Standardized PatiEnt-CenTered medicatiOn Review (SPECTORx) in Home Hospice
Phase: NA
Conditions: Hospices, Poly Pharmacy, Deprescriptions, Caregivers, Palliative Care, Prescription Drug Overuse, Interdisciplinary Communication
Sponsor: University of Massachusetts, Worcester

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Standardized Patient-Centered Medication Review in 
Home Hospice 
This title should include, where possible, information on the participants, condition being evaluated, and 
intervention(s) studied. 
Unique Protocol Identification Number:  
National Clinical Trial (NCT) Identified Number: NCT03972163 
Principal Investigator: Jennifer Tjia 
Sponsor:  
"Sponsor" indicates an institution, foundation, or individual who takes responsibility for and initiates a 
clinical investigation; often times this is the university with which the Principal Investigator is affiliated. 
Grant Title: PILOT STUDY OF STANDARDIZED PATIENT-CENTERED MEDICATION 
REVIEW (SPECTORX) IN HOME HOSPICE 
Grant Number: R21 AG060017 
Funded by: NIA 
Version Number: v.1.004 
30 January 2020 
All versions should have a version number and a date. Use an international date format (e.g.,YYYY-MM-
DD [2017-12-21] or write out the month (e.g., 21 December 2017). 
For the initial submission of a protocol to the IRB, indicate "Not applicable; this is the first version of the 
protocol." in the table below. For any subsequent amendment being submitted to the IRB, add details of 
the specific changes that are being implemented in the amendment. Please note that Section 10.4 is a 
high-level summary of all formal protocol versions/amendments. 
 
 
Summary of Changes from Previous Version: 
Affected Section(s) Summary of Revisions Made 
Rationale 
8.4 - Unanticipated 
problems 
Included language to address 
possible situation that participants 
may use telephone surveys to ask 
clinical questions  
To ensure participant safety, this 
change establishes a procedure to 
escalate clinical questions to the 
clinical hospice team in a timely and 
systematic manner 
  
  
  
 
 

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Table of Contents 
Statement of Compliance .............................................................................................................................................. 4 
Investigator's Signature.............................................................................................................................................. 4 
1 Protocol Summary ....................................................................................................................................................... 6 
1.1 Synopsis ................................................................................................................................................................ 6 
1.2 Schema ............................................................................................................................................................... 10 
1.3 Schedule of Activities ......................................................................................................................................... 11 
2 Introduction............................................................................................................................................................... 13 
2.1 Study Rationale .................................................................................................................................................. 13 
2.2 Background ........................................................................................................................................................ 13 
2.3 Risk/Benefit Assessment .................................................................................................................................... 14 
2.3.1 Known Potential Risks ................................................................................................................................. 14 
2.3.2 Known Potential Benefits ............................................................................................................................ 14 
2.3.3 Assessment of Potential Risks and Benefits................................................................................................ 14 
3 Objectives and Endpoints.......................................................................................................................................... 16 
4 Study Design .............................................................................................................................................................. 18 
4.1 Overall Design .................................................................................................................................................... 18 
4.2 Scientific Rationale for Study Design ................................................................................................................. 18 
4.3 Justification for Intervention .............................................................................................................................. 19 
4.4 End-of-Study Definition ...................................................................................................................................... 19 
5 Study Population ....................................................................................................................................................... 20 
5.1 Inclusion Criteria ................................................................................................................................................ 20 
5.2 Exclusion Criteria ................................................................................................................................................ 20 
5.3 Lifestyle Considerations ..................................................................................................................................... 21 
5.4 Screen Failures ................................................................................................................................................... 21 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 21 
6 Study Intervention(s) or Experimental Manipulation(s) ........................................................................................... 23 
6.1 Study Intervention(s) or Experimental Manipulation(s) Administration ........................................................... 23 
6.1.1 Study Intervention or Experimental Manipulation Description ................................................................. 23 
6.1.2 Administration and/or Dosing .................................................................................................................... 23 
6.2 Fidelity ................................................................................................................................................................ 23 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING ............................................................................................ 23 
6.3 Measures to Minimize Bias: Randomization and Blinding................................................................................. 24 
6.4 Study Intervention/Experimental Manipulation Adherence ............................................................................. 24 
6.5 Concomitant Therapy ......................................................................................................................................... 24 
6.5.1 Rescue Therapy ........................................................................................................................................... 24 
7 Study Intervention/Experimental Manipulation Discontinuation and Participant Discontinuation/Withdrawal ... 25 
7.1 Discontinuation of Study Intervention/Experimental Manipulation ................................................................. 25 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 25 
7.3 Lost to Follow-Up ............................................................................................................................................... 26 
8 Study Assessments and Procedures .......................................................................................................................... 27 
8.1 Endpoint and Other Non-Safety Assessments ................................................................................................... 27 
8.2 Safety Assessments ............................................................................................................................................ 27 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 28 
8.3.1ADVERSE EVENTS ......................................................................................................................................... 28 

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8.4 Unanticipated Problems..................................................................................................................................... 29 
9 Statistical Considerations .......................................................................................................................................... 30 
9.1 Statistical Hypotheses ........................................................................................................................................ 30 
9.2 Sample Size Determination ................................................................................................................................ 30 
9.3 Populations for Analyses .................................................................................................................................... 30 
9.4 Statistical Analyses ............................................................................................................................................. 30 
9.4.1 General Approach ....................................................................................................................................... 30 
9.4.2 Analysis of the Primary Endpoint(s) ............................................................................................................ 30 
9.4.3 Analysis of the Secondary Endpoint(s)........................................................................................................ 31 
9.4.4 Safety Analyses............................................................................................................................................ 31 
9.4.5 Baseline Descriptive Statistics ..................................................................................................................... 31 
9.4.6 Planned Interim Analyses ............................................................................................................................ 31 
9.4.7 Sub-Group Analyses .................................................................................................................................... 32 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 32 
9.4.9 Exploratory Analyses ................................................................................................................................... 32 
10 Supporting Documentation and Operational Considerations ................................................................................ 33 
10.1 Regulatory, Ethical, and Study Oversight Considerations................................................................................ 33 
10.1.1Informed Consent Process ......................................................................................................................... 33 
10.1.2Study Discontinuation and Closure ............................................................................................................ 34 
10.1.3Confidentiality and privacy ........................................................................................................................ 35 
10.1.4Future Use of Stored Specimens and Data ................................................................................................ 36 
10.1.6Safety Oversight ......................................................................................................................................... 36 
10.1.7Clinical Monitoring ..................................................................................................................................... 37 
10.1.8Quality Assurance and Quality Control ...................................................................................................... 37 
10.1.9Data Handling and Record Keeping ........................................................................................................... 38 
10.1.10 Protocol Deviations ................................................................................................................................. 38 
10.1.11 Publication and Data Sharing Policy ....................................................................................................... 39 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 39 
10.2 Additional Considerations ................................................................................................................................ 40 
10.3 Abbreviations and Special Terms ..................................................................................................................... 40 
10.4 Protocol Amendment History .......................................................................................................................... 41 
11 References ............................................................................................................................................................... 43 
References ............................................................................................................................................................ 43 
 
 
 

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STATEMENT OF COMPLIANCE 
Provide a statement that the trial will be conducted in compliance with the protocol, International 
Council on Harmonisation Good Clinical Practice (ICH GCP) and applicable state, local and federal 
regulatory requirements. Each engaged institution must have a current Federal-Wide Assurance (FWA) 
issued by the Office for Human Research Protections (OHRP) and must provide this protocol and the 
associated informed consent documents and recruitment materials for review and approval by an 
appropriate Institutional Review Board (IRB) or Ethics Committee (EC) registered with OHRP. Any 
amendments to the protocol or consent materials must also be approved before implementation. Select 
one of the two statements below. If the study is an intramural NIH study, use the second statement 
below: 
1. The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
o 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
OR 
2. The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the [specify NIH Institute or Center (IC) [ Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the funding agency and documented approval from the 
Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection and ICH GCP Training. 
For either option above, the following paragraph would be included: 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
INVESTIGATOR'S SIGNATURE 
Principal Investigator or Clinical Site Investigator: 

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Signed: 
  
Date: 
  
Name*:  
Jennifer Tjia 
Title*:  
Principal Investigator 
 
 
Investigator Contact Information: 
Affiliation*:  UMass Medical School 
Address:  
368 Plantation Street, Worcester, MA 01605 
Telephone:  774-455-3538 
Email:  
jennifer.tjia@umassmed.edu 
 
For multi-site studies, the protocol should be signed by the clinical site investigator who is responsible  
for the day to day study implementation at his/her specific clinical site: 
Signed: 
  
Date: 
  
Name:  
Jennifer Tjia 
Title:  
Principal Investigator 
Affiliation:  UMass Medical School 
  
Signed: 
  
Date: 
  
Name:  
Margaret Clayton 
Title:  
Co-Investigator 
Affiliation:  University of Utah 
  
Signed: 
  
Date: 
  
Name:  
Susan DeSanto-Madeya 
Title:  
Co-Investigator 
Affiliation:  Boston College 
 
 

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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
Standardized Patient-Centered Medication Review in 
Home Hospice 
Grant Number: 
R21 AG060017 
Study Description: 
Background 
    Over 1.3 million Americans aged 65 years and older receive 
hospice services annually and 45% are cared for at home.5 These 
patients are prescribed an average of 10-12 medications daily6 7 
8and have progressively declining organ function that increases their 
risk of drug-related harm9 10. Furthermore, many take questionably 
beneficial medications11 12 13until death while simultaneously being 
prescribed an increasing number of end-of-life (EOL) symptom 
management drugs. This changing combination of medications 
contributes to stress and confusion for family caregivers (FCG) who 
are responsible their management and administration.14 3  
  
Study Design 
   This protocol describes a pilot multi-site cluster randomized trial of 
a behavioral education intervention to standardize hospice clinician 
approach to medication management support for family caregivers 
of patients in home hospice vs attention control of an educational 
handout about medication management for older adults education 
from the NIA.  The primary outcome if feasibility and acceptability of 
the trial as measured by trial enrollment and completion.  Secondary 
outcomes include family caregiver medication administration 
burden, family caregiver satisfaction with care, polypharmacy, 
medication regimen complexity, patient quality of life, patient 
symptom burden, adverse events including hospitalizations and 
emergency department and adverse drug withdrawal events.  
Objectives*: 
Primary 
Objective: 
To determine, among patients admitted to 
home hospice with life-limiting illness, the 
acceptability and feasibility of enrollment 
and completion of a trial of a medication 
support program delivered by home hospice 
clinical staff. 

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Secondary 
Objective: 
Secondary analysis will investigate the 
following outcomes: 
• 
Family caregiver medication burden, as 
measured by the Family Caregiver 
Medication Administration Hassle Scale. 
• 
Family caregiver satisfaction with care, as 
determined by likelihood to recommend 
• 
Polypharmacy 
• 
Potentially inappropriate medication use, 
as determined by a modified Medication 
Appropriateness Index 
• 
Medication regimen complexity, as 
measured by the Medication Regimen 
Complexity Scale 
• 
Medication changes 
• 
Adverse drug withdrawal events, as 
measured by a single item single item 
measure of change in medication since last 
visit and associated symptom change 
• 
Patient Quality of life (QOL), as measured 
by the McGill QOL Questionnaire (MQOLQ) 
• 
Patient Symptoms, as measured by the 
Edmonton Symptom Assessment System 
(ESAS) 
• 
Performance status, as measured by the 
Karnofsky Performance Status sale (KPS) 
• 
Unanticipated Events (whether study-
related or not), as measured by time to 
first important event, consisting of:  
o 
admission to a hospital for any 
reason 
o 
admission to an emergency 
department for any reason 

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• 
Overall survival, as measured by time-to-
death 
  
Endpoints*: 
Primary Endpoint: Trial completion 
Secondary 
Endpoints: 
As described in Secondary Objectives 
Study Population: 
Eligible participants are adults aged 65 years and older with 
advanced life-limiting illness with an estimated prognosis of 1-
6 months who are prescribed 5 or more medications and their 
family caregivers.  
Phase* or Stage: 
Feasibility Trial 
Description of Sites/Facilities 
Enrolling Participants: 
Hospice Sites. EOL practices vary regionally.13 15Thus, we are 
partnering with two large, geographically distinct home hospice 
agencies to begin exploring the generalizability of SPECTORx 
nationally. Each agency has multiple offices serving different 

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local regions within their states. Care Dimensions 
(Massachusetts) has 2 offices serving 4 counties in Eastern 
MA, and CNS Home Health & Hospice (Utah) has 10 offices 
throughout Utah. 
Description of Study 
Intervention/Experimental 
Manipulation: 
The study intervention is a patient-centered medication review and 
FCG support program called “Standardized PatiEnt-CenTered 
medicatiOn Review (SPECTORx) in Home Hospice”. This intervention 
combines 3 innovative, complementary, educational programs that, 
together, train hospice staff to create a comprehensive, patient-
centered, medication management plan. These evidence-based 
tools equip hospice staff: 1. to systematically identify medications 
that can be stopped or tapered using STOPPFrail (Screening Tool of 
Older Persons Prescriptions) criteria; 2. to discontinue medications 
appropriately; and 3. to educate and support FCGs with medication 
administration and management challenges. The SPECTORx program 
also creates an online learning community for hospice clinicians to 
promote ongoing education and practice change. 
Study Duration*: 
Estimated study duration from earliest enrollment to 
completion of data collection is 12 months. 
Participant Duration: 
Estimated time it will take for each individual participant to 
complete all study-related tasks (i.e. time from enrollment to 
patient death, discharge from hospice, or end of study) is 6 
months. 
 
 

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1.2 SCHEMA 
 
 
 

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1.3 SCHEDULE OF ACTIVITIES 
  
STUDY PERIOD 
  
Screening / 
Enrollment 
  
Post-allocation 
Close-out 
TIMEPOINT 
  
Baseline 
(Day 0-3) 
  
2 weeks 
4 weeks 
  
  
6 weeks 
8 weeks and 
monthly 
24 weeks or 
death 
ENROLLMENT 
Eligibility screening 
x 
  
  
  
  
  
Informed consent 
x 
  
  
  
  
  
FEASIBILITY 
SPECTORx Intervention 
  
  
  
  
  
  
Attention Control 
  
  
  
  
  
  
ASSESSMENTS (Source/Items) 
FCG/Demographics 
x 
  
  
  
  
  
FCG/Family Caregiver 
Medication Administration 
Hassle Scale 
x 
 x 
 x 
x 
x  
  
FCG/Potential medication 
related symptom change 
  
x 
x 
x 
x 
  
FCG/Patient Centered 
Medication 
Communication  
x 
x 
x 
x 
x 
  
FCG/Satisfaction with Care 
(Likelihood to recommend) 
  
  
  
  
  
x 
EMR/ PT Demographics 
x 
  
  
  
  
  
EMR/ PT Primary Hospice 
Admitting Diagnosis* 
x 
  
  
  
  
  
EMR/ PT Comorbid Illness* 
x 
  
  
  
  
  
EMR/PT Medications* 
x 
x 
x 
x 
x 
  
EMR/PT KPS* 
x 
x 
x 
x 
x 
  
EMR/PT Survival* 
  
x 
x 
x 
x 
  
EMR/PT Health resource 
utilization (hospital 
admissions, emergency 
department visits)* 
  
x 
x 
  
x 
x 
  

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EMR/Potential Drug Related 
Problem Screen 
x 
x 
x 
x 
x 
  
Patient/Potential Drug 
Related Problem 
  
x 
  
x  ( & 
monthly 
thereafter) 
  
  
Patient/MQOLQ 
x 
x 
x 
x 
x 
  
Patient/ESAS 
x 
x 
x 
x 
x 
  
 
 

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2 INTRODUCTION 
2.1 STUDY RATIONALE 
Need for a Comprehensive, Patient-Centered, Medication Review and FCG Support Program 
  
A tremendous challenge in home hospice care is ensuring that medication prescribing is appropriately 
aligned to patients’ goals of care and that medications are appropriately managed by FCGs. 
  
There are no intervention studies addressing medication appropriateness in home hospice. Our 
literature review16 found one uncontrolled, retrospective study in geriatric palliative care that reviewed 
and simplified regimens by reducing unnecessary drug use by 65% (from 1.7 to 0.6 per patient).17 
Investigators reported that 74% of patients used at least 1 unnecessary medication (defined as drugs 
with lack of indication, lack of effectiveness, or prolonged duration of therapy). Their study provided 
“proof of concept” that it is possible to systematically review and simplify medications in geriatric 
palliative care.17 However, such studies have focused on geriatrics18 19 20 21 22 23and nursing homes,24 25 
and not home hospice. 
  
Few studies examine FCG medication management needs.14 3 26 27 FCGs have many challenges, including 
dealing with patients’ non-adherence, deciding which medications to give, juggling administration times 
and monitoring for side effects.14 3 Furthermore, patient symptom outcomes depend on appropriate 
medication administration. (Figure 1) The implication is that high-quality, patient-centered care needs to 
address both medication appropriateness and FCG medication management support. 
  
Therefore, we propose a novel approach that trains hospice staff to (a) regularly review, simplify, and 
align patients’ prescribed medications with their goals of care as their illness progresses, 16 and (b) 
support FCGs’ with education that empowers them to understand each medication’s use, develop skills 
for safe administration, and understand when stopping medications may be beneficial.3 26  
 
 
2.2 BACKGROUND 
Polypharmacy for Home Hospice Patients is Burdensome, Harmful and Costly 
Over 1.3 million Americans aged 65 years and older receive hospice services annually and 45% are cared 
for at home.5 These patients are prescribed an average of 10-12 medications daily6 7 8 and have 
progressively declining organ function that increases their risk of drug-related harm.9 Furthermore, 
many take questionably beneficial medications11 12 13 until death while simultaneously being prescribed 
an increasing number of end-of-life (EOL) symptom management drugs.8 This changing combination of 
medications contributes to stress and confusion for family caregivers (FCG) who are responsible who are 
responsible for patient medication management and administration.14 3 

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Family (Informal) Caregivers Find Managing Complex Home Hospice Medication Regimens Stressful 
Family (informal) caregivers are defined as “any relative, partner, friend or neighbor who has a 
significant personal relationship with, and provides a broad range of assistance for [an older 
person]”. 4 Hospice is a particularly challenging setting for FCGs because they are responsible for 
complicated medication administration tasks that are usually reserved for licensed healthcare 
professionals.28  An estimated 44 million adults, mostly women, provide this informal (i.e. unpaid) 
care. 29 They often feel inadequately prepared for this responsibility 30 and have fears about doing 
something wrong.28 30  
 
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
The risks and costs vs benefits of reducing polypharmacy for patients with advanced disease and their 
family caregivers remains a genuine clinical uncertainty.  Multiple studies support the use of myriad 
individual chronic disease medications, such as statins, in elderly adults with appropriate indication. 
However, the benefit of continuing chronic disease medications after hospice admission on quality of 
life, family caregiver medication hassle, or patient survival is unknown.  Simplifying medication regimens 
through a process of depresribing is one remedy to medication complexity as death approaches, but 
may be associated with potential risk of stress to family caregivers about making decisions regarding 
stopping medications and additional potential risk of adverse drug withdrawal events after stopping 
medications - a particular concern when abruptly stopping medications with long half lives that are 
known to require tapering protocols. 
2.3.2 KNOWN POTENTIAL BENEFITS 
Multiple studies support reduction of polypharmacy in elderly patients with multi-morbidity. Less is 
known to support the benefit of medication discontinuation among patients in hospice. One exception is 
the question of benefit from stopping statins used for primary prevention among eldelry patients with 
advanced illness, a question addressed in a randomized controlled trial of statin discontinuation by 
Kutner et al.  These data show that statin discontinuation does not contribute to shorted survival, and 
may be associated with improved quality of life.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
Polypharmacy has known patient burden and associated patient side effects. This is attributable to the 
accumulation of individual medication effects, and known drug-drug interactions resulting from complex 
medication regimens. For patients with life-limiting conditions who take one or more chronic disease 
medications along with symptom directed therapies, the balance of medication efficacy vs burden 
remains unclear.  Finally, the psychological impact of using or discontinuing chronic disease medications 
in the setting of advanced life-limiting illness is largely unknown.  Patients may feel relief when not 

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taking as many pills, anticipating the potential for fewer side effects, and paying less medication costs 
for medications not covered by hospice yet desired by the family. Conversely, there may be increase 
worry or distress when discontinuing a medication that a patient and their family was told would need 
to be taken for the rest of their lives.  
 
 

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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary 
Feasibility and 
Acceptability 
• 
Intervention 
Delivery to Hospice 
Staff 
• 
Patient and Family 
Caregiver 
Recruitment Goals 
• 
Completion of FCGs 
Assessments 
• 
Completion of 
Patient 
Assessments 
• 
Time for completing 
FCG assessments 
• 
Time for completing 
Patient 
Assessments 
• 
Yield of FCG 
Eligibility Criteria 
• 
Yield of Patient 
Eligibility Criteria 
• 
Measurements of 
Intervention Uptake 
• 
Measures of 
Recruitment Yield 
• 
Measure of 
Outcome 
Assessment Success 
  
Secondary 
Efficacy and Safety 
• 
FCG Burden 
• 
Medication 
Regimen 
Complexity 
• 
Patient-Centered 
Medication 
Communication 
• 
Primary Outcome 
for trial 
• 
Patient medication 
burden    
• 
Quality of 
prescribing for 
patients 
  
   

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
• 
Potentially 
Inappropriate 
Medications, as 
measured by 
modified 
Medication 
Appropriateness 
Index 
• 
Medication changes 
• 
Patient QOL, as 
measured by McGill 
QOL Questionnaire 
• 
Patient Symptoms, 
as measured by 
Edmonton 
Symptom 
Assessment System 
(ESAS) 
• 
Overall Survival 
• 
Suspected 
Unexpected Serious 
Adverse Reactions 
(SUSAR) 
• 
Drug Related 
Problems 
  
  
• 
Key patient outcome 
  
  
  
• 
Key patient outcome 
  
  
  
• 
Key patient outcome 
• 
Assessment of risk 
for study population 
• 
Risk assessment for 
intervention 
Tertiary/Exploratory 
  
  
  
  

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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
A pilot, single-blinded, cluster randomized, pragmatic trial of the SPECTORx intervention. 
We will compare outcomes within and across 2 large, multi-office, hospice agencies from Utah and 
Massachusetts. Within each hospice agency, we will randomize 1 office to intervention and 1 office to 
attention control. Target enrollment is 30 FCG-patient dyads per agency (n=15 intervention, n=15 
control), for a total trial target of n=60 FCG-dyads of patients aged ≥65 years, with an estimated life 
expectancy of >1 month, and polypharmacy (defined as ≥5 regularly scheduled daily medications). 
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This is a controlled study to evaluate the effect of a medication review, education and communication 
intervention on improving medication administration burden by family caregivers in home hospice. The 
unit of randomization is the team within a hospice agency, the intervention is aimed at the hospice 
clinicians, and patient and family caregivers are the units of analysis. We randomize at the level of the 
hospice to reduce cross-contamination at the clinician level.  
  
Study Design. We will compare outcomes within and across 2 large hospice agencies using a cluster 
randomized trial study design. Within each hospice agency, we will recruit 30 eligible FCG-patient dyads 
(total n=60) of patients ≥65 years old, an estimated life expectancy >1 month, and polypharmacy 
(defined as ≥5 regularly scheduled daily medications). [Eligibility Criteria for details] 
Hospice Sites. EOL practices vary regionally.13 15 Thus, we are partnering with two large, geographically 
distinct home hospice agencies to begin exploring the generalizability of SPECTORx nationally. Each 
agency has multiple offices serving different local regions within their states. Care Dimensions 
(Massachusetts) has 2 offices serving 4 counties in Eastern MA, and CNS Home Health & Hospice (Utah) 
has 10 offices throughout Utah. Combined, they had over 5,000 hospice admissions in 2016. Both have 
recently participated in a research studies. (see Letters of Support) 
Randomization and Attention Control. Within each of the 2 hospice agencies, we will randomize 1 
office to intervention and 1 to control status. Target enrollment is 15 FCG-patient dyads at each office 
(total 30 FCG-patient dyads per hospice agency). As the attention control, we will refer staff in control 
offices to the NIA’s website on “Medicines and Medication Management” 37 to review content and 
materials for use in FCG support.   
 
 

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4.3 JUSTIFICATION FOR INTERVENTION 
High-quality, patient-centered care about medication management in hospice needs to address both 
medication appropriateness and FCG medication management support. We propose a novel approach 
that trains hospice staff to (a) regularly review, simplify, and align patients’ prescribed medications with 
their goals of care as their illness progresses, 16 and (b) support FCGs’ with education that empowers 
them to understand each medication’s use, develop skills for safe administration, and understand when 
stopping medications may be beneficial. 3 26 
  
  
 
 
4.4 END-OF-STUDY DEFINITION 
A FCG participant is considered to have completed the study if he or she has completed the baseline 
assessment, and at least the 2 week assessment and the post-death follow-up assessment (or at 6 
months if patient survives 6 months after hospice admission). 
  
A patient participant is considered to have completed the study if he or she has completed the baseline 
assessment, and at least the 2-week assessment. 
  
The end of the study is defined as completion of the 6-month follow-up assessment shown in the 
Schedule of Activities (SoA), Section 1.3. 
 
 

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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Participants (patients, FCGs, and clinical hospice staff) will be recruited for both intervention and control 
arms. 
  
FCG-Patient Dyads.  
  
Patient - Eligible patients are newly admitted home hospice enrollees, aged ≥65 years old with: 1. 
advanced life-limiting illness; 2. an estimated life expectancy of >1 month; 3. recent functional status 
decline (defined as change in Karnofsky Performance Status [KPS] 1 to < 80% in prior 3 months); 4. 
polypharmacy (defined as ≥ 5 regularly scheduled medications [excluding antimicrobials]); 5. cognitive 
ability to provide informed consent based on a Short Portable Mental Status Questionnaire (SPMSQ) 
score ≥6 2 OR, with a legally authorized representative who is willing and able to provide proxy consent. 
These variables are easily assessed on hospice intake forms on admission. 
  
FCG – FCGs are eligible if: they self-identify as “usually” or “always” providing care to the eligible 
patient; are English-speaking; have telephone access; and have cognitive ability to participate. 3 Family is 
operationally defined “any relative, partner, friend or neighbor who has a significant personal 
relationship with, and provides a broad range of assistance.” 4 
  
Hospice Clinicians - 
  
Hospice clinicians are eligible if : nurses, social workers, chaplains and medical directors deliver care or 
communicate with home hospice patients in the course of their primary hospice-related job 
responsibility; pharmacists are eligible if their primary responsibility is to oversee safety of prescribing of 
medications to home hospice patients or coordination of medication-related decisions with hospice 
prescribers. 
 
 
5.2 EXCLUSION CRITERIA 
A patient who meets any of the following criteria will be excluded from participation in this study: 
1. Life expectancy of < 1 month 
2. Age < 65 years old 
3. Cognitively unable to provide informed consent AND no legally authorized representative (LAR) to who is 
willing to provide proxy consent 

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4. No family caregiver 
 
 
5.3 LIFESTYLE CONSIDERATIONS 
 
 
5.4 SCREEN FAILURES 
We will not consent participants to do not meet eligibility criteria. It is possible that consenting, enrolled 
patients may die quickly after enrollment despite meeting eligibility criteria. This is not unexpected for 
this study population.   
  
  
 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Patient and family caregiver participants will be recruited through the participating home hospice 
clinical sites.  Each site minimally includes a dedicated Site Investigator and Research Assistant capable 
of enrolling in and conducting the study. 
  
The total enrollment is up to 60 consenting patient-FCG dyads. Within each of the 2 hospice agencies, 
we will randomize 1 office to intervention and 1 to control status. Target enrollment is 15 FCG-patient 
dyads at each office (total 30 FCG-patient dyads per hospice agency). 
  
Hospice clinician participants will be recruited at each hospice site. In cooperation with hospice 
administrative leaders, we will present the study to the hospice clinical teams and invite teams 
randomized to the intervention to complete the online education training intervention about 
medication review, education, and deprescribing.  
  
The Site PI will develop study-specific recruitment strategies in consultation with the local hospice 
administration.  Site RA and CRCs and other study staff will attend an introductory training program 
covering research related-communication, ethics, recruitment planning and implementation. 
  
The screening and recruitment algorithms will be developed for each site, delineating expected 
processes and highlighting potential hurdles so that effective solutions can be developed.  Key messages 
for the recruitment call/visit, supporting study diagrams, recruiting scripts, strategies for working with 

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bereaved family members, and simplified consent language will be developed. Tools will be practiced 
through role plays:  refresher role plays will be repeated periodically during the study to ensure quality 
and consistency. Recruitment metrics will be monitored on a regular basis and will including screening 
eligibility, study completion, study withdrawal rates; progress will be presented to Site Investigators and 
staff.  If a study site should encounter particular difficulty with enrollment, the study team may conduct 
a site visit to review obstacles and devise solutions, presenting results for review to the existing study 
stakeholder panel. 
  
Site specific screening will follow this general scheme, but may be adapted (as described herein) to local 
workflow procedures to minimize impact on clinical care delivery: 
In general, hospice staff (i.e. front-line hospice nurses or local administrative staff) will preliminarily 
screen eligible patients on their daily hospice census list and, at their discretion within the first week 
after the hospice admission visit, provide an IRB-approved generic brochure about research in hospice 
and palliative care; if there is interest in learning more about the study, the patient and family caregiver 
will also be given an IRB-approved study-specific brochure. A variation at some hospices routinely places 
an IRB-approved generic brochure about research in hospice and palliative care in the hospice admission 
packet along with information about how to contact the hospice to opt-out of being screened and 
contacted for research, or similarly routinely provides patients and families to opt-out of being screened 
for research based on the local hospice's forms and policies. We will work with local hospice leadership 
to identify the most appropriate approach for their system. Then, a list of eligible participants will be 
identified and confirmed by a CITI-trained RA who will examine the daily admissions for hospice to 
identify participants who meet eligibility criteria among patients who have indicated interest in hearing 
about the study to front-line staff (or, as applicable, has not opted-out to being screened for research. 
This will generate a final list of eligible patient and family, and the hospice will then forward contact 
information to the study team among eligible participants indicating in the form of an authorization to 
contact form.  
  
  
The Site RA will follow-up to lead recruitment efforts.  
 
 

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6 STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION  
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION  
  
Intervention:  We will present the SPECTORx educational intervention to clinical hospice staff 
randomized to the intervention.  This is comprised of 3 x 20-25 minute online in-service modules about 
systematic, patient-centered, medication review, educational support for family caregivers about 
medication administration, and deprescribing of potentially inappropriate medications. The intervention 
patient and family caregiver participants will be given a study-specific notebook including a blank 
notepad, a blank medication tracking sheet, and printed information about the Medications in Older 
Adult website, as well as printed guidance from the NIA's Medicine's and Medication Management 
website (https://www.nia.nih.gov/health/topics/medicines-and-medication-management) about "What 
Do I Need to Tell the Nurse and Doctor?", and clinical information handouts about medications 
commonly used in hospice (e.g. Haldol, Morphine, Understanding Nausea, Understanding Pain and 
Symptoms). 
  
Attention control:  We will refer clinical hospice staff randomized to control offices to "Medications in 
Older Adults" website sponsored by the American Geriatrics Society’s Health in Aging Foundation. 
(https://www.healthinaging.org/medications-older-adults)  Based on personal preferences, these 
materials can be shared via electronic link or the information can be printed and distributed in paper 
form to patients and their family caregivers. The attention control patient and family caregiver 
participants will be given a study-specific notebook including a blank notepad, a blank medication 
tracking sheet, and information about the Medications in Older Adult website.  
  
At the end of the trial, staff in control offices will be offered the SPECTORx educational intervention 
training. 
  
6.1.2 ADMINISTRATION AND/OR DOSING 
  
Staff will be referred to this attention control resources one time, but will be able to access the 
resources as many times as they deem clinically appropriate for the care of their patients. 
 
 
6.2 FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
  

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We will track completion of online learning of the three 20-25 minute SPECTORx educational modules, 
including self-assessment quizzes by tracking completion online and by asking consenting participants to 
complete brief self-assessments before and after the educational intervention. Study staff will 
periodically check in with hospice clinical staff to inquire about adherence to the study intervention. We 
will also track fidelity be asking FCGs of consenting hospice nurses brief questions about whether 
hospice staff conducted medication reviews, offered education and support about medication 
administration and management, and discussed the option of deprescribing medications that are 
potentially inappropriate. 
 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Randomization is at the level of the office location within each hospice agency.  
  
Outcomes assessments will be blinded with withholding intervention assignment data from the clinical 
research coordinator responsible for data collection related to the measurement of patient and family-
caregiver outcomes and from the adjudication team responsible for measuring ADE and ADWEs.  
 
 
6.4 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
The intervention is a medication support care intervention delivered by hospice clinical team, led by the 
hospice nurse.  Hospice teams are randomized to SPECTORx intervention or attention control of 
standard American Geriatric Society/NIA funded educational materials of medication management for 
older adults. 
 
 
6.5 CONCOMITANT THERAPY 
  
6.5.1 RESCUE THERAPY 
  
 
 

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7 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION  
The study intervention, which targets hospice clinical staff, will be delivered one time at the beginning of 
the study and will be delivered to any new clinical staff joining the intervention site teams.  We will 
inform the clinical sites of the end of the study when we 3 months after completion of study enrollment 
to allow for adequate, uncontaminated, collection of outcome data for all participants.  
  
When a subject discontinues study procedures will be completed as indicated by the study protocol.  If a 
clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
  
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for determining the 
need to discontinue 
• 
If the participant is due to complete assessments within 2 weeks of being discontinued from the study 
intervention, those assessments will be administered at the time of discontinuation; if the next scheduled 
assessments are more than 2 weeks from the discontinuation date, the discontinued participant will wait 
for the next scheduled assessment. Thereafter, the participant will be included in all future scheduled 
assessments, even though not participating in the intervention. 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
Participants (family caregivers and patients) are free to withdraw from participation in the study at any 
time upon request. 
  
An investigator may discontinue a participant from the study for the following reasons: 
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up study data 
would not be in the best interest of the participant or might require an additional treatment that would 
confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) that 
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The reason for participant discontinuation or withdrawal from the study will be recorded on the 
[specify] Case Report Form (CRF). 
  
Clinical staff participants (nurses, social workers, chaplains, physicians, pharmacists) area also free to 
withdraw from the study at any time. Consenting clinical participants who are randomized but do not 
receive the study intervention may be replaced. Consenting participants who are randomized and 
receive the study intervention, and subsequently withdraw, or are discontinued from the study, will be 
replaced when possible. 
 
 
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if study staff are unable to contact the participant after 
at least 3 attempts. 
The following actions must be taken if a participant fails complete study assessments:   
• 
The site will attempt to contact the participant and ascertain if the participant wishes to and/or should 
continue in the study 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter 
to the participant’s last known mailing address or local equivalent methods). These contact attempts will 
be documented in the participant’s medical record or study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up 
 
 

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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
The endpoint of the study is either patient death, disenrollment from hospice, or completion of 6 
months of follow-up after study enrollment. 
 
 
8.2 SAFETY ASSESSMENTS 
In accordance with applicable regulatory requirements and principles for the ethical conduct of 
research, a Safety Officer will be appointed by the NIA to oversee the safety of study participants. 
  
Because the study population has, per the eligibility criteria, a limited expected prognosis of less than 
one year, death and the preceding associated development of symptoms related to the natural 
progression of disease are expected. Because the study setting is home hospice, hospitalizations related 
to the natural progression of disease are expected to be unusual.  However, deaths, hospitalizations, 
and emergency department visits will be monitored. 
  
Because the focus of the trial educational intervention focuses on medication-related management, 
review and support, medication changes and symptom changes potentially related to drug related 
problems (DRPs) will be monitored, including potential DRPs present upon study enrollment which, by 
definition, are not related to the research. 
  
Medication changes will be identified by collecting medication lists every 2 weeks and iteratively 
identifying changes between lists. DRPs will be monitored by a trained research assistant who will 
screen the medical record using a Screening Algorithm of Potential Drug Related Problems at study 
enrollment and every 2 weeks up to 2 months for a retrospective chart review, and then monthly up to 6 
months.  These medical record will be reviewed for new clinical events, symptoms, abnormal lab events 
and drug levels, new reported drug allergies or drug associated problems identified by clinicians. 
Secondarily, a trained research assistant will also conduct a screening telephone interview with patients 
(or their caregiver, if patient is unable to participate) for potential DRPs using a method by 
Chrischilles31 at 2 weeks and monthly thereafter. 
  
To ensure that potential DRPs, emergency department visits, hospitalizations and deaths are indeed 
unrelated to the research, these will be closely monitored by the study's Event Classification Pharmacist 
(ECP) comprised of a pharmacist using a procedure described below in Section 8.3. 
  
  

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8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 ADVERSE EVENTS 
  
Any event due to the presence or progression of illness that a patient had on study enrollment will not 
be considered an adverse event (AE), including changes in symptoms, hospitalizations, emergency 
department presentations, and death more likely related to disease progression than not related to 
disease progression. Only events more likely not related to known underlying illness will be considered 
an AE. 
  
If such an event is also related to the research and is unanticipated, regardless of its level of severity, 
this would require expedited (prompt) reporting to the local IRB in keeping with its reporting 
requirements for a suspected unanticipated problem involving risks to subjects or others (suspected 
UPIRTSO). 
  
AEs are classified as to whether or not they are serious (SAE), namely life threatening (resulting in 
hospitalization, emergency department presentation or death), leading to permanent disability or 
judged a SAE by the site PI. AEs will be graded according to seriousness, and then designated as more 
likely expected or unexpected (yes/no), and more likely related or unrelated to the research (yes/no). 
Other characteristics of the AE to be recorded include date identified, diagnosis, outcome and date 
resolved. 
  
SAEs will be classified as to whether or not they are a Suspected Unexpected Serious Adverse Reaction. 
(SUSAR)  SUSARs are defined as events that are a suspected adverse reaction AND serious AND 
unexpected. This approach focuses the Safety Officer's and IRB's attention on potentially study 
participating-related events rather than on a large number of anticipated events that are part of normal 
disease progression and unrelated to the intervention.  If a SUSAR, then expedited reporting and 
processes must be followed, as outlined below.  If not a SUSAR, standard reporting for AEs is followed 
(for all AEs and SAEs), unless, as described above, the event meets the definition of a suspected 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO). An event can be a SAE, but not 
a SUSAR (e.g. a person hospitalized for hip fracture and not attributable to underlying known illness, but 
not suspected to be related to the study intervention). 
  
The ECC will review a pre-specified proportion of all hospitalizations and deaths. The ECC will determine 
if the hospitalization/death or drug related problem (DRP) was an expected event, SAE, or SUSAR. 
Results will be reported to the Safety Officer and the NIA Project Officer. 
  

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Cumulative aggregated AE data will be presented to the Safety Officer and the NIA Project Officer, along 
with tabulated outcomes data. This includes AEs, SAEs and SUSARs, plus survival, health resource 
utilization, and patient reported outcomes. 
  
The Study PI is also responsible for contacting the NIH grant program officer in the event that any action 
resulting in temporary or permanent suspension of the trial occurs.  (Because this trial does not involve 
any investigational medication, the action would be limited to an IRB- or investigator-initiated 
suspension or discontinuation of the study.) 
  
  
  
  
 
 
8.4 UNANTICIPATED PROBLEMS 
See discussion of UPIRTSO above in 8.3. 
  
Further, there is the possibility that the patient and/or family caregiver will ask clinical questions (e.g. 
about symptom management) of the study research assistant during a telephone interviews for study-
related outcomes assessment.  If this occurs, the research assistant will  1. provide the hospice triage 
phone number to the participant and direct him/her to call about their clinical questions and 2. call the 
hospice triage phone number directly, inform hospice that the participant had clinical questions, and 
request a call back to the patient/family caregiver.  
 
 

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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
• 
Primary Endpoint(s): For this exploratory study, the primary endpoints are: acceptability and feasibility of 
the SPECTORx intervention by hospice stakeholders; feasibility of a brief, standardized, ‘interest in 
research’ screen upon hospice admission to refer FCG-patient dyads for recruitment; acceptability, 
burden and completion of FCG assessments (FCG Medication Administration Hassle Scale 32 at baseline, 2 
weeks, 4 weeks, 6 weeks, 8 weeks, and monthly). 
• 
Secondary Efficacy Endpoint(s): medication regimen complexity index scores33 for chronic daily 
medications and prevalence of potentially inappropriate medications (baseline, 2 weeks, 4 weeks, 6 
weeks, 8 weeks, and monthly and death), patient quality of life, patient symptom burden 
 
 
9.2 SAMPLE SIZE DETERMINATION 
Sample Size Justification. In this exploratory study, we chose a sample size sufficient to enable a decision 
about feasibility.34 This sample size is larger than many pilot palliative care trials and sufficient to 
determine acceptability in each of the two hospice agencies.35 This sample size is also attainable. Target 
enrollment is 30 FCG-dyads at each hospice agency who, combined, have over 400 admissions a month. 
We lack power to establish efficacy for the intervention on outcomes. 
 
 
9.3 POPULATIONS FOR ANALYSES 
While we aim to enroll dyads of family caregivers and patients, the population for analysis include family 
caregiver outcome separate from patient outcomes. 
 
 
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
  
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
Feasibility and Acceptability. We will use descriptive statistics to analyze quantitative feasibility 
outcomes. We will calculate the mean number of eligible patient-FCG dyads screened and enrolled per 
week, accrual, retention, and training completion. We will use Chi-square (for comparisons of rates and 

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proportions) and t-tests (for mean comparisons) to explore differences by site and participant 
characteristics, including sex. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
A secondary goal of this pilot is to estimate preliminary intervention treatment effect size for a large-
scale, R01-funded trial. Comparisons will be made between the baseline and follow-up assessments, 
both within and across intervention and control sites. Descriptive analyses will establish data 
distributions for continuous outcomes (e.g. FCG Hassles Scale). We will use linear mixed effects models 
to account for cluster randomization for continuous outcomes. Clusters are hospice agencies, offices 
within agencies, clinicians within office, and patients within clinicians/nurses. Even with small samples, 
we can explore the relationship between change in measures (e.g. # PIMs) and FCG/patient factors. 
Mixed effects models are robust with small sample sizes and adjust for correlations from repeated 
measures within individuals and from clustering.    
     Missing Data. Descriptive analyses will characterize missing data frequency and examine associations 
with key characteristics (e.g. admitting diagnosis, race). Variables associated with missingness will be 
included in analyses as covariates to account for possible effects from the missing pattern (missing at 
random). 36 
9.4.4 SAFETY ANALYSES 
  
Safety reports will be sent to the Safety Officer and Project Officer at every 3 months and will include a 
detailed analysis of study progress, data and safety issues, including interim analyses as described in 
9.4.6. 
  
  
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
  
1. Baseline characteristics of the patients and family caregivers. 
  
9.4.6 PLANNED INTERIM ANALYSES 
1. Recruitment by week/month; 
2. Treatment phase of patients & family caregivers (screened, enrolled, follow-up phase); 
3. Completeness of data (assessments completed, % of expected forms submitted, % of submitted forms 
passing edit); 
4. Missed assessments and missing information within assessments; 
5. Summary of adverse events by type; 

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6. Summary of adverse events by body system; 
7. Summary of actual medication changes; 
8. Listing of adverse events (including duration, severity, seriousness, relatedness, action taken, resolution); 
9. Descriptive information for each endpoint without statistical testing except at designated interim 
monitoring points if requested by the DSMB, including # and details of medication changes for each 
patient during the study; 
10. Compliance information (completion of intervention training by clinical staff); and 
11. Quality control analyses. 
9.4.7 SUB-GROUP ANALYSES 
  
Analyses by intervention and control status. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
  
9.4.9 EXPLORATORY ANALYSES 
  
 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS  
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
To alleviate the burden of obtaining written consent from these typically home-bound patients and their 
family caregivers, we will use a telephone based consent procedure. That is, we will obtain a waiver of 
written documentation of informed consent for this minimal risk participation study for family 
caregivers and patients, since their involvement requests only access to medical records and completion 
of telephone questionnaires. 
  
If a patient and family caregiver a potentially interested in study participation, they will be given a Fact 
Sheet by the hospice staff that summarizes the relevant information about the study, including the risks, 
benefits, and rights as a study participant. Hospice staff will not answer questions about the study 
consent, but will refer all questions to trained study staff who will be scheduled to call the patient within 
1 week of referral to the study staff. The fact sheets will describe the study in detail the study 
intervention, study procedures, and risks. 
  
Potentially eligible patients will be referred to the study team. To minimize burden of making a 
unnecessary study enrollment calls to ineligible patients, we will request a HIPAA waiver for medical 
record review for the express purpose of confirming eligibility by the study team. If confirmed to be 
eligible, the study team will call the patient and family caregiver to explain the study, answer any 
question about participation and the fact sheet, and to obtain telephone recorded consent. 
  
Persons with dementia will be given the opportunity to consent for themselves because cognitive 
impairment is not always associated with the lack of capacity to provide informed consent to participate 
in research. Study staff will explain the study and assess capacity to consent based on the standard 
decision-making capacity criteria of: (a) ability to communicate a yes or no decision; (b) ability to 
understand relevant information; (c) ability to appreciate the situation and its likely consequences; and 
(d) ability to manipulate information rationally. If the patient is unable to meet all 4 of these criteria, we 
will obtain consent from a legally authorized representative (LAR). Further, study staff will obtain 
consent from the LAR for persons with a documented dementia severity of FAST 6 or greater as this 
indicates severe dementia with limited speech ability, or individuals has been ruled incompetent by a 
court of law or with documentation by a qualified practitioner in the medical record that the individual 
lacks capacity to make the decision to participate in the proposed study. 
  
Utah and Massachusetts hospice sites will provide lists of individuals who are authorized to consent 
when the patient ins unable to consent on their own behalf. In Utah this includes any married person for 

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a spouse and any person 18 years of age or older for his or her parent who is unable to reason of age, 
physical or mental condition, to provide such consent. In Massachusetts this includes a health care agent 
or guardian. 
  
The LAR will be provided with the description of the research study and informed of their role and 
obligation to protect the rights and welfare of the patient participant. The LAR must be informed that 
the obligation as a surrogate decision maker is to try to determine what the participant would decide if 
the participant were able to make such decisions. In the case of this study, the patient's participation 
would be limited to providing HIPAA waiver for access to the medical record for data collection. 
  
The following consent materials are submitted with this protocol. 
• 
Study fact sheet for patients 
• 
Study fact sheet for family caregivers 
• 
Telephone consent script 
• 
Assessing Capacity to Consent Form 
  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, the investigator and the funding 
agency (NIA). If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance of study staff to the protocol (i.e., significant protocol violations) 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the funding agency, sponsor, IRB, or Safety Officer. 

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10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally-identifiable 
information from the study will be released to any unauthorized third party without prior written 
approval of the sponsor/funding agency. 
  
All research activities will be conducted in as private a setting as possible. 
  
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, hospice or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
  
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the University of Massachusetts Medical School Data Coordinating 
Center. This will not include the participant’s contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification number. The study 
data entry and study management systems used by clinical sites and by the University of Massachusetts 
Medical School Data Coordinating Center research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived at the the University of 
Massachusetts Medical School Data Coordinating Center. 
  
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies It is NIH 
policy that the results and accomplishments of the activities that it funds should be made available to 
the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 
traceable to a specific study participant). Plans for archiving and long-term preservation of the data will 
be implemented, as appropriate. 
  
Certificate of Confidentiality 
  

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To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), 
has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, 
clinical or other human subjects research funded wholly or in part by the federal government. Recipients 
of NIH funding for human subjects research are required to protect identifiable research information 
from forced disclosure per the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). 
As set forth in 45 CFR Part 75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported 
research covered by this Policy are required to establish and maintain effective internal controls (e.g., 
policies and procedures) that provide reasonable assurance that the award is managed in compliance 
with Federal statutes, regulations, and the terms and conditions of award. It is the NIH policy that 
investigators and others who have access to research records will not disclose identifying information 
except when the participant consents or in certain instances when federal, state, or local law or 
regulation requires disclosure. NIH expects investigators to inform research participants of the 
protections and the limits to protections provided by a Certificate issued by this Policy. 
  
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Data collected for this study will be analyzed and stored at the University of Massachusetts Medical 
School Data Coordinating Center. After the study is completed, the de-identified, archived data will be 
transmitted to and stored at the Palliative Care Research Collaborative Data Repository, for use by other 
researchers including those outside of the study. Permission to transmit data to the Palliative Care 
Research Collaborative Data Repository will be included in the informed consent. 
  
During the conduct of the study, an individual participant can choose to withdraw consent to have data 
stored for future research. However, withdrawal of consent with regard to data storage may not be 
possible after the study is completed. 
  
When the study is completed, access to study data will be provided through the Palliative Care Research 
Collaborative Data Repository. 
  
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Safety Officer (SO) who is a physician with relevant 
study and disease-specific expertise appointed by the study sponsor/NIA.  The SO is independent from 
the study conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest.  The SO will review the safety and data monitoring plan, informed consent 
documents, and participant recruitment and retention milestones.  At predetermined intervals (e.g. 
every 3 months) the study team will prepare safety reports to be reviewed by the SO and the NIA for 
recommendations for or against the trial's continuation, as well as any modification to the study.  The 
SO will be unblinded to safety data.  
  

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10.1.7 CLINICAL MONITORING 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Council on Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). Monitoring activities will be as follows: 
• 
Data Coordination and Quality Control. Data will be entered into REDCap data capture 
software, and then extracted to SAS for analysis. For all assessments, RAs will complete CRFs on 
paper for subsequent entry into REDCap. One part of the CRF will remain at the local site and 
the other part will be sent to the UMMS central study site for quality checking. The project 
biostatistician will conduct regular quality control analyses for missing data, internal consistency 
reliability, the number and type of forms failing to edit, and data distribution looking for 
outliers. We will conduct data audits by reviewing select, high-risk, data [e.g. patient 
characteristics and medications] against source documents from every 5th patient enrolled (i.e. 
~10% sample). If systematic errors are detected, further data will be audited to determine the 
cause(s) and monitoring reports will be generated and distributed accordingly.   
  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. All sites will follow a common quality management 
plan. 
  
Quality control (QC) procedures will be implemented as follows: 
  
Informed consent - Study staff will review both the documentation of the consenting process as well as 
a percentage of the completed consent documents. This review will evaluate compliance with GCP, 
accuracy, and completeness. Feedback will be provided to the study team to ensure proper consenting 
procedures are followed. 
  
Source documents and the electronic data - Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database. To ensure accuracy site staff will compare a representative sample of source data against the 
database, targeting key data points in that review. 
  
Intervention Fidelity Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking. 
  
Protocol Deviations The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. Should independent monitoring become necessary, the PI will provide direct access to all trial 

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related sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
  
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1  DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
  
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data. 
Hard copies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study. Data recorded in the electronic 
case report form (eCRF) derived from source documents will be consistent with the data recorded on 
the source documents. 
  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into RedCAP, a 21 CFR Part 11-compliant data capture system provided 
by the University of Massachusetts Medical School DCC. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
  
10.1.9.2  STUDY RECORDS RETENTION 
Study documents will be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Council on Harmonization (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor/funding agency, if applicable. It is the responsibility of the 
sponsor/funding agency to inform the investigator when these documents no longer need to be 
retained. 
  
10.1.10 PROTOCOL DEVIATIONS 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions will be developed by the site and 
implemented promptly. 

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These practices are consistent with ICH GCP: 
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3 
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1 
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2. 
It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working days 
of the scheduled protocol-required activity. All deviations must be addressed in study source 
documents, reported to the UMass Med Data Coordinating Center. Protocol deviations must be sent to 
the reviewing IRB per their policies. The site investigator is responsible for knowing and adhering to the 
reviewing IRB requirements. Further details about the handling of protocol deviations will be included in 
the MOP. 
  
10.1.11 PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
  
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. Data from this study may be requested from other researchers x years after the 
completion of the primary endpoint by contacting the University of Massachusetts Medical School or 
the PCRC data repository. Considerations for ensuring confidentiality of these shared data are described 
in Section 10.1.3. 
  
10.1.12 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership 
in conjunction with the University of Massachusetts Medical School  has established policies and 

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procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
Determination of ADE and ADWE 
  
  
 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
ADE 
Adverse Drug Event 
ADWE 
Adverse Drug Withdrawal Event 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
ED 
Emergency Department 
FCG 
Family Caregiver 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 

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GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator's Brochure 
ICH 
International Council on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
  
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
  
  
  
  
  
  
  
  
  
  
  
  

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