Evaluating the Use of Preemptive Pharmacogenomic Testing to Personalize Supportive Oncology
Phase: NA
Conditions: Cancer, Depression, Pain
Sponsor: Wake Forest University Health Sciences

 
 
 
Protocol #: LCI-SUPP-NOS-PGx-001 
Protocol Version No. and Date: v7.0 02/20/2024 
 
TITLE: Evaluating the Use of Preemptive Pharmacogenomic Testing to Personalize 
Supportive Oncology  
 
Short title: Pharmacogenomic Testing to Personalize Supportive Oncology 
 
Coordinating Center: 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte NC, 28204 
 
Sponsor-Investigator: 
Jai N. Patel, PharmD, BCOP, CPP 
Levine Cancer Institute, Atrium Health 
LCI Cancer Pharmacology 
Research and Academic Headquarters 
1021 Morehead Medical Drive, Suite 3100 
Charlotte, NC 28204 
Phone: (980) 442-4113 
Email: Jai.Patel@atriumhealth.org 
 
 
Statisticians: 
Danielle M. Boselli, MS 
Levine Cancer Institute 
Department of Cancer Biostatistics 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Phone: 980-442-2388 
Email: Danielle.Boselli@atriumhealth.org 
 
James Symanowski, PhD 
Levine Cancer Institute 
Department of Biostatistics 
Phone: (980) 442-2371 
Email: James.Symanowski@atriumhealth.org 
 
 
Trial Supported by: 
American Cancer Society 
 
 
_____________________________________________________________________________ 

 
 
 
The study will be conducted in compliance with the protocol, ICH/GCP, and any applicable 
regulatory requirements. 
 
 
 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. 
Hence, the appearance of product names without these symbols does not imply that these names 
are not proprietary. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation. Reproduction or disclosure of this document - whether in part 
or in full - to parties not associated with the clinical investigation, or its use for any other purpose, 
without the prior written consent of the Sponsor-Investigator is not permitted. 

 
 
 
 
PROTOCOL SIGNATURE PAGE 
PROTOCOL TITLE: A Prospective Trial Evaluating the Use of Preemptive 
Pharmacogenomic Testing to Personalize Supportive Oncology 
 
VERSION No.: v7.0  
VERSION DATE: 02/20/2024 
 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
 
 
 
    
___________________________________________________________________ 
 
Signature of Sponsor-Investigator                      
 
 
Date 
 
 
__Jai N. Patel________________________  
Sponsor-Investigator Name (printed) 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
 
SYNOPSIS 
TITLE 
Evaluating the Use of Preemptive Pharmacogenomic Testing to 
Personalize Supportive Oncology 
STUDY POPULATION 
Adult cancer patients ≥ 18 y/o presenting with moderate to high pain (≥ 
4/10) and/or depression (≥3/10 or patients diagnosed with depression with 
a clinical need to adjust depression medications) on the Edmonton 
Symptom Assessment Scale (ESAS) during the initial consultation or a 
follow-up visit that occurs more than 1 year since the last visit in the 
palliative medicine clinic, able and willing to sign informed consent, and 
able to provide a buccal sample for pharmacogenetic testing.  
SUMMARY OF STUDY 
RATIONALE 
Over 90% of cancer patients experience cancer- or treatment-related 
symptoms, including pain and depression. At least 50% have uncontrolled 
symptoms throughout their lifetime. This significantly impacts patients’ 
quality of life, response to therapy, and potentially survival. Many 
medications used to treat these symptoms are plagued with a system of 
trial and error, with prolonged time to symptom control or improvement. 
Objective tools are needed to improve drug selection and reduce symptom 
burden. Pharmacogenetics (PGx) allows for personalized medical 
decisions based on patient-specific genetics and provides a unique 
opportunity to reduce arbitrary drug selection and improve personalized 
prescribing, especially for pain and depression medications. By studying 
the application of a PGx test to alter drug prescribing patterns and 
improve treatment outcomes in supportive oncology, these results will 
provide critical information to understand the feasibility and utility of 
performing preemptive, real-time PGx testing. We believe this study will 
help shift supportive care prescribing paradigms from a trial-and-error 
approach to a personalized, genomics-driven method. Ultimately, using 
PGx to optimize medication selection and control cancer-related 
symptoms may improve quality of life throughout the cancer care 
continuum, potentially extending overall survival. 
STUDY DESIGN  
This is a prospective clinical trial of adult cancer patients presenting with 
pain and depression, newly referred to the Department of Supportive 
Oncology’s palliative medicine clinic (or previously established patients 
without a visit in the past year) and receiving PGx testing for genes 
related to supportive care prior to their Baseline study visit. Patients will 
be screened and identified for eligibility after their initial consultation in 
palliative medicine. If meeting the ESAS score cutoffs for pain and 
depression and meeting all other eligibility criteria, patients will be 
approached for consent and undergo buccal swabs collection after 
informed consent is obtained. Genotyping results will be returned within 
approximately 4-5 business days. A PGx specialist will provide detailed 
clinical interpretations to the referring provider and upload a copy of the 
test results into the subject’s medical chart. A consultation note will also 
be placed in each subject’s chart detailing the pharmacogenomics results.  
Supportive Oncology clinicians will be instructed to consult a pharmacist 
to evaluate PGx test results prior to prescribing supportive care therapies, 
especially pain and depression medications. The number of consults and 
recommendations will be documented, in addition to test results, 
demographic data, medical/medication history, ESAS symptom scores, 
PHQ9 depression scores, and side effects of supportive therapy. The 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
number of ambulatory clinic visits and hospitalizations will be used to 
estimate health care utilization and costs. Subjects will complete a short 
survey at the end of the study period regarding their knowledge about 
PGx, and whether access to PGx information improves satisfaction with 
care and communication. 
OBJECTIVES 
Primary Objective:  
•  To estimate the proportions of subjects undergoing PGx testing 
who receive at least one drug/dose selection or modification based 
on their test results within any of the study visits where PGx 
results are available. 
•  
Secondary Objectives: 
• To determine the impact of PGx on treatment outcomes by 
measuring pain scores using the Edmonton Symptom Assessment 
Scale (ESAS) (Appendix A) and depression scores using the 
Patient Health Questionnaire (PHQ) 9 (Appendix B) at study visits 
after the Baseline study visit. Symptom scores will also be 
compared between those receiving PGx testing and a matched 
control receiving clinical management alone. 
• To describe subject perspectives (Appendix C) of PGx testing 
using a survey administered to subjects after/at the Final visit (or 
sooner if withdrawn). 
•  
Exploratory objectives: 
•  To determine the types & frequencies of actionable genotypes that 
result in drug/dose selection or modification(s) and those that do 
not result in drug/dose selection or modification(s). 
• To describe the types of new medications prescribed (using 
medications of interest list; Appendix D) or medication/dose 
adjustments based on the PGx results. 
• To determine the type & frequency of drug/gene interactions 
present at the Baseline and the Final study visit using CPIC 
guidelines and FDA’s pharmacogenomics table. 
• Summarize PGx best practice advisory alerts among participants 
enrolled after the transition to Epic to describe the proportion of 
participants that had a BPA fire in the EMR, the number and type 
of BPAs per participant, and any actions taken from the BPA. 
KEY INCLUSION 
CRITERIA  
• Adult cancer patients ≥ 18 years of age who have had either an 
initial visit in the Department of Supportive Oncology’s palliative 
medicine clinic or a re-establishment of care visit with the last 
visit being at least 1 year prior, able and willing to sign the 
informed consent and provide a buccal sample for PGx testing. 
• Hematologic malignancy or any stage solid tumor malignancy. 
Presenting with pain score ≥ 4/10 and/or depression score ≥ 3/10 
on ESAS (or patients diagnosed with depression with a clinical 
need to adjust depression medications) 
STATISTICAL 
CONSIDERATIONS 
 
The evaluable population for the primary objective is defined as enrolled 
subjects with confirmed malignancy (per provider documentation) 
completing an on-study visit with PGx results available. We anticipate 
enrolling 80 eligible subjects, of which we estimate 65 will be evaluable. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
With this sample size, the width of the 95% Clopper-Pearson confidence 
interval will be ≤25%, regardless of the observed DDSM rate. 
NUMBER OF 
SUBJECTS 
80, to achieve 65 evaluable subjects 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
SCHEMA 
   
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
 
TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................................................... I 
SCHEMA................................................................................................................................................................... IV 
1. 
BACKGROUND AND RATIONALE .......................................................................................................... 8 
1.1 
Background ........................................................................................................................................................................ 8 
1.2 
Study Rationale and Study Design ................................................................................................................................... 10 
2. 
STUDY OBJECTIVES AND ENDPOINTS............................................................................................... 11 
2.1 
Objectives ......................................................................................................................................................................... 11 
2.2 
Endpoints ......................................................................................................................................................................... 12 
3. 
SUBJECT SELECTION .............................................................................................................................. 13 
3.1 
Subject Identification and Recruitment ............................................................................................................................ 13 
3.2 
Inclusion Criteria .............................................................................................................................................................. 13 
3.3 
Exclusion Criteria ............................................................................................................................................................. 13 
3.4 
Subject Withdrawal .......................................................................................................................................................... 14 
3.5 
Screen Failures ................................................................................................................................................................. 14 
4. 
REGISTRATION ......................................................................................................................................... 14 
4.1 
Sequence Number Assignment ......................................................................................................................................... 14 
5. 
STUDY PLAN ............................................................................................................................................... 14 
5.1 
Study Intervention and Pharmacogenomics Testing ......................................................................................................... 15 
6. 
STUDY CALENDAR ..................................................................................................................................... 8 
6.1 
Table 2. Study Procedures and assessments ....................................................................................................................... 8 
7. 
DETAILS ON STUDY PROCEDURES ....................................................................................................... 9 
7.1 
Registration procedures ...................................................................................................................................................... 9 
7.2 
Baseline Procedures ........................................................................................................................................................... 9 
7.3 
Study Visits ........................................................................................................................................................................ 9 
7.4 
Final Visit ......................................................................................................................................................................... 10 
7.5 
Correlative Study Procedures ........................................................................................................................................... 10 
8. 
REMOVAL OF SUBJECTS FROM STUDY ............................................................................................ 11 
8.1 
Off Study .......................................................................................................................................................................... 11 
9. 
DATA AND SAFETY MONITORING PLANS ........................................................................................ 11 
10. 
POTENTIAL RISKS/UNANTICIPATED PROBLEMS .......................................................................... 12 
10.1 
Potential Risks .................................................................................................................................................................. 12 
10.2 
Unanticipated Problems (UAP) ........................................................................................................................................ 13 
11. 
STATISTICAL CONSIDERATIONS ........................................................................................................ 13 
11.1 
Milestones ........................................................................................................................................................................ 13 
11.2 
Sample Size and Accrual .................................................................................................................................................. 14 
11.3 
Analysis Populations ........................................................................................................................................................ 14 
11.4 
Analysis Methods ............................................................................................................................................................. 14 
12. 
STUDY COMPLETION OR TERMINATION ......................................................................................... 17 
12.1 
Completion ....................................................................................................................................................................... 17 
12.2 
Termination ...................................................................................................................................................................... 17 
13. 
STUDY MANAGEMENT ........................................................................................................................... 17 
13.1 
IRB Approval ................................................................................................................................................................... 17 
13.2 
Informed Consent ............................................................................................................................................................. 18 
13.3 
Protocol Adherence .......................................................................................................................................................... 18 
13.4 
Changes to the Protocol and/or Informed Consent ........................................................................................................... 18 
13.5 
Protocol Deviations .......................................................................................................................................................... 18 
13.6 
Retention of Records ........................................................................................................................................................ 18 
13.7 
Ethical and Legal Conduct of the Study ........................................................................................................................... 18 
13.8 
Confidentiality of Records ............................................................................................................................................... 19 
14. 
REFERENCES ............................................................................................................................................. 20 
15. 
APPENDIX A. EDMONTON SYMPTOM ASSESSMENT SCALE ....................................................... 25 
16. 
APPENDIX B. PATIENT HEALTH QUESTIONNAIRE (PHQ) 9 ........................................................ 26 
17. 
APPENDIX C. PGX PATIENT SURVEY ................................................................................................. 27 
18. 
APPENDIX D.  MEDICATIONS OF INTEREST LIST .......................................................................... 28 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
8 
 
 
1. BACKGROUND AND RATIONALE 
1.1 
Background 
 
Early palliative care after diagnosis with incurable cancer improves quality of life (QOL) 
and may prolong overall survival [1-7]. However, there is large inter-individual variability 
in response to supportive care medications, such as those for pain and depression [6,8]. 
Pain affects more than 75% of cancer patients with advanced disease. Less than one-third 
of all patients achieve pain improvement with conventional strategies within one month of 
presentation [9]. Depression affects about one-third of cancer patients and has been linked 
to poorer prognosis and survival [10-13]. Pain, depression, and fatigue often coexist as a 
symptom cluster in cancer patients [14,15]. The combined effects of pain and depression is 
a significant public health crisis, particularly in the era of the opioid epidemic. Patients 
with moderate to severe depression are more than twice as likely to misuse opioids for 
non-pain symptoms compared to non-depressed patients [16]. Improper opioid prescribing 
has prompted the Center for Disease Control and Prevention (CDC) to issue guidelines for 
improving prescribing to mitigate abuse and addiction concerns [17]. Suboptimal 
management of cancer-related symptoms like pain and depression compromises potential 
cancer therapy benefits, disrupts clinic workflow, increases emergency room visits, and 
impacts patient satisfaction [18]. 
 
Pharmacogenomics (PGx) – the impact of genetic variation on drug response – is well 
documented [19] and can significantly impact response to supportive therapy, especially 
pain and depression medications [18,20]. Data suggests >90% of individuals carry a PGx 
variant contributing to drug response [21]. As this data grows along with more affordable 
analytic technology, it will soon be standard of care to perform routine PGx testing prior to 
treatment. The truest value of this data can only be fully realized when it is implemented 
preemptively into the routine workflow and embedded within care pathways, as discussed 
in previous reviews [21,22]. The Clinical Pharmacogenetics Implementation Consortium 
(CPIC) has thus far published approximately 45 drug-specific, peer-reviewed guidelines on 
how to best apply PGx to guide therapy (at least a dozen of which are related to supportive 
care medications) [23]; however, there is also an emerging level of relevant genes not 
currently covered by these guidelines. Effective integration of PGx-guided treatment 
pathways can help personalize medication selection in supportive oncology [18,20] and 
help determine the magnitude of drug-drug and drug-drug-gene interactions [24]. Several 
genes have been implicated with response to supportive care medications (Table 1). 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
9 
 
Table 1. Summary of potential drug-gene interactions 
 
 
Opioid PGx: CYP2D6 activates codeine, tramadol, oxycodone, and hydrocodone to 
stronger opioids: morphine, o-desmethyltramadol, oxymorphone, and hydromorphone, 
respectively. CYP2D6 polymorphisms can significantly alter opioid pharmacology [25]. 
For example, codeine-related deaths reported in ultra-rapid metabolizers (UMs) resulted in 
a black-box warning recommending against its use [26-32]. Alternatively, poor 
metabolizers (PMs) may have ineffective analgesia due to impaired activation to morphine. 
Similar mechanisms are noted with tramadol, oxycodone, and hydrocodone [33-37]. CPIC 
recommends CYP2D6 UMs and PMs avoid codeine, tramadol, oxycodone and 
hydrocodone due to increased toxicity or lack of analgesia, respectively [38]. A base-pair 
substitution in the gene coding the mu-opioid receptor, OPRM1, can result in 60%–100% 
more morphine required for equal analgesia [39-41]. Analgesia can also be enhanced by 
presence of catecholamines, which are metabolized by the enzyme COMT. A base-pair 
substitution in COMT reduces enzyme activity by 3-4-fold, increases catecholamine 
exposure, increases opioid sensitivity, and lowers morphine equivalents required for 
analgesia, whereas those with higher activity may require at least doubling of the dose 
[39,42,43]. 
 
Antidepressant PGx: CYP2C19 metabolizes and inactivates citalopram, escitalopram, and 
sertraline. CYP2C19 PMs have increased toxicity risk with these medications, including 
QT prolongation [44,45]. Alternatively, UMs have lower plasma concentrations and 
increased risk of not responding [46]. CPIC recommends a 50% dose reduction in 
citalopram, escitalopram, and sertraline for CYP2C19 PMs and avoiding the drugs in UMs 
[47]. Paroxetine is primarily metabolized by CYP2D6; thus, PMs are at increased risk of 
adverse effects, particularly gastrointestinal [48,49], while UMs are at risk of poor drug 
response [50]. CPIC recommends avoiding paroxetine in CYP2D6 UMs and PMs [47]. 
Fluoxetine is metabolized by CYP2D6 and CYP2C19, thus similar mechanisms can 
influence drug response. Vortioxetine is primarily metabolized by CYP2D6 and the FDA 
label recommends a maximum dose of 10 mg/day in PMs [51]. Polymorphisms in the 
serotonin transporter gene, SLC6A4, and/or serotonin receptor gene, HTR2A, may result 
in reduced response to selective serotonin reuptake inhibitors. Randomized trials have 
Gene 
Polymorphism(s)/variant(s) 
Supportive care medications potentially affected 
CYP3A4 
*1B, *22 
Oxycodone, hydrocodone, fentanyl, methadone 
CYP3A5 
*3, *6, *7 
Oxycodone, hydrocodone, fentanyl, methadone 
CYP2D6 
*2, *3, *4, *5, *6, *9, *10, *17, 
*29, *41, duplications/copy 
number variations 
Codeine, tramadol, oxycodone, hydrocodone, 
ondansetron, amitriptyline, imipramine, clomipramine, 
desipramine, doxepin, fluvoxamine, nortriptyline, 
fluoxetine, paroxetine, duloxetine, atomoxetine, 
amphetamines,  
CYP2C9 
*2, *3, *6, *8, *11 
Diclofenac, ibuprofen, meloxicam, celecoxib, phenytoin 
CYP2C19 
*2, *3, *17 
Esomeprazole, lansoprazole, omeprazole, 
pantoprazole, amitriptyline, citalopram, clomipramine, 
doxepin, escitalopram, imipramine, sertraline  
CYP2B6 
*4, *5, *6, *18 
Methadone, bupropion, ketamine 
COMT 
Val158Met 
All opioids 
OPRM1 
118A>G 
All opioids 
SLC6A4 
Short or long allele 
Selective Serotonin Reuptake Inhibitors 
HTR2A 
rs7997012 
Citalopram 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
10 
 
shown better clinical response with PGx-guided antidepressant selection [52-54] and tools 
have been developed to assist with PGx-based antidepressant prescribing [55,56]. 
 
PGx tests are now commercially available; however, due to their novelty, healthcare 
payors are reluctant to reimburse preemptive PGx screening and mandate further proof-of-
concept and efficacy trials before coverage. Nonetheless, preemptive PGx testing increases 
the value proposition and prior studies suggest improved medication adherence and cost 
savings with PGx [57,58].  Further, many of the genes discussed earlier can affect non-
oncology or non-supportive oncology medications that may be prescribed by other 
providers within the same health system (e.g., clopidogrel and CYP2C19). PGx results 
may be informative for management of other medications. Despite widespread availability 
of PGx tests and declining diagnostic costs, there is little data on the practicality of using 
PGx to improve supportive cancer care. 
 
The Edmonton Symptom Assessment Scale (ESAS) (Appendix A) is a validated 10-item 
questionnaire assessing self-reported perceptions of pain, fatigue/energy, nausea, 
depression, anxiety, drowsiness, appetite, wellbeing, and shortness of breath. Each item is 
ranked from 0 to 10, with 10 representing the worst symptom. ESAS is routinely 
performed during all palliative medicine clinic visits. ESAS can be used to identify cancer 
patients presenting to palliative medicine with uncontrolled symptoms and can also be 
used to track symptom improvement or progression over time.   
 
In a prior analysis we identified 46% of cancer patients at Levine Cancer Institute were 
prescribed a supportive care medication within 90 days of intake to the cancer hospital, 
mainly for pain (69%) and/or nausea (46%). Of these, 86% received at least one supportive 
care medication with PGx evidence and 84% received a CYP2D6-metabolized drug. Based 
on reported CYP2D6 allele frequencies conferring altered metabolism, 650 (20%) were 
expected to have altered drug response, suggesting preemptive PGx testing may have 
broad applicability in this population. PGx testing in this high-risk population may 
improve medication management and symptom control. 
 
1.2 
Study Rationale and Study Design 
 
Over 90% of cancer patients experience cancer- or treatment-related symptoms, and at 
least 50% have uncontrolled symptoms throughout their lifetime. This significantly 
impacts patients’ QOL, response to therapy, and potentially survival. Thus, guidelines 
recommend early palliative intervention for all cancer patients with advanced disease; 
however, many medications used to treat these symptoms are plagued with a system of 
trial and error, with prolonged time to symptom control or improvement. 
 
Objective tools are needed to improve drug selection and reduce symptom burden. PGx 
allows for personalized medical decisions based on patient-specific genetics and provides a 
unique opportunity to reduce arbitrary drug selection and improve personalized 
prescribing. By studying the application of a PGx test to alter drug prescribing patterns for 
pain and depression and improve treatment outcomes in supportive cancer care, these 
results will provide critical information to understand the feasibility and utility of 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
11 
 
performing preemptive, real-time PGx testing in a busy, outpatient clinic. This study will 
help shift supportive care prescribing paradigms from a trial-and-error approach to a 
personalized, genomics-driven method. Ultimately, using PGx to optimize medication 
selection and control cancer-related symptoms may improve QOL, as measured by 
aggregate ESAS scores, throughout the cancer care continuum, potentially extending 
overall survival. 
 
We propose a prospective clinical trial of adult cancer patients at Levine Cancer Institute 
presenting to the Department of Supportive Oncology’s palliative medicine clinic with 
moderate to high pain and depression (screened using ESAS at initial palliative medicine 
visit). Genotyping results will be returned within five business days. A PGx specialist will 
provide detailed clinical interpretations to the palliative medicine clinic and upload a copy 
of the results as well as a clinic note into the subject’s medical chart. Each subject will also 
be counseled on their test results. A note will be placed in each subject’s chart alerting the 
provider that the subject is on study and should be referred for pharmacy consultation to 
evaluate PGx test results prior to prescribing supportive therapy during the study period. 
The number of pharmacy consults for subjects undergoing PGx testing, type of medication 
recommendations, actionable genotypes, and rate of acceptance by the provider will be 
documented. Other data elements to be collected include all PGx test results, demographic 
data, medical/medication history, ESAS (Edmonton Symptom Assessment System) 
symptom scores, and PHQ9 (Patient Health Questionnaire) scores. The number and 
duration of emergency department visits and hospitalizations will be used to estimate 
health care utilization and costs. Subjects will complete a short survey at the end of the 
study period (from enrollment [day of the buccal swab] to the Final visit) regarding their 
knowledge about PGx, and whether access to PGx information improves satisfaction with 
care and communication. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
• Estimate the proportions of subjects undergoing PGx testing who receive at least one 
drug/dose selection or modification based on their test results within any of the study 
visits where PGx results are available. 
2.1.2 Secondary Objectives 
• Determine the impact of PGx on treatment outcomes by measuring pain scores using 
the Edmonton Symptom Assessment Scale (ESAS) (Appendix A) and depression 
scores using the Patient Health Questionnaire (PHQ) 9 (Appendix B) at study visits 
after the Baseline study visit. Symptom scores will also be compared between those 
receiving PGx testing and a matched control receiving clinical management alone. 
• Describe subject perspectives (Appendix C) of PGx testing using a survey 
administered to subjects after/at the Final visit (or sooner if withdrawn). 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
12 
 
2.1.3 Exploratory Objectives 
• Determine the types & frequencies of actionable genotypes that result in drug/dose 
selection or modification(s) and those that do not result in drug/dose selection or 
modification(s). 
• Describe the types of new medications prescribed (using medications of interest list; 
Appendix D) or medication/dose adjustments based on the PGx results. 
• Determine the type & frequency of drug/gene interactions present at the Baseline and 
the Final study visit using CPIC guidelines and FDA’s pharmacogenomics table. 
• Summarize PGx best practice advisory alerts among participants enrolled after the 
transition to Epic to describe the proportion of participants that had a BPA fire in the 
EMR, the number and type of BPAs per participant, and any actions taken from the 
BPA. 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
A binary variable will be recorded for each subject undergoing PGx testing to indicate 
whether or not the subject received at least one drug/dose selection or modification based 
on their test results at any study visit where PGx results were available.  
 
2.2.2 Secondary Endpoints 
• A count variable will be recorded for each subject undergoing PGx testing indicating 
the total number of drug/dose selections or modifications received across all study 
visits where PGx results were available.  
• Pain scores assessed by the ESAS and depression scores using PHQ9 will be recorded 
for each subject at the Baseline and all the visits.  
• Health care resource utilization (HCRU) and costs will be estimated based on the 
number of inpatient, emergency department, outpatient, and pharmacy encounters, 
among others, occurring one year prior to and during the study period. 
• Discrete variables will be recorded to indicate subject survey responses. 
2.2.3 Exploratory Endpoints 
• Binary variables will be recorded for each subject, indicating the presence or absence 
of an actionable genotype for each of the tested genotypes. 
• Discrete variables will be recorded for each subject indicating the new medications 
prescribed or medication/dose adjustments made using the PGx results. 
• Discrete variables will be recorded for each subject indicating the drug/gene 
interactions present at the Baseline and at the Final study visit. A count variable 
indicating the number of interactions will also be recorded.  
• PGx best practice advisory (BPA) alerts: BPA alerts are fired within Epic when there 
is presence of a drug-gene interaction at the time of medication order entry. The 
following will be determined for study participants enrolled after the transition to 
Epic: a binary variable indicating the presence of a BPA in their EMR and a count 
variable indicating the total number of BPAs in their EMR. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
13 
 
3. SUBJECT SELECTION 
3.1 
Subject Identification and Recruitment 
Accrual is expected to be 80 eligible subjects. All patients will complete ESAS during a 
regularly scheduled visit to the Department of Supportive Oncology’s palliative medicine 
clinic (Palliative medicine clinic).  Potential candidates will be identified by reviewing 
the EMR to identify patients with ESAS pain ≥ 4/10 and/or depression ≥ 3/10 (or 
diagnosed with depression with a clinical need to adjust depression medications).  
 
It is expected that 80 eligible subjects will be required to enroll 65 evaluable subjects.  In 
the event that more subjects are required to achieve 65 evaluable subjects, subject 
enrollment will continue until 65 evaluable subjects have been enrolled. 
 
Target accrual period of this study will be approximately 30 months. 
3.2 
Inclusion Criteria 
 
Subjects must meet all of the following criteria: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information  
2. Completion of ESAS at initial palliative medicine clinic visit, presenting with 
moderate to high pain (≥ 4/10) and/or depression (≥ 3/10) or diagnosed with 
depression with a clinical need to adjust depression medications identified by the 
provider. 
3. New patients ≥ 18 years of age who have had either an initial visit in the Department 
of Supportive Oncology’s palliative medicine clinic or a re-establishment of care visit 
with the last visit being at least 1 year prior to the date of consent, with hematologic 
malignancy or any stage solid tumor malignancy according to the provider. Patients 
without confirmation of malignancy at the time of enrollment can be enrolled based 
on radiographic evidence suggesting the likelihood of malignancy per investigator 
discretion. 
4. Agree to at least one additional palliative medicine clinic visit per protocol.  
5. Able to provide a buccal sample for PGx testing 
3.3 
Exclusion Criteria 
 
Subjects meeting any of the criteria below may not participate in the study: 
  
1. Psychiatric illness, social situations, or active/recent (within 30 days) history of illicit 
substance (e.g., cocaine, heroin) abuse that would limit compliance with study 
requirements (e.g., study visits, medication compliance, etc.) as determined by the 
Investigator. 
2. Patients who have had prior multiple visits in palliative medicine clinic less than one year 
prior to consent. 
3. History of prior allogeneic stem cell transplant or liver transplant 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
14 
 
3.4 
Subject Withdrawal 
 
Subjects MAY be withdrawn from the study for the following reasons: 
 
• More than 8 weeks pass between the completion of ESAS and the Baseline study visit. 
• Subject withdraws consent from study procedures. A subject will be removed from the 
trial at his/her own request. At any time during and without giving reasons, a subject may 
decline to participate further. The subject will not suffer any disadvantages as a result. 
• If, in the Investigator’s opinion, compliance with study procedures is compromised and 
affects the integrity of the trial. 
• Death. 
 
Subjects MAY be withdrawn from the study for the following reasons: 
 
• The subject is unable to undergo one or more study visits.  
• Use, or suspicion of use, of illicit drugs or substances (i.e., positive urine drug screening) 
that may, in the opinion of the Investigator, have a reasonable chance of contributing to 
medication non-compliance 
• Developing a concurrent illness or situation that would, in the Investigator’s judgment, 
significantly affect assessments of clinical status and trial endpoints. 
• DNA from buccal swabs is not viable, and the laboratory cannot perform PGx testing. 
Subjects may be asked to provide additional swabs if recollection performed no later than 
one week prior to the Baseline study visit. 
 
Any subject removed from the trial will remain under medical supervision per standard of care 
procedures until discharge or transfer is medically acceptable.  
3.5 
 Screen Failures 
A subject who, for any reason (e.g., failure to satisfy the eligibility criteria or withdraws 
consent), terminates his/her study participation before being enrolled to the study is regarded as a 
screen failure. All screen failures will be tracked. Reasons for screen failure (e.g., specific 
inclusion/exclusion criteria not met) will be recorded in the CTMS/Subject Console. 
4. REGISTRATION  
4.1 
Sequence Number Assignment 
Following informed consent, subjects will be registered by the LCI Data Coordinating Center 
and assigned a Sequence Number.  
 
The study intervention (PGx testing) is not blinded to the subject or the Investigator. 
5. STUDY PLAN 
 
The study design is a prospective interventional clinical trial designed to investigate the 
application of PGx testing to personalize cancer symptom management, particularly pain and 
depression. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
15 
 
 
Potential candidates will be presented with consent; screening data for these patients, including 
ESAS symptom scores, will be captured and used for analysis (Section 11.4.5). A full waiver of 
consent and HIPAA for data collection will be requested for the control cohort, which includes 
patients (with pain ≥ 4/10 and/or depression ≥3/10 who have not been presented with consent 
and who were presented with consent but decline participation in the study (i.e., do not consent). 
Study subjects who consent and subsequently screen fail for any reason will also be included in 
the control cohort. Patients who agree will undergo the informed consent process, and subjects 
who consent will be screened for eligibility. Those meeting eligibility criteria will be enrolled 
and undergo buccal swab collection. Enrollment day will be considered at the buccal swabs 
collection day.  If the collected buccal swabs do not contain enough viable DNA for PGx 
testing, subjects may be asked to provide additional swabs. No less than 2 weeks and no more 
than 8 weeks should pass between the first ESAS completion and the date of the Baseline study 
visit. The Baseline study visit may be completed during a clinic visit (in person or virtually) or 
over the phone. It is estimated that PGx results will be available within five business days of 
swab receipt by the laboratory, and a detailed report will be sent to the clinic. A copy of the test 
results in PDF (Portable Document Format) format and PGx consultation note will be uploaded 
to the subject’s medical chart. Apart from the availability and use of PGx test results to guide 
pharmacotherapy, subjects will receive standard of care treatment and undergo ESAS screening 
during the palliative medicine visits. PHQ9 will be collected by the research team electronically, 
during the study visit by paper, or by phone. Data, including symptom scores and medications, at 
each visit, will be captured until the Final study visit. Subjects will be asked to complete a short 
survey within 30 days after the Final study visit to assess their perspectives on PGx testing and 
the care they received (administered preferably electronically, alternatively via paper during the 
Final visit at a clinic or over the phone).  
Subjects presenting with depression score 3 or greater and/or experiencing depressive symptoms 
during the clinical trial are highly encouraged to receive treatment in the LCI psycho-oncology 
clinic. 
Subjects will be offered the option to complete study visits during a clinic visit (in-person or 
virtually) or over the phone. 
Subjects will not be reimbursed for study participation; however, they will receive PGx testing at 
no cost and will receive a full copy of their test results at their request.   
5.1 
Study Intervention and Pharmacogenomics Testing 
• After obtaining the informed consent, two buccal swabs will be collected at least one 
week prior to the Baseline study visit (the next palliative medicine visit after informed 
consent). Buccal swabs may be collected by the subject at home or on site. 
• Buccal swabs will be transferred to the Levine Cancer Institute’s Molecular Biology 
Laboratory on the same or following day of collection for DNA extraction and 
genotyping. Subjects who collect samples at home will be instructed to collect and ship 
overnight only on Monday through Thursday (samples should not arrive at the lab on the 
weekend or on holiday). 
• Genotyping will occur at the Molecular Biology Laboratory for polymorphisms in 
candidate genes potentially related to pain and depression medications.  
• Raw data will feed into an online HIPAA compliant web portal for translation of results 
into genotype-phenotype data. Each test result will be reviewed by the lab for accuracy of 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
16 
 
results and quality control. The laboratory director and/or Sponsor-Investigator (S-I) or 
sub-investigator if S-I is not available will approve final genotype calls. 
• Pharmacists will interpret genotype and phenotype results and translate PGx results into 
actionable prescribing decisions. Guidelines, including CPIC (https://cpicpgx.org/) and 
FDA (https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-
associations), and clinical judgment will be used to make medication recommendations. 
A test report will be developed for each subject. The pharmacist will send a copy of the 
report to the referring provider and upload a copy into the medical chart along with a PGx 
consultation note. 
• Subjects will continue to receive supportive care and undergo scheduled study visits 
throughout the study. Changes to medications can be made during scheduled study visits, 
on-call visits, or virtually over the phone to mimic standard practice. Providers will be 
encouraged to refer all study subjects requiring pharmacologic intervention for pharmacy 
consultation to evaluate PGx results prior to drug prescribing. However, this is not 
protocol-mandated, and a deviation will not occur if a provider modifies treatment 
regimens without consulting the pharmacist. The number of pharmacy consults, types of 
medication recommendations, actionable genotypes, and acceptance rate by the provider 
will be documented. Data will be collected up to the completion of the Final visit. 
5.1.1 Schedule of Clinic Assessments 
Every visit can occur during a clinic visit (in-person or utilizing virtual care) or over the phone. 
A subject can be assessed by a trained and delegated Palliative care provider, PharmD, study 
coordinator, or RN: 
• Baseline (day 0) study visit should be no earlier than 2 weeks and no later than 8 weeks 
from the first ESAS completion. 
• A total of 3 subsequent study visits and the Final visit will occur every 4 weeks (± 1 
weeks) after the Baseline visit. Additionally, non-protocol-directed visits may occur on an 
as-needed basis (e.g., an emergency due to uncontrolled symptoms).  
 
5.1.2 Symptom Assessment Tools 
• ESAS (Appendix A) is a 10-item questionnaire assessing self-reported perceptions of 
pain, fatigue/energy, nausea, depression, anxiety, drowsiness, appetite, wellbeing, and 
shortness of breath. Each item is ranked from 0 to 10, with 10 representing the worst 
symptom. ESAS is routinely performed during all palliative medicine clinic visits.  
 
• PHQ9 (Appendix B) is a multipurpose instrument for screening, diagnosing, monitoring, 
and measuring the severity of depression. PHQ9 incorporates depression diagnostic 
criteria with other leading major depressive symptoms into a brief self-report tool.  PHQ9 
scores of 0-4 indicate normal or no depression, 5-9 mild, 10-14 moderate, 15-19 
moderately severe, and 20-27 severe depression.  PHQ9 will be collected for this study, 
preferably electronically, within 2 business days prior to the study visit or by phone call 
within 2 business days prior to the study visit. Alternatively, PHQ9 can be collected 
during a clinic visit on paper. 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
17 
 
5.1.3 Subject Survey (Appendix C) 
The patient survey is intended to assess the subject’s perspective of pharmacogenomics testing. 
The survey will be administered preferably electronically, alternatively over the phone or on 
paper during a clinic visit at the Final visit time-point or sooner if withdrawn. 
  
If data from ESAS, PHQ9 questionnaires, and Subject survey are missing, when possible, the 
reason for the missing data will be categorized and documented as follows: 
• the subject felt too ill; 
• clinician or nurse felt the subject was too ill; 
• the subject felt it was inconvenient or took too much time; 
• the subject felt it was a violation of privacy; 
• the subject didn't understand the actual language or was illiterate; 
• administrative failure to distribute the questionnaire; 
• other, specify; 
• unknown. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
8 
 
6. STUDY CALENDAR 
6.1 
Table 2. Study Procedures and assessments 
Study Procedures 
Registration 
Baseline1,3 
Study Visits2,3 
Final Visit2,3 
Informed Consent 
X 
 
 
 
Subject demographics4 
 
X 
 
X 
Buccal swab collection for genotyping 
X5 
 
 
 
Medical/treatment history6 
 
X 
 
 
Drug allergies7 
 
X 
X 
X 
PHQ98 
 
X 
X 
X 
ESAS9 
X10 
X 
X 
X 
Medication list11 
 
Continuously throughout the study from the Baseline to the Final visit 
Document use of PGx test results12 
 
Document use of healthcare resource 
utilization (HCRU)13 
 
Final visit survey14 
 
 
 
X 
1The Baseline study visit should be completed no earlier than 2 weeks and no later than 8 weeks from the first ESAS completion. 
2A total of 3 subsequent study visits will occur every 4 weeks (± 1 week) after the Baseline visit. The Final study visit will occur 4 weeks (± 1 week) after the third completed Study Visit. Subjects will be 
offered the option to complete study assessments during a clinic visit (in person or virtually) or over the phone. 
3All the study visits and assessments (including the Baseline visit) can occur during a clinic visit (in-person or utilizing virtual care) or over the phone. Study visits/assessments may be performed by a trained 
and delegated provider, RN, research coordinator or Pharm D. 
4Demographics collected during the Baseline visit will be race, ethnicity, insurance status, and zip code. Demographics collected on the Final visit will be annual household income and education level. 
5Buccal swab collection (Enrollment day) should be performed no later than one week prior to the Baseline study visit (second palliative medicine visit) at the clinic or the subject’ home. The specimen may 
be obtained the same day after the informed consent is signed. 
6Medical/treatment history: cancer type, stage of disease, ECOG performance status, active chemotherapy, surgery, and radiation therapy within 30 days of the Baseline visit. 
7Only to medications listed in Appendix D   
8Research team will collect PHQ9 prior to the study visit, preferably electronically or by phone, within 2 business days and send them to the Supportive Oncology provider and Sponsor-Investigator. If the 
response for the PHQ9 question #9 is anything greater than 0, a research designee will contact the applicable LCI social worker. Alternatively, PHQ9 can be collected during clinic visits on paper. 
9ESAS will be obtained during a clinic visit or utilizing virtual care. 
10ESAS score done historically visit per standard of care at the initial palliative medicine visit will be collected in the dataset and used for analysis (Section 11.4.5) 
11Medications listed in Appendix D, currently taken and/or newly prescribed during the visit, and other drugs and/or drug modifications recommended by the pharmacist or provider based on PGx test results 
outside those in Appendix D list will be collected every study visit. 
12Use of PGx test results should be documented any time a drug/dose modification is made (during palliative medicine visits or in between visits). 
13HCRU (defined as any encounter classified as an outpatient (OP), inpatient (IP), or emergency department (ED) encounter) occurring during the study period will be collected by a research designee. Each 
encounter will be counted as unique per classification. IP encounters that result from an emergency department presentation will be classified as both an ED encounter and IP encounter. Any encounter lasting 
longer than 24 hours will be considered an IP encounter. Insurance status and/or type and reason for presentation at each encounter will also be collected. 
14Survey will be preferably administered electronically (distributed to the subject`s email within 30 days after the Final visit). Alternatively, a research designee can collect a survey via paper during the Final 
visit at the clinic (or sooner if withdrawn) or over the phone as an option.

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
9 
 
7. DETAILS ON STUDY PROCEDURES 
Please also refer to the Study Calendar in Section 6. 
7.1 
Registration procedures 
o Informed consent 
o Buccal swab collection should be performed no later than one week prior to the 
Baseline study visit  
7.2 
Baseline Procedures  
Baseline study visit should be completed no earlier than 2 weeks and no later than 8 weeks 
from the first ESAS completion during the clinic visits or utilizing virtual care. 
o Subject demographics: Race, Ethnicity, Work Status, Insurance Status, Zip code  
o Medical history: data related to disease and/or diagnosis, including cancer type, 
stage of disease, and ECOG performance status 
o Treatment history: therapeutic interventions including surgery within 30 days of 
Baseline, active chemotherapy, active radiation, and active supportive care 
therapy 
o Drug allergies to medications listed in Appendix D 
o ESAS Appendix A collected as a SOC 
o PHQ9 Appendix B collected preferably electronically within 2 business days prior 
to the study visit, or alternatively on paper during the clinic visit or by phone call 
within 2 business days prior to the study visit 
o Medications listed in Appendix D, currently taken at the time of Baseline study 
visit and/or newly prescribed during the visit and, other drugs and/or drug 
modifications recommended by the pharmacist or provider based on PGx test 
results outside those in Appendix D 
o Use of PGx to guide/modify pharmacotherapy regimen 
o HCRU 
7.3 
Study Visits  
• A total of 3 subsequent study visits will occur every 4 weeks (± 1 week) after the 
Baseline visit. 
• During each study visit (in a clinic or virtually), the following information will be 
collected: 
o Drug allergies to medications listed in Appendix D 
o ESAS Appendix A collected as a SOC 
o PHQ9 Appendix B collected preferably electronically within 2 business days prior 
to the study visit, or alternatively on paper during the clinic visit or by phone call 
within 2 business days prior to the study visit 
o Addition or change in medications listed in Appendix D, and/or dosages, and  
other drugs and/or drug modifications recommended by the pharmacist or 
provider based on PGx test results outside those in Appendix D 
o Use of PGx to guide/modify pharmacotherapy regimen 
o HCRU 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
10 
 
7.4 
Final Visit  
• The Final study visit will occur 4 weeks (± 1 week) after the third completed Study Visit. 
o Drug allergies to medications listed in Appendix D 
o ESAS Appendix A collected as a SOC 
o PHQ9 Appendix B collected preferably electronically within 2 business days prior 
to the study visit, alternatively via paper during a clinic visit or by phone call 
within 2 business days prior to the study visit  
o Addition or change in medications listed in  Appendix D and/or dosages, and 
other drugs and/or drug modifications recommended by the pharmacist or 
provider based on PGx test results outside those in Appendix D 
o Use of PGx to guide/modify pharmacotherapy regimen 
o HCRU 
o Patient survey (Appendix C)  
o Subject demographics (part of the final survey): annual household income and 
education level. 
 
 
7.5 
Correlative Study Procedures 
Correlative specimens for this study include buccal swabs for DNA extraction and genotyping 
for germline pharmacogenes to be analyzed per Section 5.1.  After obtaining informed consent, 
two buccal swabs will be collected by the research designee.  No processing of samples is 
required prior to transfer. The samples will be transferred to the Levine Cancer Institute 
Molecular Biology Laboratory for DNA extraction and genotyping.   
 
7.5.1 Source and Timing of Biospecimen Collections 
 
All buccal specimens will be obtained after informed consent no later than one week before the 
Baseline study visit. The specimen may be obtained the same day as informed consent.  The 
research designee will instruct the subject on the appropriate buccal swab collection. 
 
Either the research staff member or the subject can perform the swabbing, depending on subject 
preference. Subjects will be given the option to collect buccal swabs at home, in which case a 
buccal collection kit with instructions on collection and shipping will be mailed to the subject. 
Subjects will be asked to collect buccal swabs and ship within 48 hours, ideally (max 96 hours) 
of receiving the buccal swab kit. 
 
All samples collected on site will be transported by either research or laboratory staff at ambient 
temperature to the Molecular Biology Laboratory at the Levine Cancer Institute. Samples 
collected by the subject at home will be mailed at ambient temperature directly to the Molecular 
Biology Laboratory. Samples will be logged in and processed for DNA extraction and 
genotyping per laboratory procedures. 
7.5.2 Storage of Biospecimens 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
11 
 
Specimens will be stored in the Molecular Biology Laboratory only until the pharmacogenomic 
results have been confirmed by both the Laboratory Director and Sponsor-Investigator 
(approximately one week from sample receipt). Once PGx results are confirmed by the 
Laboratory Director and Sponsor-Investigator, all samples will be discarded according to 
laboratory procedures.  
 
8. REMOVAL OF SUBJECTS FROM STUDY 
8.1 
Off Study 
 
Subjects are considered Off Study after completion of the subject survey and the Final visit that 
occurs 4 weeks (± 1 week) after the third completed Study Visit. 
 
Subjects may stop their participation in this study at any time if they no longer wish to 
participate or if the Investigator believes this to be in the best interest of the subject.  
When subjects are removed from the study, the reason for study removal and the date the subject 
was removed should be documented. Other reasons a subject may be removed from study 
include, but are not limited to: 
 
• Subject non-compliance with study participation, in the opinion of the Investigator  
• The subject or legal representative withdraws study consent 
• The subject’s tumor is confirmed to be a benign per provider 
• Buccal swab collected and shipped more than 96 hours after receiving the buccal swab kit 
or if otherwise deemed non-viable 
• The subject unwilling to recollect the buccal swabs if DNA from the first buccal swabs is 
not viable 
• The subject is lost to follow-up  
• Investigator’s decision to withdraw the subject 
• Subject death 
 
Subjects that are Off Study will not participate in any study- related procedures, including data 
collection. 
9. DATA AND SAFETY MONITORING PLANS 
Data will be collected in electronic case report forms (eCRFs). The database uses fully validated 
secure web-enabled software that conforms with 21CFR Part 11 requirements. Study personnel 
will be trained on data entry by the sponsor and provided protocol-specific eCRF guidelines. 
 
This protocol will be monitored according to the processes in effect for all LCI investigator-
initiated studies, the protocol-specific monitoring plan and will abide by applicable regulations 
and guidelines (e.g. Good Clinical Practice [GCP]).  The Sponsor-Investigator and other 
sponsor-level team members will meet regularly to monitor subject consents, enrollment and 
retention, safety data, and timeliness/validity/integrity of the data. Documentation of these 
meetings will be kept with study records. The Sponsor-Investigator will submit reports to the 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
12 
 
LCI Data and Safety Monitoring Committee according to the institutional Data and Safety 
Monitoring Plan. 
 
This study will be monitored to ensure the study is conducted in compliance with the study 
protocol, SOPs of the LCI and Atrium Health Office of Clinical and Translational Research 
(and/or other participating institutional SOPs), the FDA, and other applicable regulations and 
guidelines (e.g. GCP).  
 
Investigators and/or their delegated study personnel will be required to be available during the 
monitoring visits. 
10. POTENTIAL RISKS/UNANTICIPATED PROBLEMS  
10.1 Potential Risks 
 
There is no investigational treatment as part of this clinical trial.  All supportive care treatments 
are considered standard of care.  The primary intervention is PGx testing. The potential risks are 
limited to those associated with subject confidentiality, specimen collection, and knowledge of 
PGx test results. Nonetheless, the American College of Medical Genetics has deemed PGx 
testing as low risk since these genes are not related to disease susceptibility or prognosis.   
10.1.1 Subject Confidentiality 
 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies on subject privacy and HIPAA and that the investigator and other site 
personnel will not use such data and records for any purpose other than conducting the study. We 
do not anticipate any breach of confidentiality as no records will be shared with any personnel 
outside the research team. All medical information, including assessments and other medical 
records will be recorded and stored in a database. The databases will exist on a password 
protected secured server. Medical records data will be abstracted by the Research Designee. All 
records will be kept confidential. 
 
Pharmacogenomic test results will be added to each subjects’ Electronic Medical Record. 
Subjects will be provided a copy of his/her pharmacogenomic test results at their request, which 
can be used for other clinical/medication decisions downstream.  The subject is free to share this 
information with anyone. 
10.1.2 Biomarker Specimen Collection 
 
Buccal Swabs  
No adverse events are expected for buccal swab procedures. If a subject has an unexpected 
adverse event, the Investigator will treat the subject according to standard of care practices until 
the adverse event resolves.  

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
13 
 
  
Adverse events will not be recorded for the purposes of this study but will be a part of the 
subject’s medical record as per standard operation procedures. 
10.1.3 Emotional Distress 
Some questions in the questionnaires could create emotional distress or confusion.  If a subject 
experiences distress or confusion, the questionnaire process will be interrupted or discontinued, 
and the Research Designee will follow-up with the Sponsor-Investigator. Knowledge of PGx test 
results may result in emotional distress; however, the American College of Medical Genetics 
have identified pharmacogenes as “low risk” as they are not related to hereditary disease 
conditions, but rather how a person may metabolize or process various medications.  There is a 
low likelihood of emotional distress caused by knowledge of PGx information.  All subjects will 
be counseled on their test results by a trained pharmacist. 
 
10.2 Unanticipated Problems (UAP) 
10.2.1 Definition 
A UAP is any incidence, experience or outcome that is unexpected (e.g., a lost or stolen laptop 
computer that contains sensitive study information) given the information provided in research-
related documentation (e.g., informed consent) and the study population characteristics, that is 
related or possibly related to participation in the research study and places the participant at an 
increased risk.  
10.2.2 Reporting 
All UAPs occurring during the conduct of a protocol and meeting the definition of a UAP will be 
reported to the IRB per IRB reporting requirements.  
 
11. STATISTICAL CONSIDERATIONS 
11.1 Milestones 
Registration Date: Date of consent 
 
Enrollment Date: Date the buccal swab is collected. 
 
Off Study: Date of the Final visit that occurs 4 weeks (± 1 week) after the third completed Study 
Visit. 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
14 
 
11.2 Sample Size and Accrual 
Enrollment to the study will continue until 65 evaluable subjects have been identified (Section 
11.3). 
 
We anticipate enrolling 80 eligible subjects, of which we estimate 65 will be evaluable (defined 
in 11.3). With this sample size, the width of the 95% Clopper-Pearson confidence interval will be 
≤25%, regardless of the observed DDSM rate. 
11.3 Analysis Populations 
Analyses of the primary objectives and secondary objectives concerning counts of PGx-guided 
drug/dose selections or modifications based on their test results will be conducted on the 
evaluable population, defined as the population of enrolled subjects with confirmed malignancy 
(per provider documentation) and completing at least one study visit where PGx results are 
available (including the baseline visit). 
 
Analyses of secondary objectives concerning the impact of PGx on pain and depression scores 
will be conducted on the primary evaluable population with valid pain and/or depression scores 
for at least one post-Baseline Study visit.    
 
Analyses of secondary objectives concerning health care utilizations, costs, and subject survey 
responses and all exploratory objectives will be conducted on all enrolled subjects. 
11.4 Analysis Methods 
11.4.1 Timing of Analysis 
Final analysis will occur after all subjects have completed their Final visit or otherwise have 
come off study.  
11.4.2 Subject Disposition 
A summary of all consenting subjects will be provided at the end of the study. This will include 
those that consented, enrolled, screen failed, died, were lost to follow-up or withdrew consent. 
11.4.3 Baseline Subject Characteristics 
A summary of subject demographics will be completed. 
11.4.4 Primary Analysis 
The proportion (the denominator being the number of evaluable subjects) of evaluable subjects 
undergoing PGx testing and receiving at least one drug/dose selection/modification based on 
their test results at any study visit where PGx results are available will be calculated, alongside 
95% Clopper-Pearson confidence intervals.  

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
15 
 
11.4.5 Secondary Analysis 
 
Total counts and descriptive statistics of the number of drug/dose selection/modifications made 
due to subject PGx test results at all visits where PGx results are available will be summarized. 
 
A single-arm analysis for the PGx cohort will be performed: Descriptive statistics of ESAS pain 
scores and PHQ-9 depression scores will be calculated and summarized at study visits. Repeated-
measures linear mixed models will be estimated for pain and depression, separately, adjusted for 
baseline clinicodemographic characteristics and include a main effect for time and a random 
effect for subject.   
 
The following analysis will be performed for both the PGx and control cohorts:  
 
A matched analysis for ESAS pain and depression scores will be carried out, comparing the 
study cohort to a matched cohort of unique patients receiving clinical management alone 
during the same time period the trial is enrolling. Standard-of-care patients with ESAS pain 
≥4 and/or depression scores ≥3 at their first visit to the palliative medicine clinic or a re-
establishment of care visit with the last visit being at least 1 year prior—these visits 
occurring within the same time period the trial is enrolling—will be identified and 
considered in the matched analysis. 
 
Enrolled subjects will be matched to a similar case in cohort by:  
• ESAS pain and depression symptom scores at first visit to palliative medicine clinic (i.e., 
study screening for study cohort) 
• Age 
• Sex 
• Race 
• Clinic visit schedule. 
 
Between-group comparisons of those study subjects and control patients will be performed 
estimating repeated-measures linear mixed models for pain and depression, separately, to 
estimate the effect of PGx testing (i.e., treatment effect) on symptom scores adjusted for 
baseline clinicodemographic characteristics, a main effect for treatment, for time, an effect 
for treatment by time interaction, and a random effect for subject. 
 
Additionally, the average post-baseline symptom score will be calculated for each individual 
(separately for pain and depression). The distributions of the average post-baseline symptom 
scores will be compared between the cohorts using analysis of variance techniques with 
adjustments for clinicodemographic characteristics.  
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
16 
 
Health care utilization (e.g., instances of participant presenting at an emergency department, 
admitted as an inpatient, any outpatient encounter, or medication prescription) and reason for 
encounter will be assessed during the study period (starting on the Baseline to the Final study 
visit) for those undergoing PGx testing. HCRU in year prior to start of study enrollment will be 
collected for patients from institutional enterprise data warehouse (EDW) via raw billing and 
medical record data. Insurance status and/or type at each encounter will also be collected. An 
encounter resulting from another (e.g., ED presentation leading to IP) will be counted separately. 
Any ED encounter lasting longer than 24 hours will be considered an IP encounter. Diagnosis 
and procedure codes and priority sequence numbers will be collected from the EDW at least 6 
months following study closure to allow for final bills to accrue for HCRU encounters, for those 
that underwent PGx testing and matched controls. Diagnosis and procedure codes used in billing 
for each encounter will be used to estimate institutional costs or reimbursement and/or to 
publicly available sources (e.g., CMS fee schedule) and to obtain patient’s historical prescription 
drugs. Endpoints will be summarized by encounter-level and patient-level data files for 
frequency of HCRU and descriptive analysis of associated cost. Once data files have been 
constructed, data will be fit to appropriate statistical analyses and multivariate regression will be 
employed to interrogate the relationship between costs, resource utilization PGx results, 
sociodemographic, and clinical patient characteristics. Sensitivity and scenario analyses will be 
conducted to assess the robustness of model estimates. 
 
Subject responses to survey tool administered at the Final visit (or sooner if withdrawn) will be 
summarized and described. Regression models may be estimated to describe the association of 
response and responder characteristic, both univariately and multivariately, adjusted for relevant 
baseline characteristics.   
 
11.4.6 Exploratory Analysis 
• Frequencies of actionable genotypes that guide drug/dose selection or modification 
will be summarized and described alongside types of mutations/phenotypes for each of 
the test genotypes. 
• New medications prescribed and medication/dose adjustments based on PGx results 
will be summarized and described by frequencies of specific medication or medication 
classes prescribed and types of medication dose/adjustments, respectively.  
• Drug/gene interactions present on the Baseline and the Final study visit will be 
grouped, summarized, and described qualitatively. Additionally, summary statistics of 
the numbers of interactions will be calculated.  
• Calculate the following: 
o The proportion and 95% CI (using the Clopper-Pearson method) of PGx best 
practice advisory alerts that fire in Epic across all prescriptions across 
participants enrolled after the transition to Epic. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
17 
 
o The proportion and 95% CI (using the Clopper-Pearson method) of PGx best 
practice advisory alerts that fire in Epic across all new prescriptions within each 
participant enrolled after the transition to Epic. 
o The proportion and 95% CI (using the Clopper-Pearson method) of actions taken 
from PGx best practice advisory alerts in Epic among all alerts fired across study 
participants enrolled after the transition to Epic.   
 
12. STUDY COMPLETION OR TERMINATION 
12.1 Completion 
The study will be considered complete when one or more of the following conditions is met: 
• All subjects have withdrawn from the study 
• All subjects have discontinued from the study 
• The IRB, LCI DSMC, or Sponsor-Investigator discontinues the study because of safety 
considerations 
• The Sponsor-Investigator defines an administrative or clinical cutoff date 
12.2 Termination 
The study will be terminated when one or more of the following conditions occur: 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g., UAPs) 
o Results of parallel clinical studies 
o If the study conduct (e.g., recruitment rate, drop-out rate, data quality, protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame 
• The Sponsor-Investigator has decided to close the trial at any site and at any time 
 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local law.   
• In case of a partial study closure, ongoing subjects, including those in follow- up, must be 
taken care of in an ethical manner. 
 
13. STUDY MANAGEMENT 
13.1 IRB Approval  
The final study protocol and the final version of the informed consent form(s) must be approved 
in writing by the Sponsor IRB.  
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
18 
 
The Sponsor-Investigator is responsible for informing the Sponsor IRB of any amendment to the 
protocol in accordance with local requirements. The protocol must be re-approved by the IRB 
annually, as local regulations require.  
13.2 Informed Consent 
Before recruitment and enrollment onto this study, the potential subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Prior to a 
subject’s participation in the trial, the written informed consent form should be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion. 
13.3 Protocol Adherence 
Except for an emergency situation in which proper care for the protection, safety and well-being 
of the study subject requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.   
13.4 Changes to the Protocol and/or Informed Consent 
13.4.1 Amendments to the Protocol 
If it is necessary for the study protocol to be amended and/or the informed consent revised, the 
amendment or a new version of the study protocol (amended protocol) and/or the revised 
informed consent must be approved by the Sponsor-Investigator and the Sponsor IRB. 
13.5 Protocol Deviations  
If a deviation occurs, the event should be reported to the Sponsor-Investigator promptly. Any 
IRB reportable event that occurs must be reported to the IRB per institutional policies and 
reported to the Sponsor-Investigator as soon as possible. 
NOTE: Protocol deviations that, in the Investigator’s judgment, potentially caused harm to 
participants or others or indicates that the participants or others are at an increased risk of harm, 
or has adversely impacted data integrity will be reported promptly to the IRB per IRB reporting 
requirements.  
13.6 Retention of Records 
Essential documentation (e.g., informed consents), including all IRB correspondence, will be 
retained for at least 2 years after the investigation is completed.  Documentation will be readily 
available upon request. 
13.7 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the Investigator abide by GCP guidelines.  The study 
will also be carried out in full conformity with Regulations for the Protection of Human Subjects 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
19 
 
of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6 and 
in keeping with applicable local law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g., IRB) will be obtained for all participating 
centers before the start of the study, according to GCP, local laws, regulations and organizations.  
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigators may not modify or alter the procedures described in this protocol.   
The Sponsor-Investigator is responsible for the conduct of the trial at the sites in accordance with 
Title 21 of the CFR and/or the Declaration of Helsinki.  The Sponsor-Investigator is responsible 
for overseeing all study subjects.  The Sponsor-Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the study 
protocol and all applicable regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
13.8 Confidentiality of Records 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
20 
 
14. REFERENCES 
1. TEMEL JS, GREER JA, EL-JAWAHRI A, PIRL WF, PARK ER, JACKSON VA, ET AL. 
EFFECTS OF EARLY INTEGRATED PALLIATIVE CARE IN PATIENTS WITH LUNG 
AND GI CANCER: A RANDOMIZED CLINICAL TRIAL. J CLIN ONCOL 2017;35:834-
841 
2. TEMEL JS, JACKSON VA, BILLINGS JA, DAHLIN C, BLOCK SD, BUSS MK, ET AL. 
PHASE II STUDY: INTEGRATED PALLIATIVE CARE IN NEWLY DIAGNOSED 
ADVANCED NON-SMALL-CELL LUNG CANCER PATIENTS. J CLIN ONCOL 
2007;25:2377-2382 
3. TEMEL JS, GREER JA, MUZIKANSKY A, GALLAGHER ER, ADMANE S, JACKSON 
VA, ET AL. EARLY PALLIATIVE CARE FOR PATIENTS WITH METASTATIC NON-
SMALL CELL LUNG CANCER. N ENGL J MED 2010;363:733-742 
4. GREER JA, JACKSON VA, MEIER DE, TEMEL JS. EARLY INTEGRATION OF 
PALLIATIVE CARE SERVICES WITH STANDARD ONCOLOGY CARE FOR 
PATIENTS WITH ADVANCED CANCER. CA CANCER J CLIN 2013;63:349-363 
5. PARIKH RB, TEMEL JS. EARLY SPECIALTY PALLIATIVE CARE. N ENGL J MED 
2014;370:1075- 1076 
6. FERRELL BR, TEMEL JS, TEMIN S, SMITH TJ. INTEGRATION OF PALLIATIVE 
CARE INTO STANDARD ONCOLOGY CARE: ASCO CLINICAL PRACTICE 
GUIDELINE UPDATE SUMMARY. J ONCOL PRACT 2017;13:119-121 
7. EL-JAWAHRI A, TRAEGER L, GREER JA, VANDUSEN H, FISHMAN SR, LEBLANC 
TW, ET AL. EFFECT OF INPATIENT PALLIATIVE CARE DURING HEMATOPOIETIC 
STEM CELL TRANSPLANT ON PSYCHOLOGICAL DISTRESS 6 MONTHS AFTER 
TRANSPLANT: RESULTS OF A RANDOMIZED CLINICAL TRIAL. J CLIN ONCOL 
2017;35:3714-3721 
8. SHI Q, SMITH TG, MICHONSKI JD, STEIN KD, KAW C, CLEELAND CS. SYMPTOM 
BURDEN IN CANCER SURVIVORS 1 YEAR AFTER DIAGNOSIS: A REPORT FROM 
THE AMERICAN CANCER SOCIETY'S STUDIES OF CANCER SURVIVORS. 
CANCER 2011;117:2779-2790 
9. ZHAO F, CHANG VT, CLEELAND C, CLEARY JF, MITCHELL EP, WAGNER LI, ET 
AL.  DETERMINANTS OF PAIN SEVERITY CHANGES IN AMBULATORY 
PATIENTS WITH CANCER: AN ANALYSIS FROM EASTERN COOPERATIVE 
ONCOLOGY GROUP TRIAL E2Z02. J CLIN ONCOL 2014;32(4):312-319 
10. MASSIE MJ. PREVALENCE OF DEPRESSION IN PATIENTS WITH CANCER. J NATL 
CANCER INST MONOGR. 2004;(32):57-71 
11. SULLIVAN DR, FORSBERG CW, GANZINI L, ET AL. LONGITUDINAL CHANGES IN 
DEPRESSION SYMPTOMS AND SURVIVAL AMONG PATIENTS WITH LUNG 
CANCER: A NATIONAL COHORT ASSESSMENT. J CLIN ONCOL. 2016;34(33):3984-
3991. 
12. GIESE-DAVIS J, COLLIE K, RANCOURT KMS, NERI E, KRAEMER HC, SPIEGEL D. 
DECREASE IN DEPRESSION SYMPTOMS IS ASSOCIATED WITH LONGER 
SURVIVAL IN PATIENTS WITH METASTATIC BREAST CANCER: A SECONDARY 
ANALYSIS. J CLIN ONCOL. 2011;29(4):413-420. 
13. RIEKE K, SCHMID KK, LYDIATT W, HOUFEK J, BOILESEN E, WATANABE-
GALLOWAY S. DEPRESSION AND SURVIVAL IN HEAD AND NECK CANCER 
PATIENTS. ORAL ONCOL. 2017;65:76-82. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
21 
 
14. LAIRD BJ, SCOTT AC, COLVIN LA, MCKEON AL, MURRAY GD, FEARON KC, ET 
AL. PAIN, DEPRESSION, AND FATIGUE AS A SYMPTOM CLUSTER IN ADVANCED 
CANCER. J PAIN SYMPTOM MANAGE 2011; 42(1):1-11 
15. MANAGEMENT OF CANCER SYMPTOMS: PAIN, DEPRESSION, AND FATIGUE. 
SUMMARY, EVIDENCE REPORT/TECHNOLOGY ASSESSMENT: NUMBER 61. 
AHRQ PUBLICATION NO. 02-E031, JULY 2002. AGENCY FOR HEALTHCARE 
RESEARCH AND QUALITY, ROCKVILLE, MD. 
HTTP://WWW.AHRQ.GOV/CLINIC/EPCSUMS/CSYMPSUM.HTM 
16. GRATTAN A, SULLIVAN MD, SAUNDERS KW, CAMPBELL CI, VON KORFF MR. 
DEPRESSION AND PRESCRIPTION OPIOID MISUSE AMONG CHRONIC OPIOID 
THERAPY RECIPIENTS WITH NO HISTORY OF SUBSTANCE ABUSE. ANNALS OF 
FAMILY MEDICINE 2012; 10(4):304-311 
17. DOWELL D, HAEGERICH TM, CHOU R. CDC GUIDELINE FOR PRESCRIBING 
OPIOIDS FOR CHRONIC PAIN — UNITED STATES. MMWR RECOMM REP 
2016;65:1-49 
18. PATEL JN, WIEBE LA, DUNNENBERGER HM, MCLEOD HL. VALUE OF 
SUPPORTIVE CARE PHARMACOGENOMICS IN ONCOLOGY PRACTICE. 
ONCOLOGIST 2018; DOI: 10.1634 
19. EVANS WE, MCLEOD HL. PHARMACOGENOMICS--DRUG DISPOSITION, DRUG 
TARGETS, AND SIDE EFFECTS. N ENGL J MED 2003;348:538-549 
20. ANDERSEN RL, JOHNSON DJ, PATEL JN. PERSONALIZING SUPPORTIVE CARE IN 
ONCOLOGY PATIENTS USING PHARMACOGENETIC-DRIVEN TREATMENT 
PATHWAYS. PHARMACOGENOMICS 2016;17:417-434 
21. RODEN DM, VAN DRIEST SL, MOSLEY JD, WELLS QS, ROBINSON JR, DENNY JC, 
ET AL. BENEFIT OF PREEMPTIVE PHARMACOGENETIC INFORMATION ON 
CLINICAL OUTCOME. CLIN PHARMACOL THER 2018; 
22. DUNNENBERGER HM, CREWS KR, HOFFMAN JM, CAUDLE KE, BROECKEL U, 
HOWARD SC, ET AL. PREEMPTIVE CLINICAL PHARMACOGENETICS 
IMPLEMENTATION: CURRENT PROGRAMS IN FIVE US MEDICAL CENTERS. 
ANNU REV PHARMACOL TOXICOL 2015;55:89-106 
23. RELLING MV, KLEIN TE. CPIC: CLINICAL PHARMACOGENETICS 
IMPLEMENTATION CONSORTIUM OF THE PHARMACOGENOMICS RESEARCH 
NETWORK. CLIN PHARMACOL THER 2011;89:464-467 
24. BAHAR MA, SETIAWAN D, HAK E, WILFFERT B. PHARMACOGENETICS OF 
DRUG-DRUG INTERACTION AND DRUG-DRUG-GENE INTERACTION: A 
SYSTEMATIC REVIEW ON CYP2C9, CYP2C19 AND CYP2D6. 
PHARMACOGENOMICS 2017;18:701-739 
25. OWUSU OBENG A, HAMADEH I, SMITH M. REVIEW OF OPIOID 
PHARMACOGENETICS AND CONSIDERATIONS FOR PAIN MANAGEMENT. 
PHARMACOTHERAPY 2017;37:1105-1121 
26. CISZKOWSKI C, MADADI P, PHILLIPS MS ET AL. CODEINE, ULTRARAPID-
METABOLISM GENOTYPE, AND POSTOPERATIVE DEATH. N ENGL JMED 
2009;361:827–828. 
27. MADADI P, CISZKOWSKI C, GAEDIGK A ET AL. GENETIC TRANSMISSION OF 
CYTOCHROME P450 2D6 (CYP2D6) ULTRARAPID METABOLISM: IMPLICATIONS 
FOR BREASTFEEDING WOMEN TAKING CODEINE. CURR DRUG SAF 2011;6:36–
39. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
22 
 
28. MADADI P, JOLY Y, AVARD D ET AL. COMMUNICATING PHARMACOGENETIC 
RESEARCH RESULTS TO BREASTFEEDING MOTHERS TAKING CODEINE: A 
PILOT STUDY OF PERCEPTIONS AND BENEFITS. CLIN PHARMACOL THER 
2010;88:792–795. 
29. MADADI P, KOREN G. PHARMACOGENETIC INSIGHTS INTO CODEINE 
ANALGESIA: IMPLICATIONS TO PEDIATRIC CODEINE USE. 
PHARMACOGENOMICS 2008;9:1267–1284. 
30. GASCHE Y, DAALI Y, FATHI M ET AL. CODEINE INTOXICATION ASSOCIATED 
WITH ULTRARAPID CYP2D6 METABOLISM. N ENGL JMED 2004;351:2827–2831. 
31. SHAW KD, AMSTUTZ U, JIMENEZ-MENDEZ R ET AL. SUSPECTED OPIOID 
OVERDOSE CASE RESOLVED BY CYP2D6 GENOTYPING.THER DRUGMONIT 
2012;34:121–123. 
32. VORONOV P, PRZYBYLO HJ, JAGANNATHAN N. APNEA IN A CHILD AFTER 
ORAL CODEINE: A GENETIC VARIANT – AN ULTRA-RAPID METABOLIZER. 
PAEDIATR ANAESTH 2007;17: 684–687. 
33. ANDREASSEN TN, EFTEDAL I, KLEPSTAD P ET AL. DO CYP2D6 GENOTYPES 
REFLECT OXYCODONE REQUIREMENTS FOR CANCER PATIENTS TREATED FOR 
CANCER PAIN? A CROSSSECTIONAL MULTICENTRE STUDY. EUR J CLIN 
PHARMACOL 2012;68:55–64. 
34. STAMER UM, ZHANG L, BOOK M ET AL. CYP2D6 GENOTYPE DEPENDENT 
OXYCODONE METABOLISM IN POSTOPERATIVE PATIENTS. PLOS ONE 
2013;8:E60239. 
35. STAUBLE ME, MOORE AW, LANGMAN LJ ET AL. HYDROCODONE IN 
POSTOPERATIVE PERSONALIZED PAIN MANAGEMENT: PRO-DRUG OR DRUG? 
CLIN CHIM ACTA 2014;429:26–29. 
36. STAMER UM, MUSSHOFF F, KOBILAY M ET AL. CONCENTRATIONS OF 
TRAMADOL AND O-DESMETHYLTRAMADOL ENANTIOMERS IN DIFFERENT 
CYP2D6 GENOTYPES. CLIN PHARMACOL THER 2007;82:41–47.  
37. STAMER UM, ST€UBER F, MUDERS T ET AL. RESPIRATORY DEPRESSION WITH 
TRAMADOL IN A PATIENT WITH RENAL IMPAIRMENT AND CYP2D6 GENE 
DUPLICATION. ANESTH ANALG 2008;107:926–929. 
38. CREWS KR, GAEDIGK A, DUNNENBERGER HM, ET AL. CLINICAL 
PHARMACOGENETICS IMPLEMENTATION CONSORTIUM GUIDELINES FOR 
CYTOCHROME P450 2D6 GENOTYPE AND CODEINE THERAPY: 2014 UPDATE. 
CLIN PHARMACOL THERAP 2014;95(4):376-382 
39. KLEPSTAD P, RAKVA˚G TT, KAASA S ET AL. THE 118 A>G POLYMORPHISM IN 
THE HUMAN MU-OPIOID RECEPTOR GENE MAY INCREASE MORPHINE 
REQUIREMENTS IN PATIENTS WITH PAIN CAUSED BY MALIGNANT DISEASE. 
ACTA ANAESTHESIOL SCAND 2004;48:1232–1239. 
40. CHOU WY, YANG LC, LU HF ET AL. ASSOCIATION OF MU-OPIOID RECEPTOR 
GENE POLYMORPHISM (A118G) WITH VARIATIONS IN MORPHINE 
CONSUMPTION FOR ANALGESIA AFTER TOTAL KNEE ARTHROPLASTY. ACTA 
ANAESTHESIOL SCAND 2006;50:787–792. 
41. GONG XD, WANG JY, LIU F ET AL. GENE POLYMORPHISMS OF OPRM1 A118G 
AND ABCB1 C3435T MAY INFLUENCE OPIOID REQUIREMENTS IN CHINESE 
PATIENTS WITH CANCER PAIN. ASIAN PAC J CANCER PREV 2013;14: 2937–2943. 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
23 
 
42. RAKVA˚G TT, KLEPSTAD P, BAAR C ET AL. THE VAL158-MET POLYMORPHISM 
OF THE HUMAN CATECHOL-OMETHYLTRANSFERASE (COMT) GENE MAY 
INFLUENCE MORPHINE REQUIREMENTS IN CANCER PAIN PATIENTS. PAIN 
2005;116:73–78. 
43. RAKVA˚G TT, ROSS JR, SATO H ET AL. GENETIC VARIATION IN THE 
CATECHOL-O-METHYLTRANSFERASE (COMT) GENE AND MORPHINE 
REQUIREMENTS IN CANCER PATIENTS WITH PAIN. MOL PAIN 2008;4:64. 
44. FUNK KA, BOSTWICK JR. A COMPARISON OF THE RISK OF QT PROLONGATION 
AMONG SSRIS. ANN PHARMACOTHER 2013;47:1330–1341 
45. WANG JH, LIU ZQ,WANGWET AL. PHARMACOKINETICS OF SERTRALINE IN 
RELATION TO GENETIC POLYMORPHISM OF CYP2C19. CLIN PHARMACOL THER 
2001;70:42–47. 
46. HUEZO-DIAZ P, PERROUD N, SPENCER EP ET AL. CYP2C19 GENOTYPE 
PREDICTS STEADY STATE ESCITALOPRAM CONCENTRATION IN GENDEP. J 
PSYCHOPHARMACOL 2012;26:398–407. 
47. HICKS JK, BISHOP JR, SANGKUHL K ET AL. CLINICAL PHARMACOGENETICS 
IMPLEMENTATION CONSORTIUM (CPIC) GUIDELINE FOR CYP2D6 AND CYP2C19 
GENOTYPES AND DOSING OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS. 
CLIN PHARMACOL THER 2015;98:127–134. 
48. SUZUKI Y, SAWAMURA K, SOMEYA T. POLYMORPHISMS IN THE 5-
HYDROXYTRYPTAMINE 2A RECEPTOR AND CYTOCHROMEP450 2D6 GENES 
SYNERGISTICALLY PREDICT FLUVOXAMINE-INDUCED SIDE EFFECTS IN 
JAPANESE DEPRESSED PATIENTS. NEUROPSYCHOPHARMACOLOGY 
2006;31:825–831. 
49. ZOURKOV_A A, CESKOV_A E, HADASOV_A E ET AL. LINKS AMONG 
PAROXETINE-INDUCED SEXUAL DYSFUNCTIONS, GENDER, AND CYP2D6 
ACTIVITY. J SEX MARITAL THER 2007;33:343–355. 
50. GUZEY C, SPIGSET O. LOW SERUM CONCENTRATIONS OF PAROXETINE IN 
CYP2D6 ULTRARAPID METABOLIZERS. J CLIN PSYCHOPHARMACOL 
2006;26:211–212. 
51. BRINTELLIX (R) [PACKAGE INSERT]. TAKEDA PHARMACEUTICALS AMERICA, 
INC. DEERFIELD, IL: SEPTEMBER 2013. 
52. ALTAR CA, CARHART J, ALLEN JD ET AL. CLINICAL UTILITY OF 
COMBINATORIAL PHARMACOGENOMICS-GUIDED ANTIDEPRESSANT 
THERAPY: EVIDENCE FROM THREE CLINICAL STUDIES. MOL 
NEUROPSYCHIATRY 2015;1:145–155. 
53. PEREZ V, SALAVERT A, ESPADALER J ET AL. EFFICACY OF PROSPECTIVE 
PHARMACOGENETIC TESTING IN THE TREATMENT OF MAJOR DEPRESSIVE 
DISORDER: RESULTS OF A RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL. 
BMC PSYCHIATRY 2017;17:250. 
54. WINNER JG, CARHART JM, ALTAR CA, ALLEN JD, DECHAIRO BM. A 
PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND STUDY ASSESSING THE 
CLINICAL IMPACT OF INTEGRATED PHARMACOGENOMIC TESTING FOR 
MAJOR DEPRESSIVE DISORDER. DISCOV MED 2013;16:219-227 
55. NASSAN M, NICHOLSON WT, ELLIOTT MA, ROHRER VITEK CR, BLACK JL, FRYE 
MA. PHARMACOKINETIC PHARMACOGENETIC PRESCRIBING GUIDELINES FOR 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
24 
 
ANTIDEPRESSANTS: A TEMPLATE FOR PSYCHIATRIC PRECISION MEDICINE. 
MAYO CLIN PROC 2016;91:897-907 
56. BOUSMAN CA, FORBES M, JAYARAM M, EYRE H, REYNOLDS CF, BERK M, ET 
AL. ANTIDEPRESSANT PRESCRIBING IN THE PRECISION MEDICINE ERA: A 
PRESCRIBER'S PRIMER ON PHARMACOGENETIC TOOLS. BMC PSYCHIATRY 
2017;17:60 
57. BROWN LC, LORENZ RA, LI J, DECHAIRO BM. ECONOMIC UTILITY: 
COMBINATORIAL PHARMACOGENOMICS AND MEDICATION COST SAVINGS 
FOR MENTAL HEALTH CARE IN A PRIMARY CARE SETTING. CLIN THER 
2017;39:592-602 E591 
58. ALTAR CA, CARHART JM, ALLEN JD, HALL-FLAVIN DK, DECHAIRO BM, 
WINNER JG. CLINICAL VALIDITY: COMBINATORIAL PHARMACOGENOMICS 
PREDICTS ANTIDEPRESSANT RESPONSES AND HEALTHCARE UTILIZATIONS 
BETTER THAN SINGLE GENE PHENOTYPES. PHARMACOGENOMICS J 
2015;15:443-451 
 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
25 
 
15. APPENDIX A. EDMONTON SYMPTOM ASSESSMENT SCALE 
 
 
 
 
 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
26 
 
16. APPENDIX B. PATIENT HEALTH QUESTIONNAIRE (PHQ) 9 
 
 
 
 
 
 
 
 

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
27 
 
17. APPENDIX C. PGX PATIENT SURVEY    
 
  

Protocol: LCI-SUPP-NOS-PGx-001 
Version v7.0 02/20/2024 
 
28 
 
18. APPENDIX D.  MEDICATIONS OF INTEREST LIST 
 
Generic Name 
Allopurinol 
Alprazolam 
Amitriptyline 
Amphetamine 
Aprepitant 
Aripiprazole 
Atomoxetine 
Brivaracetam 
Bupropion 
Carbamazepine 
Carvedilol 
Celecoxib 
Cevimeline 
Citalopram 
Clomopramine 
Clonazepam 
Clopidogrel 
Codeine 
Desipramine 
Desvenlafaxine 
Dexamethasone 
Dexlansoprazole 
Dextromethorphan/quinidine 
Diazepam 
Diclofenac 
Donepezil 
Doxepin 
Dronabinol 
Duloxetine 
Efavirenz 
Escitalopram 
Esomeprazole 
Fentanyl 
Fluoxetine 
Fluvoxamine 
Fosphenytoin 
Gabapentin 
Granisetron 
Hydrocodone 
Hydrocodone/acetaminophen 
Hydromorphone 
Ibuprofen 
Imipramine 
Ketamine 
Lansoprazole 
Lorazepam 
Meloxicam 
Methadone 
Methylphenidate 
Metoclopramide 
Metoprolol 
Mirtazapine 
Modafinil 
Morphine sulphate 
Nortriptyline 
Olanzapine 
Omeprazole 
Ondansetron 
Oxycodone, oxycodone hcl 
Oxycodone/acetaminophen 
Palonosetron 
Pantoprazole 
Paroxetine 
Phenytoin 
Pregabalin 
Prochlorperazine 
Propafenone 
Rabeprazole 
Sertraline 
Simvastatin 
Tacrolimus 
Tamoxifen 
Tapentadol 
Temazepam 
Tolterodine 
Tramadol 
Trazodone 
Venlafaxine 
Voriconazole 
Vortioxetine 
Warfarin 
Zolpidem