a model for other centers including the University of Colorado 
Denver (UCD) and University of California San Francisco (UCSF) and an integral part of care for patients with 
advanced PD in Toronto addressing goals of care, refractory nonmotor symptoms, caregiver support, advance 
care planning and spiritual wellbeing. Dr. Nicholas Galifianakis (UCSF Co-I) and colleagues presented findings 
from the development of their PD palliative clinic and first 25 patients at the 2012 International Congress of 
Parkinson’s Disease and Movement Disorders.42 Relevant findings from this presentation include a description 
of their intervention and the most common referral reasons including goals of care, management of non-motor 
symptoms and caregiver support. Although our programs have always been similar, we have shared 
experiences, forms and other materials in the planning of this proposal to ensure standardization across sites.
4)
Palliative Care Needs of PD Patients and Caregivers – Quantitative Data: Dr. Kluger (PI) obtained a 
pilot grant in June 2013 from the Veterans Affairs Medical Center (VAMC) to perform a cross-sectional study of 
90 patients with PD and 45 patients with advanced cancer (inoperable or metastatic) to determine whether 
palliative issues contributed to QOL in PD and compare palliative needs in PD to those with cancer. Key 
findings of this study (manuscripts under review) relevant to this proposal include: 1) PD patients across all 
stages of the disease had similar or higher levels of symptom burden, grief, depression, QOL impairments, and 
caregiver burden as advanced cancer patients; 2) Palliative specific issues (e.g. grief, spiritual wellbeing) were 
associated with QOL even when controlled for motor severity and depression; 3) The majority (80%) of PD 
patients felt advance care planning should begin early in the disease process; 4) Caregiver burden was driven 
largely by factors not well addressed in current models of care including financial concerns, grief, depression 
and patient functional status; 5) Higher medication use was associated with high caregiver burden and reduced 
patient QOL even when controlling for disease stage; and 6) Components of symptom burden differed 
significantly between cancer and PD patients (e.g. higher psychiatric symptoms in PD population).
5)
Palliative Care Needs of PD Caregivers: Drs. Kluger and Jones (co-I) obtained a grant in September 
2013 through the University of Colorado’s National Institute on Aging funded Palliative Care Program (1 K07 
AG030337-01A2: PI - Kutner) to perform qualitative interviews and focus groups with PD patients and their 
caregivers with the goal of creating a patient-centered model of palliative care for PD. Key findings from over 
60 hours of interviews from 45 patients, caregivers and support groups (manuscript under review) relevant to 
this proposal include: 1) Both patients and caregivers expressed significant concerns about their future ranging 
from what symptoms to expect to finances; 2) PD challenged many patients’ sense of roles and identity; 3) 
Spirituality was a significant source of strength for many patients; 4) PD patients and caregivers identified 
many needs not met with current models of care including greater education, particularly regarding what to 
expect in the future; 5) Patients often under-reported symptoms to their physicians for fear of having their 
medications increased; and 6) Patients and caregivers expressed significant openness to team-based 
outpatient approaches to addressing currently unmet needs; and 7) Both patients and caregivers felt that key 
components of palliative care (e.g. spiritual counseling, frank discussions about future needs) would be a 
welcome addition to current models of care.
6)
Clinical Research Experience in PD: Dr. Kluger has experience as PI in PD trials including serving as 
co-PI in a 3-site investigator-initiated study of rasagaline for fatigue43 and PI for a single site study of 
acupuncture for fatigue recruiting 95 participants in 2.5 years (manuscript in preparation). Dr. Katz (UCSF site 

PI) has experience in PD clinical trials and will work closely with Dr. Jill Ostrem (co-I) an experienced clinical 
trialist. Dr. Miyasaki (UA site PI) similarly has a long history of serving as a site PI in multisite clinical trials.
Of note, palliative care as prescribed in the “intervention arm” of this trial is already available to and being 
utilized with PD patients at UCH.  The “comparator arm” is meant to reflect the current standard of care in the 
community at large. At UCH, this trial represents a comparison of effectiveness of 2 currently-available 
standards of care.
APPROACH (see Appendix 1 for schedule of procedures in table format)
Aim 1: Determine whether interdisciplinary outpatient palliative care for PD improves patient quality of 
life (QOL) and/or caregiver burden versus usual care including a neurologist. 
Rationale and Design: The objective of this Aim is to provide the first comparative effectiveness data on 
whether augmenting usual care with interdisciplinary outpatient palliative care improves patient QOL and/or 
caregiver burden in patients at high risk for poor outcomes. Given the unmet needs facing this population there 
are great potential benefits from incorporation of this approach. Although it may seem obvious that more care 
would be better than less, several multidisciplinary interventions in PD and palliative care have failed to meet 
their primary endpoints in randomized trials and thus could present an additional burden to patients and 
caregivers in terms of time, cost and emotional investment.44, 45 We will randomize 300 PD patients from 3 sites 
who are at high risk for poor outcomes in a 1:1 ratio to either: a) Usual care including a neurologist or b) Usual 
care augmented by an outpatient interdisciplinary palliative care team. Data regarding patient quality of life, 
symptom burden and caregiver distress will be measured at baseline, 3, 6, 9 and 12 months. Our primary 
outcomes will be differences between groups in patient symptom burden and caregiver burden at 6 months. 
This time point was chosen to capture both early effects of the intervention as well as probable measurable 
decline in control arm. We will examine symptom burden, spiritual wellbeing and mood as planned secondary 
outcomes. We predict that patient QOL and caregiver burden will be significantly improved in the palliative care 
group versus usual care at 6 months and that this difference will persist at 12 months.
Study Settings/Recruitment: Participants will be identified and recruited for this study through three institutions: 
1) The University of Colorado Denver (UCD); 2) The University of California San Francisco (UCSF); and 3) The 
University of Alberta. The institutions represent the 3 first outpatient palliative care clinics for PD in North 
America and were chosen based on their collective experience. Recruitment at each institution will occur 
through three main venues: 1) Referral from investigators’ clinics or their colleagues at primary study sites 
(tertiary care academic clinics and community health clinics); 2) Referral from community physicians with 
ongoing working relationships with site institutions and investigators; and 3) Self-referral by patients who learn 
of the study through community organizations, talks, advertisements or websites (e.g. clinicaltrials.gov; 
foxtrialfinder). To ensure inclusion of community and rural participants, each study site has partnered with 
community neurologists and regional patient organizations which provide services to rural patients. Study sites 
also provide services through inner city clinics serving indigent populations and the two US sites are partnered 
with Veterans Affairs Medical Centers. Efforts made to retain participants will include: reimbursement for travel 
and expenses; providing baseline and/or follow-up study visits at participant homes or by telehealth for patients 
and/or caregivers with health, mobility, or transportation issues; incorporation of telemedicine approaches as 
needed for rural and other locations; mailed updates of study progress to participants; incorporation of 
feedback from participants regarding study procedures; and a welcome letter referring to participants as 
important members of the study team. A caregiver will be consented/enrolled for each participant who has one 
available. In some cases, the consent process will occur in a telehealth (phone or video) meeting with the 
participant and will be performed by study personnel. The patient/caregiver/LAR will have a copy of the 
consent form and the UCD study coordinator will go through the consent process with them via phone or video, 
just as they would in person. Patient/caregiver/LAR will give verbal consent.
Participants: Inclusion Criteria: Patients must be fluent English Speakers, over age 40 and meet UK Brain 
Bank criteria for a diagnosis of probable PD46 or standard criteria for progressive supranuclear palsy (PSP),47 
corticobasal degeneration (CBD),48 multiple systems atrophy (MSA),49 or Lewy Body Dementia (LBD).50  
Although PD may be seen in individuals under age 40, it is more frequently related to specific genes and may 
display different clinical features than typical idiopathic PD. Patients must be at high risk for poor outcomes as 
identified by the Palliative Care Needs Assessment Tool (PC-NAT)38 modified for PD which screens patients 
on the basis of social factors (e.g. presence of caregiver), disease severity, and symptom burden. Every effort 

will be made to allow inclusion of patients with dementia and cognitive impairment per NIH guidelines51 (see 
Human Subjects section for details on consenting process). 
Caregivers, when present, will be identified by asking the patient: “Could you please tell us the one 
person who helps you the most with your PD outside of clinic?” For patients with severe dementia, family 
caregivers may be self-identified and may be included even if the patient has communication limitations in 
order to obtain data relevant to these highly vulnerable and underrepresented patients. We anticipate 90% of 
patients will have caregivers present based on our clinical experience and have performed separate power 
calculations for caregiver outcomes, including with lower percentages of complete dyads. Notably, our primary 
patient outcome measure has been validated in patients with dementia and with proxy caregiver reporting.52
Exclusion Criteria: Patients will be excluded if any of the following are present: 1) Immediate and urgent 
palliative care needs (these patients will not be randomized and will be offered appropriate services 
immediately); 2) Unable or unwilling to commit to study procedures including randomization, study visits or the 
addition of a neurologist to their care team if in the usual care arm and not currently seeing a neurologist; 3) 
Presence of additional chronic medical illnesses which may require palliative services (e.g. metastatic cancer); 
or 4) Already receiving palliative care and/or hospice services. We have purposefully kept our 
inclusion/exclusion criteria broad to allow for greater generalizability of results and to ensure inclusion of 
potentially underrepresented and understudied subgroups.
Randomization: Individual patients and patient-caregiver dyads will be randomized in a 1:1 fashion to either: 1) 
Usual care defined as including both a PCP and neurologist; or 2) Usual care augmented by an outpatient 
interdisciplinary palliative care team. Randomization will be stratified by site, presence of caregiver, presence 
of dementia using Movement Disorders Society Guidelines for PD-related dementia and the Montreal Cognitive 
Assessment,53, 54 and performed in balanced blocks to minimize potential biases.
Description of the Intervention and Comparator Arms: Comparator: Usual care will consist of care from the 
patient’s primary care physician (PCP) and a neurologist. We consider this the current standard on the basis of 
evidence showing that care with a neurologist results in better outcomes (e.g. falls, mortality) than care with a 
PCP alone.6 For patients without a neurologist, we will arrange appointments with a neurologist covered by 
their insurance or a patient assistance program. Patients will be asked to see their neurologist at least every 3 
months to match the frequency of visits in the intervention arm and may see their PCP at their typical 
frequency.  Data collection for those in the Usual care arm could occur in person, over the phone, using mailed 
or electronic survey distribution, or via telemedicine. To ensure treatment fidelity, investigators will not serve as 
neurologists in the comparator arm.
Intervention Arm: Out intervention will consist of Usual Care plus the addition of an outpatient interdisciplinary 
palliative care team. Palliative care visits will be performed in person (or telemedicine if needed for rural areas 
and/or limited transportation) every 3 months and will include consultation with all team members. In addition, 
visits will be supplemented by optional phone calls one week after each visit to confirm understanding of team 
recommendations and at 6 weeks to check-in with patient and caregiver. Data collection for those in the 
Intervention arm could occur in person, over the phone, using mailed or electronic survey distribution, or via 
telemedicine. Patients and caregivers may also contact the team as needed. Summaries of visits will be sent to 
the patient, caregiver, PCP and neurologist. The palliative team will enact changes related to core palliative 
care issues (Table 1) and make suggestions for care outside of palliative care issues to be sent to the patients’ 
Usual Care team.
The interdisciplinary team will consist of a neurologist, a nurse, a social worker, and a chaplain. A 
board-certified palliative care physician will also be available at each site for phone consultations and monthly 
review of charts. Visits will be standardized through checklists of topics covered by each team member to 
ensure consistency across sites as summarized in Table 1. These issues were developed on the basis of our 
collective experience and studies of palliative care needs contributing to patient QOL and caregiver burden 
(see Preliminary Data). All staff except the palliative care physician will be present for in person visits and will 
participate in summary meetings at the end of each clinic to ensure interdisciplinary feedback, integrated care, 
appropriate follow-up and completion of any needed referrals or medication changes.
Table 1. Standardized Interdisciplinary Palliative Care Team Membership and Roles
Team Member
Issues to Address
Palliative 
Neurologist
-
Medical history, medications and physical examination
-
Cognitive status and testing
-
Psychiatric symptoms (e.g. depression, hallucinations)
-
Pain, sleep, fatigue and other nonmotor symptoms

-
Swallowing, sialorrhea and falls
-
Recent hospitalizations, infections or other medical issues
-
PD education relevant to disease stage including prognosis
-
Goals of Care
Nurse
-
Advance care planning and documentation
-
Healthcare proxy designation and documentation
-
Nutritional status and diet
-
Home safety for both patient and caregiver
-
Wound care/skin integrity
Social Worker
-
Caregiver distress 
-
Need for help at home/community resources
-
Financial issues and concerns
-
Long-term care needs
Chaplain
-
Spiritual wellbeing
-
Sources of support and stress
-
Fear, anger and guilt
-
Grief and demoralization
Palliative Care 
Physician
-
Phone consultation for advanced symptom management issues
-
Monthly review of charts from palliative perspective
Primary Outcome Measures: Our primary outcomes for this proposal are the Quality of Life: Alzheimer’s 
Disease (QOL-AD) and the Zarit Caregiver Burden Interview short form (ZBI).39, 55 The QOL-AD was chosen 
for this study for several reasons including its brevity, insensitivity to cognitive impairment, validated proxy 
reporting, sensitivity to change and coverage of issues identified to be relevant to PD patients and caregivers 
in our qualitative interviews (see Preliminary Data above for these issues).56, 57 Although there is currently no 
QOL instrument specifically validated for PD patients with dementia the QOL-AD has been validated in mixed 
dementia and issues relevant to all dementias.58 The ZBI is the most commonly used self-report measure of 
caregiver distress, including in PD.59, 60 The ZBI is well validated in terms of psychometric properties and is 
notably insensitive to variations in age, gender, socioeconomic status or locale indicating that it is appropriate 
for use in diverse and mixed populations.61 It is also sensitive to change with interventions, including palliative 
care.19 
Secondary Outcome Measures: Table 2 summarizes outcomes and other relevant data collected from patients 
and caregivers. To assess patient functional status and provide an alternate QOL measure we will administer 
the PDQ-39, the most commonly used measure of health-related QOL in PD. It was developed in 1995 on the 
basis of in-depth interviews of PD patients and has excellent psychometric properties and construct validity.40, 
62 The PDQ-39 also provides validated subscores regarding mobility, activities of daily living, emotional well-
being, stigma, social support, cognition, communication and pain. The PDQ-39 is sensitive to change over time 
with disease progression and improvement with interventions and minimally clinically important differences 
have been reported for the overall scale and subscores.63 To assess symptom burden we will administer the 
ESAS-PD, a modified version of the Edmonton Symptom Assessment Scale.12 The ESAS-PD was developed 
by Dr. Miyasaki to incorporate common PD symptoms not in the original scale (e.g. confusion) and 
demonstrates adequate psychometric properties, including proxy reporting and sensitivity to change.12 Other 
patient related outcomes will include: the Hospital Anxiety and Depression Scale (HADS)64, the Prolonged 
Grief Questionnaire (PG-12; anticipatory grief)65, and the Functional Assessment of Chronic Illness Therapy-
Spiritual Wellbeing (FACIT-SW)66 Other caregiver outcomes will include the HADS. Total time for all 
assessments is estimated to be 60-90 minutes and may actually be faster for more impaired patients due to 
reliance on proxy responses.
Table 2. Data Collected from Patients and Caregivers for Aim 1
Measure
Domain of Interest
Quality of Life: Alzheimer’s Disease (QOL-AD)39
Patient Quality of Life (QOL)
Zarit Burden Interview (ZBI)34 
Caregiver Distress
Parkinson Disease Questionnaire (PDQ-39)30
Patient Functional Status and secondary QOL
Edmonton Symptom Assessment Scale (ESAS-PD)12
Patient symptom burden
Hospital Anxiety and Depression Scale (HADS)37
Patient and Caregiver Mood
Functional Assessment of Chronic Illness Therapy-
Patient and Caregiver Spiritual Wellbeing

Spiritual Wellbeing (FACIT-SP)39
Patient Reported Outcome Measurement Information 
System (PROMIS-29)
Patient QOL (Validation of NIH Common Data 
Element)
Clinical Global Impression of Change
Patient, Caregiver and Clinician’s global 
impressions of change
Prolonged Grief Questionnaire (PG-12)40
Patient and Caregiver Grief
Unified Parkinson Disease Rating Scale41
Patient Motor symptom Severity (motor exam only)
Montreal Cognitive Assessment (MOCA)46, 56
Patient Cognitive Status 
Hoehn and Yahr Scale44
Patient Disease Stage (baseline visit only)
Charlson Comorbidity Index61, 66
Medical Comorbidities (baseline visit only)
Statistical Analysis: The main objective of the study is to determine the comparative effectiveness of 
interdisciplinary outpatient palliative care versus usual care with a neurologist for PD regarding effects on 
patient QOL and caregiver burden. The primary outcome variables will be the QOL-AD and the ZBI.40, 55 
Secondary outcomes (see Table 2) include scales for symptom burden, mood, and spiritual wellbeing. 
Controlling covariates will include gender, age, disease severity (measured continuously using the Unified 
Parkinson Disease Rating Scale67), cognitive dysfunction (measured continuously using the Montreal Cognitive 
Assessment68), and baseline depression (measured continuously using the HADS Depression Subscale64). 
The explanatory variables will be checked for randomization and multicollinearity. Successful randomization 
should minimize covariate imbalances between groups, but including them in the model can adjust for lingering 
confounding effects and account for variance in the outcome variable. 
The outcomes will be modeled with mixed regression model analysis, with correlation for repeated 
measures, at baseline and at 3, 6, 9, and 12 months. The empirical covariance estimator may be used to 
safeguard against model misspecification. The models will control for time, interaction between treatment and 
time, and potential baseline confounders, including gender, age, depression, and disease severity. The default 
model will have linear time trajectories for each treatment group, and linear functions for baseline controlling 
covariates. The linearity assumptions will be checked. Non-linear functions could be approximated with piece-
wise linear functions or transforms. The main contrasts will be the difference in areas under the fixed effect 
change from baseline curves for the palliative and treatment control groups, and the mean difference in change 
between 6 months and baseline between the groups. Secondary tests will be conducted for the mean 
difference in change from baseline between the groups at the 3, 9, and 12-month time points. The contrasts, 
controlled for all covariates, will be tested for significance using T-tests and F-tests, with an alpha level of 0.05. 
The effect estimates, 95% confidence intervals, and p values will be reported. In the process, the interaction 
between time and treatment will be tested. If the time trajectories are linear, then all tests are stochastically 
equivalent to the time by treatment interaction test with one parameter. Binary outcomes and count outcomes 
will be analyzed with logistic regression and Poisson regression respectively. Generalized mixed models will 
account for repeated measures. We plan to perform subgroup analyses for patients with dementia, severe 
disease, and depression and may perform exploratory subgroup analyses depending on primary results. 
Item non-response for the scales will be dealt with using the half rule, or specific scale instructions 
when available (e.g. QOL-AD57). The half rule is the standard method for completing validated scales with 
missing items when the items are not hierarchical and generally has better performance than more complex 
imputation methods.69 Descriptive statistics will be compiled for missing scales and assessed for patterns. 
Logistic regression for missingness will be used to demonstrate its dependency on variables. The initial 
analysis will use the maximum likelihood for all available data for a response variable when data exists for all 
explanatory variables. In mixed models correlation on repeated outcomes provides some information on the 
times with missing outcome values. The data will be assumed missing at random. As a sensitivity analysis, 
joint models will combine the longitudinal outcomes of patient and caregiver proxy reports on the QOL-AD and 
use their correlations to provide additional values if a subset of the outcomes are missing. Finally, joint models 
for the longitudinal QOL scale outcomes and the time to drop out will be fit to incorporate drop out information. 
Even if outcomes for one scale are not missing at random conditional on the observed data, measurements on 
other scales at the time, or time to drop out, can serve as proxies. Models for different outcomes and time to 
drop out will be joined through shared covariance structures and/or shared random effects. 
The functions in the regression model will be checked for linearity. Piecewise linear functions or 
transforms can be used to approximate non-linearities. Crossover of group assignment will be treated in 
different ways and the results will be compared. The primary analysis will use intent-to-treat, but analysis 
according to actual treatment, with time varying covariates, and adherers only will also be considered. Results 

from models using all available data for a response variable will be compared to the models with missing data 
methods. The random effects linking together the joint models will be tested. The missing data methods 
assume missing at random (MAR). Randomization will be checked for baseline variables with summary 
statistics and two-way tables. Covariates can partially control for deviations from ideal randomization. 
Homoskedascity and approximate normality for the outcomes will be checked with standard methods. 
Homoskedascity can be remedied with heterogeneous variance structures or weights. Non-normality should 
not be much of an issue, unless severe, and can be dealt with using standard methods such as logarithmic 
transformations. With our sample size the parameter estimates should be consistent and asymptotically normal 
because of the Central Limit Theorem. All variables will be checked for outliers, and influential outliers will be 
considered for removal using standard tests (e.g. Cook’s D). 
Sample Size and Power Considerations: Allowing for up to 25 dropouts per group by the 6-month time point, a 
two sample T-test with 125 samples per treatment group (250 total) will detect a difference in our continuous 
outcomes equal to 42% of the standard deviation with 90% power and an alpha level 0.05. This is greater than 
the suggested minimal clinically significant change for the QOL-AD of 3 points.70 For our secondary measure of 
QOL the difference of half the standard deviation for the PDQ-39 has been suggested in prior studies to be 
clinically important and detectable with change over time or with outpatient interventions.63, 71, 72 For the ZBI, 
assuming 110 complete dyads per group would diminish our effect size to 44% of the standard deviation with 
90% power and an alpha level 0.05. Even a sample of 90 complete dyads would provide an effect size of 0.5 
SD/mean. Minimal clinically important differences have not been established for the ZBI but will be estimated in 
this study using caregiver global impression of improvement and an anchor based approach.73 Notably, prior 
studies of palliative interventions have found effect sizes of 0.5 SD/mean and greater for the ZBI.19 The sample 
size will also enable us to fit models with a large number of parameters and as described below, the 
longitudinal mixed models and linear time functions will increase our efficiency. Caregivers will be enrolled for 
each part
For a longitudinal model with non-linear time trajectories, the difference in area under the change from 
baseline curve can summarize treatment effect across all times. If the true time trajectory is linear, and we 
model it as a piece-wise linear function, with a common intercept and knots at each time point, and the 
outcome is difference in area under the change from baseline curve, then a sample size of 25 per treatment 
group (50 total) would achieve 90% power with an alpha level of 0.05 and an effect size equivalent to 50% of 
the standard deviation at 6 months (6 sd*months of area, 0.5 sd on average). A sample size of 125 per 
treatment group (250 total) would be virtual certain to detect the effect, even for very small alpha levels, and so 
a Bonferroni correction could be applied to handle multiple comparisons. A sample size of 125 per treatment 
group (250 total) would achieve more than 90% power with an alpha level of 0.05 and an effect size equivalent 
to 22.5% of the standard deviation at 6 months (2.7 sd*months area, 0.225 sd on average). For a test of mean 
difference in change from baseline at 6 months, a sample size 64 per treatment group (128 total) would 
achieve 90% power with an alpha level of 0.05 and an effect size equal to 50% of the standard deviation. A 
sample size of 125 per group (250 total) would almost certainly detect the effect. The test would have more 
than 90% power even after a Bonferroni adjustment for almost 50 tests. Alternatively, 125 samples per group 
(250 total) could detect an effect equal to 36% of the standard deviation with 90% power and an alpha level of 
0.05. Alternatively, for our minimal dyad size of90 samples per group (180 total) we could detect an effect 
equal to 42% of the standard deviation with 90% power and an alpha level of 0.05.All sample size calculations 
for longitudinal data models assume a compound symmetric covariance structure and a correlation of 0.5 for 
repeated measures on a participant which is relatively conservative for QOL measures.69
Aim 2: Describe the effects of an interdisciplinary outpatient palliative care intervention on patient and 
caregiver costs and service utilization. 
Rationale and Design: There is a growing interest in the economics of healthcare delivery and palliative care.74 
While there are clear motivations for examining this from a payer and systems perspective, there is also an 
emerging interest in understanding this from patient and caregiver perspectives.75 This also agrees with our 
qualitative interviews of PD patients and caregivers where one of the most frequent concerns regarding their 
present situation and the future was finances. The types of services provided for a given cost are also clearly 
important. For example, one of the services our palliative care clinics provide patients is setting up home care 
for physical therapy which benefits both patients and caregivers. Our objectives for this Aim are therefore to 
describe how the addition of outpatient palliative care may alter costs and services for patients and caregivers 
and also to assess whether recommendations of the palliative care team are implemented and maintained.

Participants: Participants will be identical to Aim 1. Data will be collected from patient-caregiver dyads through 
interviews and rater-administered questionnaires using items drawn from existing instruments modified to 
account for PD and the cognitive functioning of dyads. These may be performed by phone within a week of 
scheduled visits depending on patient/caregiver preferences to minimize fatigue and burden or in person visits.
Economic Outcomes: From the patient and caregiver perspective there are two key economic outcomes that 
affect their financial health: out-of-pocket costs for healthcare and non-medical costs resulting from changes in 
work behaviors and earnings. From a payer and systems perspective the total cost of care is the economic 
outcome of interest. These economic outcomes will be assessed at baseline and every 6 weeks during the 
course of the study via modified versions of items drawn from existing questionnaires that have been used with 
similar populations which may be administered in person or by telephone. Out-of-pocket health-related costs 
will be assessed using questions drawn from the Ambulatory and Home Care Record (AHCR) and the Medical 
Expenditure Panel Survey (MEPS). Measures of total cost of care will be derived from comprehensive service 
utilization questions described below including both public and private costs.76 Costs will be assigned uniformly 
for purchased services regardless of patients’ underlying insurance status or location using Medicare 
reimbursement rates for the Denver Metropolitan Area. For services not covered by Medicare (e.g. unskilled 
home care) we will use average rates for the Denver Metropolitan Area. Measures of work behaviors and 
earnings will be obtained from questionnaire items adapted from the Work Productivity and Activity Impairment 
Questionnaire (WPAI) and the World Health Organization Health and Work Performance Questionnaire (HPQ). 
Measures at baseline and follow up will include work activities in the week prior to the assessment, absences 
from work due to health issues or caregiving and, for caregivers only, the number of hours spent providing 
care. At baseline we will obtain detailed information on the patient’s and caregiver’s current or most recent job 
including usual weekly hours worked, earnings, industry, and occupation. This baseline information will be 
used to value work absences due to caregiving activities and caregiver’s health, time providing care for 
caregivers, and any patient absences from work. Time losses from work will be assigned a monetary value 
using the human capital approach with adjustments made by year for inflation (will use dollar value of final year 
of data collection), vacations and benefits.77 Caregiver time spent providing care will be valued using the 
human capital approach for caregivers that are employed at baseline and for those not employed at baseline 
we will value their time using local market wage rates for paid home health aides.
Service Utilization: Health care utilization data will be collected at baseline, and every 6 weeks along with the 
economic outcome assessments including information on caregiver and patient use of healthcare services (i.e. 
emergency room services, hospitalizations, hospice and palliative care services, respite care and other stays in 
long-term care facilities, home health services, and caregivers’ use of psychological health services) as well as 
outpatient visits to physicians or other services. We will also record place of service (e.g. home, community, 
tertiary center) and number of medications taken. Utilization measures will use items from the AHCR, MEPS 
and HPQ.
Statistical Analyses: To estimate economic outcomes, all costs will be aggregated for each 6 week period and 
expressed as a rate per 30 days (monthly costs). Our primary economic comparison will be for total care costs 
plus non-medical costs in the period preceding the 6-month visit using a mixed regression model with 
adjustments made for site, baseline costs and work behaviors of the caregiver. Secondary economic models 
will examine differences by specific source of cost (e.g. missed work, informal caregiving, direct healthcare 
costs) and will use linear regression analyses to determine whether patient or caregiver variables (e.g. gender, 
age, cognitive status) are predictive of costs under either interventions. We will also conduct sensitivity 
analyses of these cost measures (e.g., measuring cost of missed work and informal caregiving time using both 
a human capital approach and local wages of home health aides for caregivers not employed at baseline).
Our primary service utilization analysis will compare number of hospitalizations, emergency room visits 
and nursing home placement between groups. T-tests and regression analyses will be used for continuous 
outcomes, Poisson regression will be used for count outcomes, and chi-square association tests, Fisher’s 
exact association tests, and logistic regression will be used for binary outcomes. Secondary analyses will 
examine utilization and place of service for ancillary therapies (e.g. physical, occupational and speech 
therapy). We will use regression models to determine if total number of medications is associated with QOL 
and ZBI (as it was in our Preliminary data) and whether palliative intervention influences medication use.
Sample Size and Power Calculations: A two sample T-test with a sample size 125 subjects per group (250 
total) could detect an effect equal to 42% of the standard deviation with 90% power and an alpha level of 0.05. 
For the cost per month model with longitudinal data, if the contrast is the difference in mean total cost between 
treatment groups after 6 months of follow up, then a sample size of 125 per group (250 total) would achieve 

90% power for an effect of 1.75 sd*months (0.29 sd on average) and an alpha level of 0.05.  Here sd is in cost 
per month.  If the contrast is the difference in mean total cost between treatment groups after 12 months of 
follow-up time, then an effect size of 3 sd*months (0.25 sd on average).  The power calculations assume a 
compound symmetric covariance structure with a correlation of 0.5 for repeated measures on a patient.
For a binary outcomes, the following arrangements achieve 90% power with an alpha level of 0.05 and 
a sample size of 125 per group (250 total):  26% for the control group and 10% for the treatment group, a 
difference of 0.16 and an odds ratio of 0.316; 50% for the control group and 30% for the treatment group, a 
difference of 0.2 and an odds ratio of 0.429.  For a Poisson count outcome, if the control rate is 0.5 per person 
year, and the exposure time is one year, then a sample size of 125 per group (250 total) would achieve 90% 
power with a rate ratio of 0.53 and an alpha level of 0.05.
Aim 3: Identify opportunities to optimize outpatient palliative care by: a) describing PD patient and 
caregiver characteristics associated with intervention benefits; and b) through direct patient and 
caregiver interviews. 
Rationale and Design: As the first randomized controlled trial of a palliative care intervention we have based 
our trial on our collective experience providing services to PD patients and their caregivers as well as literature 
from other illnesses. The objectives of this Aim are too optimize this intervention and plan for future 
implementation and dissemination efforts by answering two critical questions. First, given the expense and 
potential inconvenience of this intervention it is critical to identify patients and caregivers who are most likely to 
benefit from these additional services. This data may be used to further revise the PC-NAT for PD. Aim 3A will 
use regression models to determine whether patient or caregiver factors predict benefit from the palliative care 
intervention in terms of QOL-AD or ZBI. Second, is to capture patient and caregiver input regarding what 
services are most beneficial, what additional services may be needed and preferences for delivery methods. 
Aim 3b will engage patients and caregivers through semistructured interviews. As palliative care in neurology is 
relatively new, it is imperative that we elicit patient and caregiver input for process evaluation, particularly as 
Preliminary data presented above suggests that these persons have unique needs not reflected in palliative 
approaches to cancer or other diseases. Regarding delivery methods, this is particularly relevant as 
telemedicine, group clinics and other novel approaches have begun to show efficacy for other applications and 
may offer advantages to patients and caregivers regarding access, social support, efficiency and cost.78, 79 
Participants: Participants for Aim 3a will be identical to Aim 1. For Aim 3b (qualitative interviews), we will select 
a subgroup of participants and caregivers using purposive sampling to complete an additional interview 
following the final study visit to assess patient/caregiver satisfaction and suggestions of optimization of 
services and delivery. We will initially use a convenience sample, however as the study progresses we will use 
maximum variance sampling to ensure heterogeneity in terms of study site, gender, age, PD severity, and 
cognitive status. We may also use contextual information brought up in interviews or through Aim 3A to inform 
recruitment. We will interview patients assigned to both the intervention and usual care group as patients in the 
usual care arm may have less biases related to our service model or personal interactions with our team.
Primary Outcomes: Our primary outcome variables will be change at 6 months in the QOL-AD and ZBI. We will 
also look at symptom burden, mood, grief and spiritual wellbeing in secondary models.
Predictor Variables: Patient features will include: age, gender, medical comorbidities, presence of a caregiver, 
depression and disease severity (Hoehn and Yahr score). Caregiver features will include age, gender, 
depression, and socioeconomic status. Other variables including educational attainment, living situation 
(independent, assisted living, nursing home), location (rural, suburban, urban) and race/ethnicity will also be 
examined if sufficient variability in data permits.
Statistical Analyses Aim 3a: Starting from the models in Aim 1, the effect modifiers will introduced as 
interaction terms, so the time function for each treatment of group can be different for different levels of the 
interacting variable. The model with the interaction will be tested against the no interaction model. Interaction 
effects at individual time points may also be tested. The treatment effects for different levels of the interacting 
variable will be reported. For categorical interacting variables, the treatment effect will be reported at all levels 
of the interacting variable. For continuous interacting variables, the treatment effect will be reported at pre-
specified values of the interacting variable (e.g. dementia and mild cognitive impairment cut-points for the 
Montreal Cognitive Assessment54), natural boundaries (e.g. decades for age), or quartiles (e.g. for baseline 
caregiver burden). Categories will be collapsed when necessary and justified to prevent sparsely populated 
cells. An overall test for treatment effect across the different levels of the interacting variable will be performed 
as a multiple comparisons safe guard. Each interaction effects will be considered in separate models.

Qualitative Interview: For Aim 3B we will perform semi-structured interviews with patients and caregivers to 
determine patient and caregiver perspectives on what services are most helpful, what services may be 
needed, delivery of services and timing of services (see Table 3). Additionally, after consenting, we will assess 
providers’ perspectives as to the effectiveness, satisfaction and quality of delivering palliative care services 
using telemedicine. While the quantitative assessments will occur after each telemedicine visit with a patient, 
qualitative interviews with the providers will occur late in year 2 of the project, after the majority of participants 
complete their 12-month visits. We will also validate and build upon prior qualitative data from our group (see 
Preliminary Data) regarding needs to ensure adequate coverage by our intervention. These interviews will be 
performed by an investigator not part of the primary intervention team who will ask patients and caregivers for 
their honest opinions to avoid potential biases related to pleasing clinicians. Interviews will be performed in 
clinic or at patient’s home following the final study visit. We will also attempt to interview participants who 
discontinue the study to avoid potential selection bias in our final dataset. Finally, for patients who are receiving 
care via telemedicine we will administer a brief survey to get their feedback on how well this type of visit 
worked in meeting their needs.
Table 3. Interview Domains and Sample Questions 
Interview Domain
Sample Questions
Satisfaction with 
Services Provided
What services provided by the palliative care team did you find helpful? Were there any 
services provided you did not need? Providers’ questions: Satisfaction with technical 
quality, convenience, and/or care that was able to be provided?
Optimization of 
Services
Were there any services which you did not receive from the palliative care team or 
others that you think would be helpful? Providers’ questions: Did the use of 
telemedicine have an impact on your ability to engage or treat the patient and/or 
caregiver?
Care Delivery
How would you prefer (service discussed earlier) to be provided? For example, in 
person visits versus phone call.
Other Services
What additional services could be provided to improve you quality of life?
Timing of Services
When in the course of PD do you think palliative services should be started?
Who to Refer
Thinking of yourself and other people you know with PD, who do you think would 
benefit most from these services?
Mixed Method Analyses Aim 3b: To meet the goal of understanding patient and caregiver preferences for 
services and delivery methods we will utilize an iterative, inductive and deductive toolkit of analytical strategies 
drawing on field notes, qualitative content methods of analysis, consultative and reflexive team analysis, and 
member checking.80 ATLAS.ti will be used for data management. Analysis will commence with the first 
participant and proceed alongside data collection, informing and modifying our interview guide and recruitment. 
Initial coding will be done independently by the PI and PRA who will then discuss codes, establish inter-code 
reliability, and create an initial master code list. Dr. Jones will be available for adjudication if coding differences 
persist. The code list will be revisited and revised with continued data collection and with input from the 
multidisciplinary team. Text within and between codes will be compared to develop themes. Tables will be 
developed displaying counts of codes to search for patterns, similarities and differences between patients. 
Through this process we will develop figures of themes which will be modified based on feedback from our 
multidisciplinary team of advisors. Observer triangulation (using multidisciplinary team) and member checking 
(eliciting feedback on themes from subsamples of participants) will be employed to increase validity.
Per NIH Mixed Methods Best Practice Guidelines81, we will be using a sequential quantitative-to-
qualitative design for the purposes of Triangulation (use of qualitative data to increase confidence in survey 
results and trial outcomes), Complementarity (use of qualitative data to increase depth of understanding), and 
Expansion (use of qualitative data to identify novel issues not measured in surveys). Integration of Data will 
occur at the levels of: 1) Participant Selection through the use of survey results and interim analyses to guide 
maximum variance sampling; 2) Analysis through the use of survey data to enrich qualitative interviews and 
the use of qualitative responses to evaluate accuracy and adequacy of surveys; and 3) Interpretation through 
the combination of qualitative and quantitative data in evaluating and optimizing our current intervention and 
developing novel care delivery strategies.   
Sample Size and Power Calculations: In a situation where the treatment effect interacted with a binary 
variable, and the sample was evenly distributed among the four combination of treatment and the interacting 
binary variable, achieving 80% power with an alpha level of 0.05 and 63 samples in each combination (252 
total) would require a difference in treatment effect equal to 71% of the standard deviation. Alternatively, a 

sample of 252 total would be able to detect an increase in the R2 statistic of the regression model of 0.031 with 
80% power and an alpha level of 0.05. A test for the treatment effect within a subgroup of half the sample (126 
out of 252, 63 palliative care and 63 standard care patients), with an alpha level of 0.05, would require effect 
sizes of 51% and 59% of the standard deviation to achieve 80% and 90% power respectively. 
Longitudinal mixed models and linear time functions however would increase this efficiency. For a 
model with piece-wise linear functions for the time trajectories, with knots at each time point, and in a situation 
where the true time trajectories are linear, the treatment effect interacts with a binary variable, and the sample 
was evenly distributed among the four combinations of treatment and the interaction binary variable, a sample 
size of 63 in each combination (252 total) could achieve 90% power with an alpha level of 0.05 and a 
difference in treatment effect equal to 44% of the standard deviation at 6 months (5.3 sd*months area, 0.44 sd 
on average) . A test for a treatment effect within a subgroup of half the sample could achieve 90% power with 
an alpha level of 0.05 and a treatment effect equal to 32% of the standard deviation at 6 months (3.8 
sd*months area, 0.32 sd on average). If the time functions are linear, and linear slopes are used for the model, 
then 252 samples, equally partitioned among the combinations, could detect, with 90% power, a difference in 
treatment effect of 32%, and a within group treatment effect of 23%, of the standard deviation at 6 months.  
The sample size calculations for longitudinal data models assume a compound symmetric covariance structure 
and a correlation of 0.5 for repeated measures on a participant. Adjusting for multiple comparisons would make 
the individual tests more conservative.  A model with linear time functions eliminates the need for comparisons 
at different time points.
For Aim 3b, based on our prior work we will aim for 30 patients and up to 30 caregivers taking into 
account that not all patients will have a caregiver. Rather than controlling the dyad experience we will allow for 
a more naturalistic occurrence of living with PD, i.e. with or without a caregiver. Based on our iterative analysis 
of these qualitative data we will determine the need to increase or stop data collection. We aim to reach a point 
where no new context variation is evident or dominant. To ensure we have explored the experiences to optimal 
potential we will use maximum variation sampling in later patient identification based on our analysis. We will 
apply this logic to both intervention and usual care participant groups.
Study Management across Sites
Laura Palmer will act as project coordinator across sites and will handle issues relating to budget, regulatory 
concerns and conduct of the study in coordination with the PI, Dr. Kluger. This will include annual site visits to 
review study related procedures and documentation. All data will be entered into a central electronic HIPAA 
compliant database (REDCAP) housed and managed at the University of Colorado and maintained by our 
UCD biostatisticians Drs. Stefan Sillau and Diane Fairclough. Sr. Sillau will routinely check database for 
accuracy and completeness and notify local PI's and coordinators for any issues. Hard copies of all study 
related documents will be housed at local sites and kept in locked filing cabinets in locked research offices and 
kept for a minimum of 5 years following completion of the study. Ongoing and frequent coordination and 
communication between all three sites will occur with ad hoc, as well as regularly scheduled monthly calls and 
emails.  This will allow for quick response to concerns if/as they arise during the study.
Potential Problems and Alternative Strategies 
1)
As the intervention is enacted by 3 experienced teams at tertiary care centers will it be replicable or 
relevant for typical clinical practice? We have taken several measures to ensure that our intervention is 
replicable across study sites and other centers. Our first planned manuscript will include our study protocol and 
a detailed description of our intervention and clinic related forms to allow dissemination to interested sites. Our 
study neurologists have not completed formal palliative training; rather the clinic structure itself is the key to 
providing the time and interdisciplinary skills needed to address patient and caregiver needs.
2)
What if the intervention is not successful in meeting primary or secondary outcomes? This will be an 
important, if undesired, result that would still contribute to this field and suggest a need for alternate 
approaches. The value of Aim 3 will be heightened in this scenario by examining benefits to subgroups 
(suggesting a need for better screening) and eliciting patient and caregiver input on services and delivery.
3)
What if recruitment is slow or retention below expected? Our recruitment goals are modest and similar 
goals have been achieved by investigators at all study sites. If needed, further recruitment efforts may include 
adding additional local sites through community partners and/or more aggressive advertising strategies. A high 

drop-out rate would also be an important data point suggesting a need to revise delivery method. 
4)
This population is heterogenous and it is possible that outcomes may not apply to all subgroups or that 
important outcomes for particular subgroups are missed. This is a significant challenge facing palliative care for 
PD which may be one factor hampering palliative research for this disease versus more homogenous illnesses 
such as amyotrophic lateral sclerosis and Alzheimer’s disease.82 As this heterogeneity is a naturally occurring 
feature of PD we have made every effort to include the full spectrum of PD in our screening forms and 
intervention. Aim 3 will provide subgroup analyses to inform future interventions and screening efforts.
5)
Will results be biased without blinding? It is impossible to truly blind an intervention of this nature. We 
have used patient-reported outcomes to increase the relevance of results as there are no objective biomarkers 
relevant to our research questions. Despite this, prior multidisciplinary and palliative intervention trials have 
reported negative results suggesting that blinding biases do not overwhelm clinical effects.44
Future Directions
If this intervention is successful in improving patient QOL and/or caregiver distress we would plan to explore 
alternate delivery methods to improve the efficiency and dissemination of this approach including telemedicine, 
group visits, smaller teams and mixed approaches (e.g. in person physician visit and telehealth counseling). 
Cost-effectiveness studies would also be an important follow-up question to influence system level decisions 
for this model of care. Lastly, application to other progressive neurological illnesses, including mixed 
populations, may be warranted as patients with advanced chronic neurological illness tend to be similar in 
terms of symptoms and needs.
If this intervention is not successful, future studies would be guided by the results of Aim 3. Benefits 
found in specific subgroups would suggest a need for the development of better screening instruments, while 
poor responses across the sample would suggest a need for a different model. High drop-out rates or 
noncompliance with the intervention would suggest a need for alternate delivery methods.
HUMAN SUBJECTS
1. Risks to Human Subjects
1.a. Human Subjects Involvement, Characteristics and Design
Due to the nature of our research questions regarding clinical, psychosocial and spiritual needs in PD patients 
and their family caregivers we feel that involvement of human research subjects is necessary and justified. As 
we will discuss below, the risks of this research to human subjects are minimal and the potential for benefit for 
the involved human subjects, other people and family members living with PD, and society is significant.
We will recruit PD patients over age 40 diagnosed with probable PD using UK Brain Bank Criteria46 or 
atypical parkinsonian disorders (APD) who are identified to have high potential for palliative care needs using 
the Palliative Care Needs Assessment Tool.38  When present their family caregivers will also be included. We 
plan to recruit a total of 300 PD patients and project that at least 80% will have family caregivers who will also 
be included in this study.
We will select participants using the following inclusion and exclusion criteria described above.
PD patients with dementia (PDD) may be considered a vulnerable population but are necessary to 
answering our research questions. For all patients with cognitive impairment we will formally assess capacity to 
consent using the University of California Brief Assessment of Capacity to Consent (UBACC) modified for our 
specific study design where needed.83 For patients who fail this screen or if investigators have additional 
concerns we will require that their guardian participate in the consenting process and sign an informed 
consent. We will also require that PDD subjects give consent, or at minimum assent if fully informed consent is 
not possible. Our protocol and consent forms will be approved by our local IRBs before approaching any 
potential subjects.
Caregivers will be consented and enrolled using a caregiver-specific consent form.
After enrollment, screening and consent, patients will be randomized in a 1:1 ratio to either usual care 
or an usual care supplemented by an outpatient interdisciplinary clinic. The interdisciplinary team will consist of 
a neurologist with palliative care experience, a nurse, social worker, and a chaplain. For the usual care arm, 
patients not currently seeing a neurologist randomized to this arm have appointments with a neurologist 

covered by their insurance or patient assistance programs arranged by the study team. Patients will be asked 
to see their neurologist at least every 3 months to match the frequency of visits in the intervention arm and may 
see their PCP at their typical frequency. In the intervention arm, palliative care visits will be performed in 
person (or telemedicine if needed for rural areas and/or limited transportation or health issues) every 3 months. 
In addition, visits will be supplemented by phone calls one week after each visit to confirm understanding of 
team recommendations and at 6 weeks to check-in with patient and caregiver. Patients and caregivers may 
also contact the team as needed. Summaries of visits will be sent to the patient, caregiver, PCP and 
neurologist and suggestions for care outside of palliative care issues will be left to the patients’ Usual Care 
team.
1.b. Sources of Materials
Data will be obtained from subjects non-invasively via interviews, questionnaires, cognitive testing, and 
neurological examination as described above.
This data will be accessible only to the research team and, if requested, by appropriate regulatory bodies such 
as the IRB and FDA. All documents generated by this study, including consent, will be stored in a locked filing 
cabinet in the locked office of the Principal Investigator (PI). Electronic data will be de-identified with the 
exception of a correlational spreadsheet including demographic information and study IDs for scheduling and 
safety contact purposes. This, and all other data, will be stored on a password protected network drive and 
backed-up on the hard-drive of the PI, also password protected, and kept in the PI’s locked office. Identifying 
information will not be shared outside of the research team or regulatory bodies (e.g. IRB).
1.c. Potential Risks
There are minimal risks involved in the proposed research. There are no known significant risks from the 
intervention, interviews or surveys proposed for this study. Experiences from collaborators on this study 
suggest that most patients and caregivers welcome the opportunity to talk about their experiences, even on 
these potentially delicate subjects. Our interviewers will be cognizant of signs of emotional distress in 
participants and will suggest breaks and remind them that participation is voluntary. Cognitive testing and 
surveys as proposed in this study may induce boredom or restlessness. Any new diagnoses detected during 
screening (e.g. depression or dementia) will be referred for appropriate treatment, including emergent 
treatment if indicated. There are no known significant risks to the proposed team-based intervention for 
addressing palliative care needs. Participants will be reminded of the voluntary nature of this research and 
informed that we can follow them outside of the intervention or they can completely discontinue the study if 
they find it excessively burdensome or otherwise troubling.
2. Adequacy of Protection Against Risks
2.a. Recruitment and Informed Consent
Participants will be recruited from the academic medical centers (University of Colorado, University of 
California San Francisco, University of Alberta), associated clinics, community neurologists, and direct 
advertisements and contact with patients (e.g. clinicaltrials.gov, community seminars). Protocols will be 
approved by the relevant regulatory body at each institution before any contact is made with potential 
participants. We will obtain informed consent before any study related activities are performed. Potential 
subjects will be specifically told that their participation or lack of participation will not affect the clinical care they 
receive. For PD Dementia subjects, special procedures will be in place to involve both guardians and patients 
in the informed consent process, and both guardians and subjects will be required to give consent in person or 
by phone if performing visit by telehealth (or assent for PDD subjects unable to give full informed consent). The 
consenting process will use standard IRB terminology and will include a full description of expected subject 
involvement, procedures, risks, rights, and benefits. Capacity will be formally assessed in any patients with 
cognitive impairments and guardian consent and patient assent will be required in these cases.83
2.b. Protections Against Risks
All subjects will be reminded that they can take breaks or discontinue the study at any time if they find it 
upsetting. PD dementia subjects will be required to give consent (if they have capacity) or assent with 
caregiver consent to avoid potential manipulation of a vulnerable population. Regarding patient privacy, all 
research procedures will be performed in a confidential setting. All documents generated by this study, 
including consent, will be stored in a locked filing cabinet in the locked office of the PI. Electronic data will be 
de-identified with the exception of a correlational spreadsheet including demographic information and study IDs 
for scheduling and safety contact purposes. This, and all other data, will be stored on a password protected 

network drive and backed-up on the hard-drive of the PI, also password protected, and kept in the PI’s locked 
office. Identifying information will not be shared outside of the research team or regulatory bodies (e.g. IRB).
3. Potential Benefits of the Proposed Research to Human Subjects and Others
All subjects participating will receive a free neurological examination and history from a movement disorder 
trained specialist, and screening for dementia and depression. These results will be reviewed by a study 
neurologist and referred for appropriate care if abnormalities are identified. Participants randomized to the 
usual care arm will have care with a neurologist arranged if they do not already have this in place. Participants 
randomized to the palliative intervention will have access and care from an interdisciplinary team. This 
proposal has the potential to further our knowledge of care models in PD and has the potential to influence our 
ability to address many currently unmet needs for patients and caregivers. As discussed below, the knowledge 
gained by this proposal has a significant potential to advance our knowledge of palliative needs in PD which 
has large positive implications for PD patients, the scientific community and society.
4. Importance of Knowledge to be Gained
Parkinson’s disease (PD) affects 1-2% of adults over age 65 representing approximately 1.5 million Americans. 
Although PD is traditionally characterized by motor symptoms such as tremor and slowed movement more 
recent research shows that PD patients also commonly experience non-motor symptoms such as pain, fatigue, 
depression and dementia. PD interferes with patients’ quality of life, leads to disability, decreases length of life 
and causes significant distress for caregivers. Unfortunately, many of the needs most important to patients and 
their caregivers (e.g. depression, planning for the future) are poorly addressed under current models of care. 
The goal of this proposal is to take a patient-centered approach to answering these questions. Our specific 
objectives are to: 1) Determine whether an outpatient palliative care team improves patient quality of life and 
caregiver distress compared to usual care with a neurologist; 2) Determine what patient and caregiver 
characteristics best predict benefit from palliative care services; and 3) Interview patients and caregivers to 
optimize service delivery and selection. This project is important to patients and their family caregivers 
because it assesses a new approach to PD care that has the potential to improve quality of life, caregiver 
burden and other important outcomes (e.g. nursing home placement). By testing the effectiveness of this 
approach and determining who benefits most we hope to provide a new option to assist those PD patients at 
highest risk for poor outcomes. Information generated by this proposal will also be important for other 
stakeholders interested in PD including hospitals, insurers and patient advocacy organizations.
5. Data and Safety Monitoring Plan
We will not assemble a Data and Safety Monitoring Board (DSMB) as this is a minimal risk study comparing 
the effectiveness of two currently available approaches to the care of PD and APD patients. The site PI will be 
notified of any adverse events occurring at all sites and will notify the study’s central IRB (COMIRB) of all 
adverse events and any change in our appraisal of the risks and benefits of this study from our data or other 
published literature.
6. ClinicalTrials.gov Requirements
We will register this trial with clinicaltrials.gov prior to enrollment of the first participant at any site. 
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Study Procedures
Baseline
6 wk 
assessment
3 
mos. 
visit
6 wk 
assessment 
after 3 
mos. visit
6 
mos. 
visit
6 wk 
assessment 
after 6 
mos. visit
9 
mos. 
visit
6 wk 
assessment 
after 9 
mos.  visit
12 mos. 
visit
Optional 
post study 
interview & 
Telemedicine 
Surveys
Consent ΩΩ
P, C, 
Poviders 
(for 
telemed)
University of California Brief Assessment of 
Capacity to Consent (UBACC)ΩΩ
P
Medications ΩΩ
P
P
P
P
Need Assessment Tool – PD (NAT – PD)*
P
History *
P
Charlson Comorbidity Index *
P
Hoehn and Yahr Staging *
P
UK Brain Bank Clinical Diagnostic Criteria*
P
MDS UPDRS Motor Subscale*
P
P
P
MOCA* 
P
P
P
Patient Performance Scale*
P
P
P
Inclusion/Exclusion*
P
QOL – AD ΩΩ
P, C
P, C
P, C
P, C
P, C
Zarit Burden of Care Instrument  (ZBI) β
C
C
C
C
C
 Advance Directives
 Pt
 Pt
 Pt
Edmonton Symptom Assessment Scale 
(ESAS –PD)ΰ
P
P
P
P
P
Functional Assessment Of Chronic Illness – 
SP (FACIT – SP)ΰ
P,C
P,C
P,C
P,C
P,C
Hospital Anxiety and Depression Scale 
(HADS) ΩΩ
P, C
P, C
P, C
P, C
P, C
Parkinson’s Disease Questionnaire – 39 
(PDQ – 39) ΰ
P
P
P
P
P
Prolonged Grief Questionnaire – 12 (PG – 
12)ΰ
P
P
P
P
P
PROMIS – 29 ΰ
P
P
P
P
P
Demographics ΩΩ
P, C
Health Utilization Questionnaire ΩΩ
P, C
P, C
P
P, C
P
P, C
P
P, C
P, C
Strata Adherence ΩΩ
P
P
P
P
Randomization
P

APPENDIX 1
* administered by clinician – inclusion/exclusion form,  NAT – PD, MOCA, MDS UPDRS Motor Subscale,  Hoehn and Yahr Staging, History, UK Brain Bank Clinical 
Staging, Patient Performance Scale and  Charlson Comorbidity Index
ΩΩ administered by coordinator – consent, UBACC, QOL – AD, PROMIS – 29, Medications, Demographics and Health Utilization
ΰ self-administered (patient) - PDQ – 39, ESAS –PD, FACIT – SF, PG -12 and PROMIS -29
β self- administered (caregiver) -  Zarit Burden of Care Instrument, EQ-5D
After review of consent with subject, UBACC then should be administered next by the coordinator to see if subject has the capacity to consent prior to signing 
consent.  
No study procedures should be completed prior to the consent process.
QOL – AD and Zarit Burden of Care Instrument (ZBI) [care giver] if applicable, should be administered first prior to any other study procedures.
Please note, CGI will be administered by coordinator at 3 and 9 month visit (omit questions 2C at 3 and 9 month visits) and at 6 and 12 month visit it will be 
administered by the clinician.
 6 week assessment after every scheduled visit will be done by phone.
 3, 6, 9 and 12 month visit, only capture medication changes. 
Data collection for all study visits can be done by phone, online survey, via telehealth, or in person.  
Time windows for study visits and data collections are as follows:

The 3, 6, 9, and 12-month visits should occur within +/- 4 weeks of scheduled date.

 The one week follow-up phone call should occur within 1 week of scheduled date.

The six week follow-up phone call should occur within 2 weeks of scheduled date.

The six-week health care utilization survey call should occur within 2 weeks of scheduled date.  
Qualitative Interview
P, C, 
Providers