Pharmacogenetic-guided Choice of Post-surgery Analgesics
Phase: NA
Conditions: Acute Pain, Post Operative Pain
Sponsor: University of Pennsylvania

 
Protocol (#851447)– PRECISE 
Page 1 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
CLINICAL RESEARCH PROTOCOL 
INVESTIGATIONAL 
PRODUCT(S): 
 
16-gene pharmacogenetic panel test 
STUDY 
NUMBER(S): 
IRB 
Number 
851447 
 
 
PROTOCOL(S) TITLE: 
PhaRmacogEnetic-guided ChoIce of post-SurgEry analgesics 
(PRECISE) 
 
 
REGULATORY 
SPONSOR: 
 
University of Pennsylvania Institutional Review Board 
FUNDING SPONSOR(S): 
University of Pennsylvania Penn Center for Precision Medicine 
 
 
ORIGINAL PROTOCOL 
DATE: 
May 24, 2022 
VERSION NUMBER: 
v 5.0 
VERSION DATE: 
August 29, 2023 
 
 

 
Protocol (#851447)– PRECISE 
Page 2 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
1  
Study Summary .......................................................................................................... 7 
1.1  
Synopsis .................................................................................................................. 7 
1.2  
Key Roles and Study Governance ..................................................................... 10 
1.3  
Schema ................................................................................................................. 11 
2  
Introduction and Rationale ..................................................................................... 12 
2.1  
Study Rationale ................................................................................................... 12 
2.2  
Background .......................................................................................................... 12 
2.2.1  
Description of intervention ........................................................................... 15 
2.3  
Risk/Benefit Assessment ..................................................................................... 15 
2.3.1 
Known Potential Risks .................................................................................. 15 
2.3.2  
Known Potential Benefits ............................................................................. 16 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 16 
3  
Study Objectives and Endpoints............................................................................. 17 
4  
Study Plan ................................................................................................................. 18 
4.1 
Study Design ........................................................................................................ 18 
4.1.1  
Medication selection and dose recommendations based on genotype ...... 19 
4.2  
Scientific Rationale for Study Design ................................................................ 19 
5  
Study Population ...................................................................................................... 19 
5.1  
Inclusion Criteria ................................................................................................ 19 
5.2  
Exclusion Criteria ............................................................................................... 20 
5.3  
Screen Failures .................................................................................................... 20 
5.4  
Strategies for Recruitment and Retention ........................................................ 20 
5.5  
Duration of study participation ......................................................................... 20 
5.6  
End of Study Definition ...................................................................................... 21 
6  
Study Intervention ................................................................................................... 21 
6.1  
Study Intervention Administration ................................................................... 21 
6.1.1  
Study Intervention Description .................................................................... 21 
6.1.2  
Dosing and Administration .......................................................................... 23 
6.2  
Study Intervention Compliance ......................................................................... 23 
6.3  
Discontinuation of Study Intervention .............................................................. 23 
6.4  
Participant Discontinuation/Withdrawal from the Study ............................... 24 
6.5  
Lost to Follow-Up ................................................................................................ 24 
7 
Study Assessment and Procedures ......................................................................... 25 
7.1 
Provider on attitudes toward and knowledge of PGx testing (Baseline)........ 25 
7.2  
Provider education .............................................................................................. 25 
7.3  
Screening and identification ............................................................................... 25 
7.4 
Informed consent ................................................................................................. 25 
7.5 
Randomization .................................................................................................... 25 
7.6  
Genotyping (Baseline) ......................................................................................... 26 
7.7 
Clinical data collection (Baseline) ...................................................................... 26 
7.8 
Return of pharmacogenetic results ................................................................... 26 
 

 
Protocol (#851447)– PRECISE 
Page 3 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
7.9 
Implementation metrics (0-30 days) .................................................................. 27 
7.10 
Data collection after surgery (0 to 2 months) ................................................... 27 
7.11 
Patient survey on knowledge and satisfaction of PGx testing (30 days 
post-study) ............................................................................................................ 28 
7.12 
Data collected from medical records (EMR) (1 year) ...................................... 28 
8 
Safety and Adverse Events ...................................................................................... 28 
8.1 
Adverse Events and Serious Adverse Events ................................................... 28 
8.1.1 
Definition of Adverse Events (AE) .............................................................. 28 
8.1.2 
Definition of Serious Adverse Events (SAE) ............................................... 28 
8.1.3 
Classification of an Adverse Event .............................................................. 29 
8.1.4 
Time Period and Frequency for Event Assessment and Follow-Up ......... 29 
8.1.5 
Adverse Event Reporting ............................................................................. 30 
8.1.6 
Serious Adverse Event Reporting ................................................................ 30 
8.2 
Unanticipated Problems ..................................................................................... 31 
8.2.1 
Definition of Unanticipated Problems (UP) ................................................ 31 
8.3 
Unanticipated Problem Reporting .................................................................... 31 
9 
Statistical plan .......................................................................................................... 32 
9.1 
Sample Size .......................................................................................................... 32 
9.1.1 
Populations for Analyses .............................................................................. 32 
9.2 
Statistical Analyses .............................................................................................. 32 
9.2.1 
General Approach ......................................................................................... 32 
9.2.2 
Analysis of the Primary Endpoint(s) ........................................................... 33 
9.2.3 
Analysis of the Secondary Endpoint(s) ....................................................... 33 
10 Supporting Documentation and Operational Considerations ............................. 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 34 
10.1.1 
Informed Consent Process ............................................................................ 34 
10.1.2 
Study Discontinuation and Closure ............................................................. 34 
10.1.3 
Confidentiality and Privacy ......................................................................... 35 
10.1.4 
Future Use of Stored Specimens and Data ................................................. 36 
10.1.5 
Source documents ......................................................................................... 36 
10.1.6 
Case report forms .......................................................................................... 36 
10.1.7 
Study monitoring, auditing, and inspecting ................................................ 36 
10.1.8 
Safety Oversight ............................................................................................ 36 
10.1.9 
Clinical Monitoring ....................................................................................... 37 
10.1.10 
Study Records Retention .............................................................................. 37 
10.1.11 
Protocol Deviations ....................................................................................... 37 
10.1.12 
Publication and Data Sharing Policy .......................................................... 37 
10.1.13 
Conflict of Interest Policy ............................................................................. 38 
10.2 
Protocol Amendment History ............................................................................ 38 
11 Study finances........................................................................................................... 39 
11.1 
Funding source .................................................................................................... 39 

 
Protocol (#851447)– PRECISE 
Page 4 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
12 References ................................................................................................................. 39 
13 Appendices ................................................................................................................ 42 
13.1 
Schedule of Activities (SoA) ............................................................................... 42 
13.2 
CYP2D6 Phenoconversion ................................................................................. 43 
13.3 
Morphine milligram equivalence ....................................................................... 44 
13.4 
Analgesic medication selection and dosing algorithm for CYP2C9 ............... 45 
13.5 
Analgesic medication selection and dosing algorithm for CYP2D627 ............ 46 
13.6 
Medication information ...................................................................................... 47 
13.6.1 
Dosing information for oral analgesics ....................................................... 47 
13.6.2 
Dosing adjustments for clinical factors ....................................................... 47 
13.6.3 
Clinical adverse drug reaction profile ......................................................... 48 
13.7 
Pharmacist detailed note to patient summarizing PGx results ....................... 50 
13.8  Survey Code Letter ............................................................................................. 53 
13.9 
Pharmacist PGx-guided recommendations to providers consult note  
template ................................................................................................................ 54 
13.10 Text messaging script .......................................................................................... 55 
13.11 Provider survey – Pharmacogenetic testing ..................................................... 57 
13.12 Patient survey – Pharmacogenetic testing ........................................................ 60 
 
 
 
 
 

 
Protocol (#851447)– PRECISE 
Page 5 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
PRINCIPAL INVESTIGATOR SIGNATURE 
 
STUDY 
SPONSOR: 
Penn Center for Precision Medicine 
Perelman School of Medicine 
University of Pennsylvania 
STUDY TITLE: 
PhaRmacogEnetic-guided ChoIce of post-SurgEry analgesics (PRECISE) 
STUDY ID 
PROTOCOL 
VERSION 
[IRB # 851447] 
v 5.0 
I have read the referenced protocol. I agree to conduct the study in accordance to this protocol, in compliance 
with the Declaration of Helsinki, Good Clinical Practices (GCP), and all applicable regulatory requirements 
and guidelines. 
Principal 
Investigator Name:  
Sony Tuteja, PharmD, MS 
 
Signature 
 
Affiliation: 
4249 – DM-Translational Medicine and 
Human Genetics 
 
Date 
 
 
Co-Investigator 
Name:  
 
Glenda Hoffecker, PharmD 
 
Signature 
 
Affiliation: 
4249 – DM-Translational Medicine and 
Human Genetics 
 
Date 
 
 
Co-Investigator 
Name:  
 
Mary Deagostino-Kelly, MD, MSCE 
 
Signature 
 
Affiliation: 
Department: Obstetrics and Gynecology  
Date 
 
Co-Investigator 
Name: 
Affiliation: 
 
Co-Investigator 
Name:  
Stefan Gysler, MD, MHS 
Department: Obstetrics and Gynecology 
 
Lakeisha Mulugeta-Gordon, MD 
 
Signature 
 
Date 
 
Signature 
 
Affiliation: 
Department: Obstetrics and Gynecology  
Date 
 
 

 
Protocol (#851447)– PRECISE 
Page 6 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
Abbreviations 
ADE 
Adverse drug event 
ADR 
Adverse drug reactions 
AS 
Activity score 
CAP 
College of American Pathologists 
CDS 
Clinical Decision Support 
CLIA 
Clinical Laboratory Improvement Amendments 
CNV 
Copy number variation 
CPIC  
Clinical Pharmacogenetics Implementation Consortium 
CYP 
Cytochrome P450  
DGI 
Drug-gene interactions 
DNA 
Deoxyribonucleic acid 
EMR 
Electronic medical record 
IM 
Intermediate metabolizer 
LOS 
Length of stay 
MME 
Morphine milligram equivalence 
NSAID 
Non-steroidal anti-inflammatory drug 
PDMP 
Prescription drug monitoring program 
PGx 
Pharmacogenetic 
PM 
Poor metabolizer 
POD 
Postoperative day 
Postop 
Postoperative 
UM 
Ultrarapid metabolizer 
 
 
 

 
Protocol (#851447)– PRECISE 
Page 7 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
1  STUDY SUMMARY 
1.1  
Synopsis 
Title:  
PhaRmacogEnetic-guided ChoIce of post-SurgEry analgesics 
(PRECISE) 
Short Title: 
PRECISE  
Study 
Description:  
Opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) 
are used to prevent or treat acute postoperative (postop) pain yet are 
associated with adverse drug reactions (ADRs), resulting in an increase in 
medical costs and hospitalization length of stay (LOS). Efficacy and 
toxicity of opioid pain medications (tramadol, codeine, and hydrocodone) 
and NSAIDs, (celecoxib, flurbiprofen, ibuprofen, meloxicam, piroxicam) 
are impacted by pharmacogenetic (PGx) variants (i.e., CYP2D6 or 
CYP2C9, respectively). We hypothesize that availability of a multi-gene 
PGx panel test with a pharmacist consult will increase PGx test 
utilization, provide tailored pain medication recommendations and 
improve patient outcomes. This is a randomized pilot implementation 
study to determine the feasibility of integrating a preemptive PGx panel 
test into clinical care to guide analgesic selection and dosing in postop 
gynecologic surgery patients. Effectiveness of the PGx-guided approach 
will be determined by comparing the numeric pain scores, overall opioid 
consumption as assessed by morphine milligram equivalence (MME) per 
day, and incidence of opioid/NSAID-related ADRs to a control group 
receiving usual care. 
Objectives:  
Implementation Aims: 
1. To determine the feasibility of integrating a PGx panel test in the 
EMR with a pharmacist PGx consult. 
2. Determine the fidelity to genotype-guided pharmacotherapy 
recommendations. 
Effectiveness Aims: 
3. To determine if PGx testing will improve the patient self-reported 
numeric pain scores 
4. To determine if PGx testing will reduce MME 
5. To determine if PGx testing will decrease ADRs resulting from 
their pain regimen. 
Primary 
Endpoint:  
1. The proportion of PGx test results returned prior to surgery. 

 
Protocol (#851447)– PRECISE 
Page 8 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
2. The proportion of dose modifications and medication selections made 
in agreement with the genotype-guided dosing recommendations for 
analgesic medications. [Time Frame: up to 14 days after surgery] 
Secondary 
Endpoints: 
1. Mean patient self-reported numeric pain scores on POD 0, 1, & 2 
(only while admitted) and POD 3, 7, & 14 in each group. [Time 
Frame: 14 days after surgery] 
2. The total MME consumption between intervention and control groups 
on POD 0-7 and POD 1-14). [Time Frame: 14 days after surgery] 
3. The frequency of pain medication related ADRs. 
4. Baseline provider attitudes toward and knowledge of PGx testing as 
assessed by a questionnaire. [Time Frame: Prior to start of study and 
provider education] 
5. Post-study patient experience with PGx testing as assessed by a 
questionnaire. [Time Frame: 30 days after surgery] 
 
Study 
Population: 
Inclusion criteria 
1. Able and willing to provide informed consent 
2. Assigned female at birth and aged 18 years or older at the time of 
study initiation 
3. Major gynecologic surgery indicated and planned for 
hysterectomy, myomectomy, exploratory laparotomy, and open 
abdominal surgery 
4. Willing to provide a buccal swab for PGx testing and comply with 
all study-related procedures 
Exclusion criteria 
1. Receiving chronic opioid therapy defined as ≥ 3 consecutive 
months of 1-month prescriptions for an opioid (determined by 
review of the prescription drug monitoring program [PDMP]). 
2. Pregnancy 
3. Breastfeeding  
4. Treating physician does not want subject to participate 
Phase: 
N/a 
Description of 
Sites/Facilities  
1. Jordan Center for Gynecologic Cancers 
Perelman Center for Advanced Medicine (PCAM) 
Abramson Cancer Center, West Pavilion, 3rd Floor 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
2. Helen O. Dickens Center for Women’s Health:  
Hospital of the University of Pennsylvania  
1 West Gates  

 
Protocol (#851447)– PRECISE 
Page 9 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
3400 Spruce Street  
3. Penn Health for Women Radnor 
Floor 3, Suite 302 North 
145 King of Prussia Road 
Radnor, PA 19087 
4. Penn Ob/Gyn Associates 
Suite 371 
3701 Market Street 
Philadelphia, PA 19104 
5. Penn Health for Women University City 
12th floor  
3737 Market Street 
Philadelphia, PA 19104 
 
Enrolling 
Participants: 
200 participants will be enrolled 
Description of 
Study 
Intervention: 
Genetic: 16 PGx gene panel (CYP2B6, CYP2C19, CYP2C9, CYP2C 
Cluster, CYP2D6, CYP3A5, CYP4F2, DPYD, HLA-A, HLA-B, IFNL4, 
NUDT15, SLCO1B1, TPMT, UGT1A1, VKORC1) 
The study utilizes a lab developed test (OneOme, Minneapolis, MN) 
performed in a CAP and CLIA accredited environment that provides 
identification of a patient’s genotype determined from genomic DNA 
from a buccal sample with a turnaround time of 7-10 business days after 
receiving the sample.  
This is a randomized, prospective, open-label study. Patients with 
planned gynecologic surgeries will be randomized to the PGx-guided 
group or the control group (usual care). Following consent, the surgeon 
will place a PGx test order; the buccal sample will be collected by the 
participant and mailed to OneOme for genotyping. Results will be 
returned electronically to the EMR (PennChart). The results will appear 
in the EMR when available for those in the PGx-guided group and 
delayed by approximately 30 days post-surgery for those in the control 
group. A pharmacist will review the results for the PGx-guided group and 
create/send a consult note to the surgeon with recommendations for 
analgesia based on the PGx results and other clinical factors (e.g., 
renal/hepatic function, drug allergies, age, drug interactions, comorbid 
conditions, etc.). Additionally, for participants with an actionable 
genotype (variants that would require a dose adjustment or therapeutic 
alternative of an analgesic), clinical decision support (CDS) tools will 

 
Protocol (#851447)– PRECISE 
Page 10 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
alert the ordering surgeon of the PGx result and the recommended dose 
adjustment or need for an alternative therapy. The prescribing surgeon 
will ultimately decide the analgesic regimen incorporating the pharmacist 
recommendations and other relevant clinical factors. A pharmacist will 
create/send a detailed letter to the patient and their primary care provider 
explaining the patient’s PGx test results for both cohorts. 
Study Duration: 
Two years 
Participant 
Duration: 
1 year 
 
 
1.2  
Key Roles and Study Governance 
Sponsor: 
University of Pennsylvania 
Sony Tuteja, PharmD, MS 
Research Assistant Professor of Medicine 
Assistant Director, Pharmacogenomics, Penn Center for Precision Medicine 
Institution Name:  
University of Pennsylvania Perelman School of Medicine 
Department of Medicine 
Division of Translational Medicine and Human Genetics 
Address: 
Smilow Center for Translation Research  
3400 Civic Center Blvd, 11-142 
Philadelphia, PA 19104-6160 
Phone Number:  
484-431-1002 
Email: 
sonyt@pennmedicine.upenn.edu 
 
 

 
Protocol (#851447)– PRECISE 
Page 11 of 62
 
 
Confidential and Proprietary Information of the University of Pennsylvania 
 
1.3  
Schema 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant gynecologic surgery: Surgeon will 
decide analgesic regimen; incorporating the 
pharmacist recommendations and other relevant 
clinical factors. 
Total 200:  Screen potential participants by inclusion and exclusion criteria. 
Obtain informed consent. 
PGx results returned to the genomics portal and 
released to the EMR in 7-10 days.  
A pharmacist reviews PGx results & creates a 
consult note with genotype-guided medication 
recommendations. CDS will alert ordering provider 
at time of prescribing of dose adjustments or need 
for alternative analgesic. 
PGx buccal swab is collected by participant in 
office.  
Sample mailed to OneOme by office staff. 
Randomize 
Control group 
(usual care) 
n=100 
PGx-guided 
group 
n=100 
Endpoints collected prospectively:  
refer to Appendix Section 13.1, Schedule of Activities 
PGx buccal swab is collected by 
participant in office.  
Sample mailed to OneOme by office staff. 
PGx results returned in genomics portal in 7-
10 days. Results will not be released to the 
EMR until approximately 30 days after 
surgery. 
Participant gynecologic surgery: Surgeon 
will decide analgesic regimen based on 
relevant clinical factors. 
A pharmacist will create/send a detailed letter to the patient and their primary 
care provider explaining the patient’s PGx test results. 

 
Protocol #851447– PRECISE 
Page 12 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
2  INTRODUCTION AND RATIONALE 
2.1  
Study Rationale 
There are known PGx variants in CYP2C9 and CYP2D6 genes associated with efficacy and 
safety of certain opioid medications and NSAIDs.1,2 Testing for these variants in patients with 
acute postoperative pain is not routinely performed and it is unknown whether this testing can 
decrease overall opioid consumption in these patients without compromising pain control. Prior 
studies of CYP2D6 genotyping in patients with chronic pain or acute post-op pain have shown 
promising results.3,4 We will conduct a randomized, open-label, pilot implementation study to 
determine the feasibility of integrating a preemptive PGx test using a multi-gene panel into 
clinical care along with a pharmacist consult to provide patient specific analgesic 
recommendations and dosing in post-op gynecologic surgery patients. Effectiveness of the PGx-
guided approach will be determined by comparing, in variant carriers, the numeric pain scores, 
total opioid consumptions as assessed by daily morphine milligram equivalents (MME), and 
incidence of opioid/NSAID-related ADRs to a control group receiving usual care. The use of a 
preemptive 16 gene PGx panel is important for our tertiary endpoint to collect the number of 
additional CPIC Level A and B drugs prescribed in the year following surgery to understand the 
reusability of the multi-gene panel for all providers. Preemptive PGx testing is further discussed 
below in section 2.2. 
2.2  
Background 
Gynecologic surgeries are among the most commonly performed operating room procedures in 
the U.S. and cause varying levels of acute postoperative pain.5 Uncontrolled pain can lead to 
decreased quality of life, increased morbidity (e.g., compromised sleep, nausea, vomiting, 
anxiety, etc.), and chronic postoperative pain.6 Opioids and NSAIDs are commonly used to treat 
postop pain.7 Efficacy and toxicity of opioid pain medications including codeine, tramadol and 
hydrocodone are impacted by CYP2D6 variants.1 While CYP2C9 variants help to predict an 
individual’s risk for ADRs for certain NSAIDs such as ibuprofen and meloxicam.2  
The CYP2D6 enzyme metabolizes codeine and tramadol to their respective active metabolites, 
morphine and O-desmethyltramadol.8 In individuals with 1 or 2 copies of decreased or no 
function alleles (i.e. CYP2D6 intermediate metabolizers [IM] or poor metabolizers [PM]), 
morphine and O-desmethyltramadol formation is decreased, resulting in poor pain control.1 
Conversely, those with copy number variations (CNV) in CYP2D6 (i.e. ultra-rapid metabolizers 
[UM]) have an increased conversion to the active metabolite resulting in a higher incidence of 
opioid related toxicity including nausea and respiratory depression.1 NSAIDs are also commonly 
recommended for intraoperative and post-op pain management to minimize opioid use but are 
also associated with risk of severe ADRs, such as gastrointestinal inflammation, ulcers, or 
hemorrhage; acute kidney injury; acute myocardial infarction; cerebrovascular accidents; 
hyperkalemia.7,9,10 PGx testing can predict an individual’s risk for ADRs and subsequently guide 
dosing and selection of NSAIDs by detecting variations in the CYP2C9 gene.2   

 
Protocol #851447– PRECISE 
Page 13 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
Other factors such as age, comorbid conditions, renal/hepatic function, concomitant medications, 
phenoconversion, etc. can also influence medication metabolism. Phenoconversion occurs when 
non-genetic factors influence an individual’s ability to metabolize medications (phenotype), 
causing a mismatch with the genotype predicted drug metabolism.11 Phenoconversion can occur 
from drug-drug interactions, particularly with concomitant use of strong inhibitors of the 
cytochrome P450 enzymes (e.g. CYP2D6 strong inhibitors  bupropion, fluoxetine, 
paroxetine). 
CYP2D6 and CYP2C9 results can be applied in clinical practice by using peer-reviewed,  
evidence-based guidelines provided by the NIH-funded Clinical Pharmacogenetics 
Implementation Consortium (CPIC) (Table 1).1,2 Alternatives to codeine and tramadol are 
recommended for analgesia in CYP2D6 UMs and PMs,1 and dosing recommendations for 
codeine, tramadol, and hydrocodone are suggested for CYP2D6 IMs and PMs.1 Similarly, 
alternatives and/or dose adjustments to celecoxib, flurbiprofen, ibuprofen, meloxicam, and 
piroxicam are recommended for CYP2C9 IMs (Activity Score [AS] 1) or PMs.2 
Table 1. Pharmacogenes associated with pain medication treatment  
Gene 
Phenotype 
Phenotype 
frequency* 
Affected Drugs 
Effect on drug 
EU 
AA 
CYP2D6 
UM 
0.031 
0.045 
Codeine, tramadol 
Increased risk of 
toxicities 
IM 
0.39 
0.36 
Codeine, tramadol 
Decreased response 
PM 
0.065 
0.023 
Codeine, tramadol 
Decreased response 
IM or PM 
0.45 
0.39 
Hydrocodone 
Possible decreased 
response 
CYP2C9 
IM (AS 1) 
0.138 
0.05 
Celecoxib, flurbiprofen, 
ibuprofen, meloxicam, 
piroxicam 
Increased risk of 
toxicities 
PM 
0.026 
0.005 
Celecoxib, flurbiprofen, 
ibuprofen, meloxicam, 
piroxicam 
Increased risk of 
toxicities and/or 
severity of toxicities 
* Frequencies per Clinical Pharmacogenetics Implementation Consortium (CPIC); AA: African ancestry; EU: 
European ancestry; AS: activity score; UM: ultrarapid metabolizer; IM: intermediate metabolizer; PM: poor 
metabolizer 
Previous work in this area includes a pragmatic, non-randomized, open-label, prospective, 
cluster design study comparing CYP2D6 genotype-guided opioid treatment to usual care in 375 
patients with chronic pain.3  Pharmacists suggested alternative analgesics after reviewing the 
PGx results and assigning a CYP2D6 phenotype using activity scores and drug-induced 
phenoconversion for interacting concomitant medications. Hydrocodone or morphine was 
suggested for UM, PM, and IM (only where pain was uncontrolled with codeine, hydrocodone, 
oxycodone, or tramadol). They found a significant difference in the number of CYP2D6 IMs and 
PMs, who were receiving tramadol or codeine prior to study enrollment, with a 30% decrease in 
composite pain intensity in the CYP2D6-guided group compared to usual care group.  

 
Protocol #851447– PRECISE 
Page 14 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
Another randomized, open-label, type 2 hybrid implementation-effectiveness study evaluated 
CYP2D6-guided opioid selection in 260 post-op hip or knee arthroplasty patients.4 Similarly, a 
pharmacist provided analgesic recommendations based on the participant’s CYP2D6 phenotype. 
Tramadol was recommended opioid for CYP2D6 NMs and hydromorphone, morphine, or non-
opioid was recommended for CYP2D6 IMs, PMs, or UMs. They found that pain intensity was 
similar in the CYP2D6-guided group compared to the usual care group. However, the total MME 
in the CYP2D6-guided group was significantly lower compared to the usual care group. 
One strategy for testing PGx variants is by preemptive panel testing or testing for multiple 
actionable pharmacogenes in anticipation of potential future drug-gene interactions (DGIs).12  
Initial findings indicate that preemptive panel testing is cost-effective compared to reactive panel 
testing (i.e. testing multiple genes at the time of or after initiating a high-risk medication) and it 
is hypothesized that overall cost-effectiveness with the preemptive testing model increases over 
time.13  In a study conducted at the Veteran Health Administration (VHA) evaluating pharmacy 
records for over 7 million Veterans over a 6-year period, 54.8% were prescribed at least one drug 
with a DGI, 15.3% received two, and 11.7% receive 3 or more drugs.14 This study demonstrates 
that patients are prescribed multiple drugs with DGIs over a relative short period of time and the 
reusability of the PGx panel. 
Integration of PGx results in the EMR along with CDS tools to provide genotype-guided 
medication recommendations at the point of prescribing is a crucial component to enhance 
adoption of clinical PGx testing.15,16  While EMR-based tools are vital for widespread PGx 
adoptions, EMR based provider alerts are notorious for being ignored, as evidenced by a study of 
drug-drug interaction alerts, where 93% were overridden or ignored.17 This is somewhat 
improved for PGx alerts. A study evaluating PGx alerts in 6 sites published by the Electronic 
Medical Records and Genomics (eMERGE) consortium, described wide variation in acceptance 
and follow rates with 26% of alerts overridden and 12% ignored resulting in clinical responses 
followed in 42% of cases.16 It may be that application of PGx results cannot be accomplished in 
certain situations without detailed knowledge of individual patients, their clinical condition, 
ongoing therapy, and the recognition of the multiple factors that can influence therapeutic 
response such as phenoconversion. The addition of an consult by a pharmacist will allow for a 
more patient-specific recommendation by taking into account additional patient factors.18 A 
recent study found that by adding a pharmacist consult in addition to the general PGx 
information included in the PGx lab report, recommendations could be streamlined to only 
include those directly impacting the patient’s current care.18 In addition, the pharmacists included 
genotype-guided medication recommendations for untreated conditions that were not included in 
the PGx lab report.18 
Genotyping for this study will be performed by the 16-gene PGx panel from OneOme which is 
already in use for patients seen in the PGx clinic through Medical Genetics. The electronic 
interface with OneOme went live in October 2021, and the results appear as discrete 
components, which will streamline the ordering and resulting process for gynecologic clinicians. 
We have worked with the PennChart (Epic) informatics analysts at Penn Medicine to build CDS 
in the EMR for all DGIs with CPIC level A and B guidelines, except for the following genes: 

 
Protocol #851447– PRECISE 
Page 15 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
CYP2C cluster, CYP4F2, and VKORC1, which is in progress. The CDS provides guidance for 
medication selection and dosing based on PGx results and will be available to all Penn Medicine 
providers during the study period and after the study has ended. The cost of the panel test is 
equivalent to single gene tests. 
2.2.1  
Description of intervention 
This study utilizes a preemptive testing approach with a PGx panel that tests for 16 CPIC Level 
A pharmacogenes (CYP2B6, CYP2C19, CYP2C9, CYP2C Cluster, CYP2D6, CYP3A5, CYP4F2, 
DPYD, HLA-A, HLA-B, IFNL4, NUDT15, SLCO1B1, TPMT, UGT1A1, VKORC1) from a buccal 
sample provided and resulted by a CAP and CLIA accredited genotyping lab (OneOme, 
Minneapolis, MN) (See section 6.1.1 Study Intervention Description). 
2.3  
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
The risk associated with self-collection of a buccal swab is minimal. 
There can be a risk in knowing genetic information. New health information about inherited 
traits that may affect participating patients and or their blood relatives may be found during the 
research study. Most PGx results are not associated with incidental findings except for UGT1A1. 
These diseases are typically identified at birth or in early childhood19,20 and therefore PGx testing 
is unlikely to result in these incidental findings: 
UGT1A1 plays a role in the metabolism of bilirubin and is associated 
with hereditary hyperbilirubinemia syndromes. The *28 variant is a common cause of Gilbert 
syndrome.19 Individuals with Gilbert syndrome may experience transient elevations in 
unconjugated plasma bilirubin in response to various triggers (e.g., fasting, infection, or 
medications). Genotypes most implicated in Gilbert syndrome are UGT1A1*28/*28 and 
UGT1A1*6/*6.19 Crigler-Najjar syndrome type I is very rare and results from deleterious 
UGT1A1 mutations that results in hyperbilirubinemia19 and occur early in childhood therefore 
the PGx testing is unlikely to result in incidental findings. However, identification of a 
heterozygous state may have implications for prenatal genetic counseling.  
Incidental findings will be communicated to the patient through the detailed note (appendix 
section 13.7) and to the patient’s primary care physician (PCP) (if participant identifies a PCP 
and wants the letter to be sent). If the patient has additional questions, they can be referred to a 
genetic counselor. 
Additionally, there is the risk of loss of privacy with storing the health and genetic data of 
participating patients. Very rarely health or genetic information could be misused by employers 
or insurance companies; however, in such events, patients may have difficulty finding or 
maintaining a job or insurance. Laws such as the federal Genetic Information Nondiscrimination 
Act (GINA) prohibit employers and health insurers from discriminating against 

 
Protocol #851447– PRECISE 
Page 16 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
individuals based on their genetic information. However, GINA does not protect against life 
insurance or long-term care insurance. 
2.3.2  
Known Potential Benefits 
The potential benefit to the study participants is having their analgesic regimen tailored to their 
genetic profile so as to avoid medication-related toxicities and/or lack of efficacy.  
2.3.3 
Assessment of Potential Risks and Benefits 
The study is considered low risk since the medications of interest in the study are FDA-approved 
for clinical use for analgesia. The study will provide valuable information on the best methods 
for incorporation PGx testing into clinical care to improve efficacy and decrease adverse events. 
 
 

 
Protocol #851447– PRECISE 
Page 17 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
3  STUDY OBJECTIVES AND ENDPOINTS 
Hypothesis: 
The availability of a multi-gene PGx panel test with a pharmacist consult will increase PGx test 
utilization, provide tailored pain medication recommendations, and improve patient outcomes.  
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
1. To determine the feasibility of integrating a 
PGx panel test in the EMR with a pharmacist 
PGx consult for each patient. 
2. Determine the fidelity to genotype-guided 
pharmacotherapy recommendations. 
1. The proportion of PGx test results and consults 
returned prior to surgery.  
2. The proportion of dose modifications and medication 
selections made in agreement with the genotype-
guided dosing recommendations for analgesic 
medications. 
Secondary 
 
1. To determine if PGx testing will improve the 
patient self-reported numeric pain scores in 
patients  
2. To determine if PGx testing will decrease 
ADRs resulting from the opioid pain regimen. 
3. To determine if PGx testing will decrease 
ADRs resulting from the NSAID pain regimen 
in participants with actionable CYP2C9 
variants. 
4. To determine if PGx testing will decrease the 
total opioid consumption.  
5. To assess provider attitudes toward PGx 
testing. 
6. To assess patient attitudes towards PGx testing. 
1. Mean patient self-reported numeric pain scores (POD 
0, 1, & 2 (only while admitted) and POD 3, 7, & 14 in 
variant carriers in the PGx-guided group vs. control 
group. 
2. Number of opioid-related ADRs in the PGx-guided 
group vs. control group  
3. Number of NSAID ADRs in variant carriers in the 
PGx-guided group vs. control group  
4. The difference in total MME consumption in the PGx-
guided group vs. control group (POD 0-7 and POD 1-
14). 
5. Baseline provider attitudes toward and knowledge of 
PGx testing as assessed by a questionnaire.   
6. Patient experience with PGx testing at 30 days after 
surgery as assessed by a questionnaire.    
Tertiary 
 
1. To determine if PGx testing is associated with 
a decreased hospital LOS. 
2. To determine population frequency of PGx 
variants  
3. To determine reusability of the multi-gene 
panel 
4. To determine if PGx testing impacts chronic 
use of opioids. 
1. Length of hospital admission in the PGx-guided group 
vs. control group. 
2. Minor allele frequencies of CYP2D6 and CYP2C9 
actionable variants by ancestry. 
3. Number of additional CPIC Level A and B drugs 
prescribed in the year following surgery and number 
of EMR alerts fired to non-gyn surgery providers. 
4. Number of participants on chronic opioids at 6 
months and at 1 year.  

 
Protocol #851447– PRECISE 
Page 18 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
4  STUDY PLAN 
4.1  
Study Design 
This is a single site, randomized, prospective, open-label pilot implementation study to 
determine the feasibility of integrating a PGx testing into clinical care. The effectiveness of the 
PGx-guided approach will be determined by comparing the numeric pain scores, overall opioid 
consumptions as assessed by total MME, and incidence of opioid/NSAID-related ADRs to a 
control group (usual care). 
Once enrollment is open, patients seen at any of the practice sites for surgical consultations, will 
be evaluated by their treating physician for eligibility based on the planned gynecologic surgery. 
Study staff will screen and identify patients for enrollment with the assistance of the treating 
physician. The study will be discussed with the patient to determine their interest. If the patient 
agrees to participate, they will be consented by their physician or study staff and randomly 
assigned to the intervention group (PGx-guided) or the control group (usual care). In the case 
where surgical intervention is likely, but not definite at the initial surgical consultation visit, once 
surgery is confirmed, study staff will contact the patient via phone to discuss participation in the 
study. Consent will be collected through My Penn Medicine (MPM) if the patient is enrolled or 
verbally if not enrolled in MPM and a copy of the consent will be emailed to the participant. 
The PGx test panel order will be signed by a surgeon; a buccal swab kit will be provided to the 
patient for self-collection; the test kit will be returned to OneOme by the office, research staff, or 
the participant if collected outside of the clinic visit. The results will be returned electronically in 
the Precision Medicine tab in PennChart after they are released from a result portal by study 
personnel. 
For the intervention group (PGx-guided group): The results will be released from the result 
portal within one business day from the day they are available in the portal for release. A 
pharmacist will review the results and create a consult note within 3 business days with analgesic 
medication selection and dose recommendations based on actionable genotypes and other 
clinical factors (e.g., renal/hepatic function, drug allergies, age, drug interactions, comorbid 
conditions, etc.). A pharmacist will create/send a detailed letter to the patient and their primary 
care provider explaining the patient’s PGx test results. CDS tools will alert providers of 
actionable genotypes and include recommendations for dosing or medication selection at the 
time of ordering an affected medication. The prescribing surgeon will ultimately determine 
analgesic selection and dosing. 
For the control group (Usual care group): The prescribing surgeon will order analgesic 
medications based on usual, standard of care practices. The results will be released from the 
result portal approximately 30 days after the participant’s surgery. A pharmacist will create/send 
a detailed letter to the patient and their primary care provider explaining the patient’s PGx test 
results. The control group (usual care) will receive PGx testing, but not receive the results for 30 
days. This is to allow us to compare the effectiveness of the PGx-guided approach to those who 

 
Protocol #851447– PRECISE 
Page 19 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
received usual care and were variant carriers. Holding results for 30 days is justified because 
doing this testing in clinical practice is not yet standard of care.  
To ensure that pharmacogenetic results are released to the patient, if surgery is not scheduled 
within 9 months after study enrollment, the pharmacogenetic results will be released to the EHR 
and the patient regardless of the study arm group they are assigned. 
For both groups, participants will receive two-way text messaging (via RedCap using Twilio as 
the SMS service) after discharge from the hospital on POD# 3, 7, and 14 to collect self-reported 
measures (see Section 7.6 and 13.9 for further details). 
The detailed letter to the patient and their primary care provider includes how to contact the PGx 
pharmacist for questions regarding their results. A pharmacist consult is available to study 
participants at no charge. If consult with a genetics provider is requested (Genetics physician or 
genetic counselor) they may be referred to the Medical Genetics clinic for an appointment, fees 
associated with this consult will be the responsibility of the patient.    
4.1.1  
Medication selection and dose recommendations based on genotype 
Genotype-guided medication selection and dose recommendations will be made according to 
peer-reviewed, evidence-based clinical practice guidelines from CPIC and patient clinical factors 
(e.g., renal/hepatic function, drug allergies, age, drug interactions, comorbid conditions, etc.). 
(See section 13.4 & 13.5 for analgesic medication selection and dosing algorithm) 
4.2  
Scientific Rationale for Study Design 
This is primarily a pilot implementation study to determine the feasibility of incorporating a 
preemptive PGx panel test into the gynecological surgery workflow. The randomized approach 
will help provide effect estimates for the relationship of the PGx testing on effectiveness (i.e., 
patient reported numeric pain score, MME, and ADEs). 
5  STUDY POPULATION 
5.1  
Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all the following criteria:  
1. Able and willing to provide informed consent 
2. Assigned female at birth and aged 18 years or older at the time of study initiation 
3. Major gynecologic surgery indicated and planned for hysterectomy, myomectomy, 
exploratory laparotomy, and open abdominal surgery 
4. Willing to provide a buccal swab for PGx testing and comply with all study-related 
procedures 

 
Protocol #851447– PRECISE 
Page 20 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
5.2  
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Receiving chronic opioid therapy defined as ≥ 3 consecutive months of 1-month 
prescriptions for an opioid. 
2. Pregnancy (per standard care, all patients will receive a urine pregnancy test pre-
operatively on the day of surgery. If pregnancy is not reasonably excluded during the 
preoperative evaluation visit a pregnancy test will be collected at that time) 
3. Breastfeeding (tramadol is not the preferred opioid in breastfeeding women) 
4. Treating physician does not want subject to participate 
5.3  
Screen Failures 
Screen failures in this study will be defined as participants who meet criteria for enrollment but 
decline to participate or the treating surgeon declines participation of their patient in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, and eligibility criteria. 
5.4  
Strategies for Recruitment and Retention 
The surgeon will discuss the study with the patient during the surgical evaluation visit and 
consent will be obtained by the surgeon, designated clinical staff, or study staff. This will occur 
in person. Participants will be given a copy of the official informed consent form and an 
opportunity to ask questions. Study staff will identify eligible patients scheduled for surgery in 
the following month who have not been approached about the study. Study staff will contact the 
patient via phone to discuss participation in the study, if interested, consent will be collected 
through My Penn Medicine (MPM) if the patient is enrolled or verbally if not enrolled in MPM 
and a copy of the consent will be emailed to the participant. 
Participants will be given a Greenphire ClinCard (reloadable debit card) for completing certain 
steps in the study. A total of $10 will be added to the Greenphire ClinCard after completing all of 
the text message questionnaires ($3.33 for each of the first 2 text message questionnaires and 
$3.34 for the 3rd text message questionnaire, totaling $10). An additional $15 will be added to the 
Greenphire ClinCard for completing the patient survey approximately 30 days after their surgery. 
The Greenphire ClinCard is a virtual card that will be emailed to the participants. 
5.5  
Duration of study participation 
Total involvement for each participant will be from the time of consent (at surgical evaluation 
visit) to 14 days post-op. Participants will be sent a survey to complete 30 days post-op (not 

 
Protocol #851447– PRECISE 
Page 21 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
likely to exceed 2 months total). Data will be collected from the EMR up to 1 year after PGx test 
pertaining to medications prescribed to participants. 
5.6  
End of Study Definition 
A participant is considered to have completed the study if she has completed all phases of 
the study shown in the Schedule of Activities (SoA), Section 13.1.  
6  STUDY INTERVENTION 
6.1  
Study Intervention Administration  
6.1.1  
Study Intervention Description 
This study utilizes PGx testing for 16 pharmacogenes (CYP2B6, CYP2C19, CYP2C9, CYP2C 
Cluster, CYP2D6, CYP3A5, CYP4F2, DPYD, HLA-A, HLA-B, IFNL4, NUDT15, SLCO1B1, 
TPMT, UGT1A1, VKORC1) from a buccal sample provided and resulted by a CAP and CLIA 
accredited genotyping lab (OneOme, Minneapolis, MN). This test does not detect all known and 
unknown variations in the genes tested. Reporting a *1 is indicative of no variations based on the 
below alleles reported.  
The following alleles will be identified: 
Table 2. Gene details of OneOme panel test 
Gene 
rsID 
Alleles Reported 
CYP2B6 
rs3745274 
*6, *7, *9 
rs28399499 
*16, *18 
rs2279343 
*4, *6, *7, *16 
rs3211371 
*5, *7 
CYP2C19 
rs4244285 
*2 
rs4986893 
*3 
rs12248560 
*4B, *17 
rs28399504 
*4, *4B 
rs6413438 
*10 
CYP2C9 
rs1799853 
*2  
rs1057910 
*3 
rs1057911 
*3 
rs56165452 
*4 
rs28371686 
*5 
rs9332131 
*6 
rs7900194 
*8 
rs28371685 
*11 
CYP2C 
Cluster 
rs12777823 
rs12777823 GG 
rs12777823 GA 

 
Protocol #851447– PRECISE 
Page 22 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
rs12777823 AA 
CYP2D6 
 
*5, *18, *34, *39, *59, *61, *65, copy number variations 
rs1080985 
*2A, *11, *14, *31, *35, *63 
rs769258 
*35 
rs1065852 
*4, *4J, *4N, *10, *36, *64, *68, *69, *114 
rs5030862 
*12 
rs201377835 
*11 
rs5030865g>t 
*8 
rs5030865g>a 
*14, *114 
rs5030656 
*9, *109 
rs28371706 
*17, *64 
rs5030655 
*6, *6C 
rs3892097 
*4, *4J, *4K, *4M, *4N 
rs35742686 
*3 
rs5030867 
*7 
rs59421388 
*29. *70, *109 
rs28371725 
*41, *69, *91 
rs16947 
*2, *2A, *8, *11, *12, *14, *17, *19, *29, *31, *35, *41, 
*42, *63, *69, *91, *114 
rs1135840 
*2, *2A, *4, *4N, *6C, *8, *10, *11, *12, *14, *17, *19, 
*29, *31, *35, *36, *41, *42, *64, *69, *70, *114 
rs267608319 
*31 
rs774671100 
*13, *15 
rs72549353 
*19 
rs72549346 
*42 
hCV32407220 
(rs765776661) 
*18 
rs79292917 
*59 
CYP3A5 
rs776746 
*3 
rs10264272 
*6 
rs41303343 
*7 
CYP4F2 
rs2108622 
*3 
DPYD 
rs3918290 
*2A 
rs67376798 
c.2846A>T (p.Asp949Val) 
rs55886062 
*13 
HLA-A 
HLA00097 
*31:01 (Negative/Positive) 
HLA-B 
rs144012689 
*15:01 (Negative/Positive) 
HLA00381 
*57:01 (Negative/Positive) 
HLA00386 
*58:01 (Negative/Positive) 
IFNL4 
(IL28B) 
rs12979860 
rs12979860 CC 
rs12979860 CT 

 
Protocol #851447– PRECISE 
Page 23 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
rs12979860 TT 
NUDT15 
rs116855232 
rs116855232 CC 
rs116855232 CT 
rs116855232 TT 
SLCO1B1 
rs4149056 
*5, *15, *17 
rs4149015 
*15, *21 
rs2306283 
*1B, *15, *17, *21 
TPMT 
rs1800462 
*2 
rs1800460 
*3A, *3B 
rs1142345 
*3A, *3C 
rs1800584 
*4 
UGT1A1 
rs4148323 
*6 
rs1976391 
*28(TA7) 
VKORC1 
rs9923231 
rs9923231 GG 
rs9923231 GA 
rs9923231 AA 
rs7200749 
rs7200749 GG 
rs7200749 GA 
rs7200749 AA 
 
6.1.2  
Dosing and Administration 
Analgesic selection and dosing recommendations will be based on the participant’s CYP2C9 and 
CYP2D6 genotype and other clinical factors as indicated in the algorithms found in Section 13.4 
and 13.5. Final medication selection and dosing will be determined by the treating surgeon 
according to their best clinical judgement. 
6.2  
Study Intervention Compliance 
Compliance to the PGx testing will be determined by tracking the test orders in PennChart. Study 
team will record the date/time of sample collection, time of sample receipt at OneOme Labs, and 
time of results posted in PennChart. Test turnaround time will be calculated, using the date of the 
order as the sample collection date to the time the results are populated in PennChart through an 
electronic interface from OneOme. 
6.3  
Discontinuation of Study Intervention 
If the participant withdraws from the study after the buccal swab has been processed by 
OneOme, the PGx test results will remain in the EMR, but no further data will be collected 
related to the research study endpoints.   

 
Protocol #851447– PRECISE 
Page 24 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
6.4  
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request, 
without prejudice to their medical care, and are not obliged to state their reasons. The study 
investigator may discontinue or withdraw a participant from the study for the following reasons: 
• Treating surgeon wishes patient to withdraw 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• Participant transfers care outside of Penn Medicine 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
participant’s Case Report Form (CRF). Subjects who sign the informed consent form but do not 
undergo genotyping may be replaced. Subjects who sign the informed consent form and are 
randomized to undergo genotyping, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
6.5  
Lost to Follow-Up 
A participant will be considered lost to follow-up if she fails to return for scheduled gynecologic 
surgery. There are no study-specific visits. Data is collected at the time of clinic visit 
(gynecologic surgical evaluation), gynecologic surgery-related hospitalization, from the medical 
record (EMR), and/or through text messaging. 
The following actions must be taken if a participant fails to return for gynecologic surgery: 
• The investigator will contact the surgeon to determine the reason for not returning for 
gynecologic surgery. 
• If the patient wishes to discontinue from the study, an attempt will be made to establish 
the reason for discontinuation (bearing in mind that the participant is not obligated to 
share her reasons).   

 
Protocol #851447– PRECISE 
Page 25 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
7 STUDY ASSESSMENT AND PROCEDURES 
7.1 
Provider on attitudes toward and knowledge of PGx testing (Baseline) 
Surgeons, including surgery residents and fellows, will be sent an optional electronic survey via 
an emailed link in RedCap to assess their knowledge and attitudes toward pharmacogenetic 
testing prior to receiving education about the study (see appendix 13.10). A paper copy will be 
made available for those without computer access. 
Surgeons, including surgery residents and fellows that practice at Jordan Center for Gynecologic 
Cancers at PCAM, Penn Health for Women Radnor, Penn Ob/Gyn Associates, Penn Health for 
Women University City, or Helen O. Dickens Center for Women’s Health at Hospital of the 
University of Pennsylvania will be asked to complete an electronic survey to assess their 
knowledge and attitudes toward pharmacogenetic testing prior to or shortly after receiving 
education about the study (see appendix 13.10).  
7.2  
Provider education 
After the survey is administered and completed, the study PGx pharmacist will conduct 
educational sessions for the physicians that includes background information about PGx testing, 
an introduction to PGx testing services currently available to the health system, and details 
pertaining to the PRECISE research study. 
7.3  
Screening and identification 
Study staff will screen and identify patients for enrollment with the assistance of the treating 
physician. 
7.4 
Informed consent  
Consent forms describing in detail the PGx test, study procedures, and risks are given to the 
participant. Participants will also receive an educational brochure about the purpose of PGx 
testing and what to expect with return of results. The informed consent signature will be 
collected electronically by the physician, study staff, or surgical coordinator through PennChart 
(Epic) or using a paper copy. A copy of the informed consent document will be given to the 
participants for their records either electronically via My Penn Medicine (MPM) or a paper copy 
Eligible patients not identified in the clinic, who are eligible, will be identified by the surgical 
residents and contacted via phone by study staff to discuss participation in the study. Consent 
will be collected through My Penn Medicine (MPM) if the patient is enrolled or verbally if not 
enrolled in MPM and a copy of the consent will be emailed to the participant. 
 
7.5 
Randomization 
The block randomization schema will be designed by the Clinical Research Computing Unit 
(CRCU) in REDCap. Randomization will be stratified based on age (<65 or ≥65 years), clinic 

 
Protocol #851447– PRECISE 
Page 26 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
location (PCAM or Dickens clinic), and gynecologic surgery type (minimally invasive vs. open 
laparotomy). Surgeon will log-in to REDCap to receive the group assignment: 1) PGx-guided 
(active) vs. 2) usual care (control). 
7.6  
Genotyping (Baseline) 
A surgeon will sign an order for the PGx test in PennChart during the surgical evaluation 
appointment. Buccal swab sample collection via OneOme test kit will be self-collected by the 
participant after study consent at this same visit or a collection kit will be sent to the participants 
home for participants consented verbally or electronically outside of a clinic visit. Collection of 
the buccal sample must occur at least 30 minutes after eating, drinking, smoking, or chewing 
gum. The participant will remove the collector swab from the packaging without touching the 
sponge tip to any surface. They will place the swab on one side of their mouth on their lower 
gums and swab back and forth 10 times. They will then switch the swab to the other side of their 
mouth and swab 10 more times. The swab will then be inserted into the provided tube and 
shaken 10 times. If the sample is collected during the office visit, it will be mailed to OneOme by 
study staff. If the sample is collected by the participant at home, the participant will mail the kit 
to OneOme. 
7.7 
Clinical data collection (Baseline) 
The following information will be obtained at screening or from the patient medical record: 
• Signed informed consent 
• Inclusion and exclusion criteria 
• Randomization 
• Name, address, telephone number, date of birth, email (if available) 
• Demographic data: age, race/ethnicity (if available), gender 
• Medical record number 
• Smoking history (if available in the EHR) 
• Diagnosis prompting surgical consultation 
• Prior medical history including history of chronic pain medication use 
• Routine physical examination: height, weight (if available from surgical evaluation) 
• Clinical chemistry: creatinine, AST, ALT (Only if available within 30 days prior to the 
scheduled surgery. These labs will not be ordered specifically for this study.) 
• Creatinine clearance (using Cockcroft-Gault formula) if creatinine is available within 30 
days prior to scheduled surgery. 
• Concomitant medications collected via medical record if available (including the 
following information if documented in the medical chart: dose, unit, frequency, route of 
administration and indication) 
7.8      Return of pharmacogenetic results 
A pharmacist will review the PGx results from OneOme through the MedView portal.  

 
Protocol #851447– PRECISE 
Page 27 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
 
For the PGx-guided group: The PGx results will be released from the portal to Epic. A consult 
note will be created and sent to the surgeon, including recommendations for post-operative 
analgesia based on the PGx results (see appendix section 13.8). A detailed note outlining 
recommendations for all PGx results will be created and sent to the participant and their PCP (if 
participant identifies a PCP and wants the letter to be sent) (see appendix section 13.7). 
 
For the Usual care group: The PGx results will be released from the portal to Epic approximately 
30 days after surgery. A detailed note outlining recommendations for all PGx results will be 
created and sent to the participant and their PCP (if participant identifies a PCP and wants the 
letter to be sent) approximately 30 days after surgery (see appendix section 13.7). 
 
7.9 
Implementation metrics (0-30 days) 
The following information will be collected to determine feasibility of PGx test implementation 
and agreement to the PGx-guided dosing recommendations: 
• Dates of sample collection, date of result transfer into PennChart, date of pharmacist 
consult note within PennChart, and date of gynecologic surgery 
• Analgesic(s) selected, and dose prescribed  
• Reasons for not adhering to the PGx guided recommendations if applicable 
• The number of actionable variants for each patient 
• Number of medication orders that align with PGx-guided dosing recommendations 
7.10 Data collection after surgery (0 to 2 months) 
Collected from review of the medical record (EMR) during hospitalization (POD 0-2): 
Data will not be collected for POD 1-2 if the subject has been discharged. 
• Daily average numeric pain score (using a 0-10 numeric scale) 
• Name, dose, units, and number of doses of pain medication taken 
• Daily calculated MME for all opioids administered 
• Naloxone administration (including dose, date/time of administration) 
Collected via two-way text messaging via REDCap using Twilio as the SMS service: 
Text messages will only be sent to discharged subjects. The following data will be collected via 
review of EMR if the subject is hospitalized during these time points. 
• Daily average numeric pain score (using a 0-10 numeric scale) on POD 3, 7, & 14 

 
Protocol #851447– PRECISE 
Page 28 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
• The total number of doses of pain medication taken (including total calculated MME for 
timeframe) post-discharge to POD 3, POD 4-7 (assessed on day 7), and POD 8-14 
(assessed on day 14).The total number of tablets/capsules remaining in their prescription 
bottle on POD 3, 7, & 14 
Collected from EMR after discharge 
• Prescriptions (including dose and units) for any new pain medication prescribed within 
30 days of the procedure  
• Adverse drug reactions to analgesic regimen (collected from the EMR from chart review 
either during hospitalization or through other encounter notes in the EMR)  
7.11 Patient survey on knowledge and satisfaction of PGx testing (30 days post-
study) 
Patients will complete an electronic survey via an emailed or texted link from RedCap to assess 
their knowledge and satisfaction of pharmacogenetic testing (see appendix 13.11). A paper copy 
will be made available for those without computer access. 
7.12 Data collected from medical records (EMR) (1 year)  
The following information will be collected up to 1-year post-surgery through review of the 
medical record (EMR): 
• Number of additional CPIC level A and B medications prescribed  
• Number of CPIC level A and B medications prescribed that align with PGx-guided 
recommendations 
 
8 SAFETY AND ADVERSE EVENTS 
8.1 
Adverse Events and Serious Adverse Events 
8.1.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. AEs in clinical 
investigation will include those associated with the study intervention (the PGx test). Adverse 
drug reactions (ADRs) associated with analgesic treatment will be collected as study outcomes, 
not as study-related adverse events. 
Anticipated AEs may include incidental findings related to PGx test results and the sharing of 
information to patients (refer to section 2.3.1).  
8.1.2 
Definition of Serious Adverse Events (SAE)  
Serious Adverse Events (SAE) 

 
Protocol #851447– PRECISE 
Page 29 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that, 
in the view of either the investigator or the sponsor, is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event when the event does not fit the other outcomes, but the event 
may jeopardize the patient and may require medical or surgical intervention (treatment) 
to prevent one of the other outcomes. 
Important medical events are those that may not be immediately life threatening but are clearly 
of major clinical significance. They may jeopardize the subject and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
8.1.3 
Classification of an Adverse Event 
AEs in clinical investigation will include AEs associated with the PGx test since the analgesic 
medications that will be administered are standard of care. These will primarily be related to 
HIPAA issues and unexpected findings. 
8.1.3.1 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to the PGx test assessed by the clinician 
who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
• Related – The AE is known to occur with the PGx test, there is a reasonable possibility 
that the PGx test caused the AE, or there is a temporal relationship between the PGx test 
and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the PGx test and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the PGx test 
caused the event, there is no temporal relationship between the PGx test and event onset, 
or an alternate etiology has been established. 
8.1.4 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by study personnel at the time of PGx test resulting. Analgesic adverse 
events described in section 8.1.2 will be documented. 

 
Protocol #851447– PRECISE 
Page 30 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Description of adverse event 
2. Date of occurrence 
3. Analgesic and other medications administered within 24 hours prior to the adverse event 
(for analgesic adverse events only) 
4. Expectedness to study intervention (PGx test) – Unexpected (yes/no) 
5. Impact on patient care – patient informed (yes/no) 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made of any changes in patient care.   
8.1.5 
Adverse Event Reporting 
AEs encountered during the study will be documented in the patient’s file and reported on the 
Case Report Form (CRF). Likelihood of the AE being attributed to the PGx test will be 
documented. 
The information that will be recorded in the patient’s file consists of” 
• Description of the event 
• Date of the event 
• Impact on patient care 
Reporting to the IRB will be done in accordance to the Penn IRB definition of reportable events 
and reporting timelines. 
Reporting Period 
Adverse events will be reported from the time of informed consent until study completion. 
8.1.6 
Serious Adverse Event Reporting  
A SAE must be reported to the study investigator by telephone within 24 hours of the event. The 
investigator will keep a copy of this form on file at the study site. Report SAEs by phone to: 
Glenda Hoffecker, PharmD 
Mobile: (484) 678-0732 
 
In the event that Dr. Hoffecker cannot be reached, report SAEs to: 
 
Sony Tuteja, PharmD 
Mobile: (484) 431-1002 
 
 
Mary Deagostino-Kelly, MD 

 
Protocol #851447– PRECISE 
Page 31 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
 
Mobile: (215) 900-5494 
 
At the time of the initial report, the following information should be provided: 
• Study name 
• Participant number 
• A description of the event 
• Date of onset 
• Current status 
• The reason the event is classified as serious 
• Investigator assessment of the association between the event and the PGx test 
 
Within the following 48 hours, the investigator must provide further information on the SAE in 
the form of a written narrative. Significant new information on ongoing SAEs should be 
provided promptly to the study investigator. 
 
Reports of all SAEs (including follow-up information) must be submitted to the IRB within 10 
working days, unless the SAE involves a death, which must be reported within 3 days. Copies of 
each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s binder.  
8.2 
Unanticipated Problems 
8.2.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.3 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) such as: 

 
Protocol #851447– PRECISE 
Page 32 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
• 
Breach of confidentiality 
• 
OneOme is unable to provide genotyping 
should be reported by the investigator to the Institutional Review Board (IRB). The UP report 
will include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number. 
• A detailed description of the event, incident, experience, or outcome.  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• UPs that are serious adverse events (SAEs) will be reported as any other SAE. 
• Any other UP will be reported to the IRB within 10 days of the investigator becoming 
aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and 
the Office for Human Research Protections (OHRP) within one month of the IRB’s 
receipt of the report of the problem from the investigator. 
9 STATISTICAL PLAN 
9.1 
Sample Size  
For the implementation aims, the sample size is based on average gynecologic surgery volume 
and anticipated number of patients that are eligible for testing. We anticipate enrolling 200 
patients in 1 year. No hypothesis testing will be performed. 
9.1.1 
Populations for Analyses 
We will evaluate effectiveness outcomes between the PGx-guided group and usual care group. 
9.2 
Statistical Analyses 
9.2.1 
General Approach 
Descriptive statistics mean, SD, median, range, counts, and percentages will be used to describe 
and compare (t-test or rank sum test for continuous variables and Fisher’s exact test for 

 
Protocol #851447– PRECISE 
Page 33 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
categorical variables) baseline characteristics between the PGx-guided group and the usual care 
group. 
9.2.2 
Analysis of the Primary Endpoint(s) 
Implementation Endpoint(s): 
a) We will report the number and proportion of tests returned prior to the gynecologic 
surgery day. 
b) We will report the proportion of medication selection and dose modifications made in 
agreement with the pharmacist genotype-guided recommendations. 
9.2.3 
Analysis of the Secondary Endpoint(s) 
Clinical endpoints: 
a) The proportion of participants achieving at least a 30% reduction in pain scores will be 
compared in the PGx-guided group vs. the control group using Fisher’s exact test. 
b) The mean patient self-reported numeric pain scores (POD 0, 1, 2 (only while 
hospitalized) and POD 3, POD 7 and 14 will be compared in the PGx-guided group vs. 
the usual care group using t-test.  
c) The change in mean patient self-reported numeric pain scores will be compared using t-
test. 
d) The total MME consumption will be calculated in the PGx and usual care groups on POD 
0-7 and POD 1-14 using t-test. 
e) The proportion patients experiencing an opioid related ADRs will be compared using a 
Fisher’s exact test.  
f) Proportion patients experiencing a NSAID-related ADRs in CYP2C9 variant carriers will 
be compared using a Fisher’s exact test. 
g) Baseline provider attitudes toward and knowledge of PGx testing using questions with 
Likert scales will be reported as means (SD). We will compare results by using linear 
regression.  
h) Patient attitudes knowledge and satisfaction of PGx testing after completing the study 
using questions with Likert scales will be reported as means (SD). We will compare the 
results by using linear regression. 

 
Protocol #851447– PRECISE 
Page 34 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
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 
Consent forms describing in detail the PGx test, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to distributing to 
participant and collecting the PGx test buccal sample. The informed consent signature will be 
collected electronically through PennChart (Epic) or using a paper copy. A copy of the informed 
consent document will be given to the participants for their records either electronically via 
MPM or a paper copy if they do not have MPM.  The following consent materials are submitted 
with this protocol: informed consent form. 
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The treating surgeon will explain the research study to the participant and answer 
any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. The 
informed consent will be collected in-person using a paper copy, electronically through 
PennChart (Epic), or verbally over the phone if the participant does not have MPM. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the PI 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, 
investigators, treating surgeons, and regulatory authorities. If the study is prematurely terminated 

 
Protocol #851447– PRECISE 
Page 35 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
or suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (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 to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
In terminating the study, the Principal Investigator will assure that adequate consideration is 
given to the protection of the subjects’ interests. 
10.1.3 
Confidentiality and Privacy 
Information about study participants will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed participant authorization informing the participant of the 
following: 
• What protected health information (PHI) will be collected from participants in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
participant authorization. 
All data related to this trial will be recorded using the patients’ assigned unique study 
number. Data will be reported only in a confidential manner such that the personal identity of 
any subject will not be identifiable. All study data will be maintained under a double locked 
system, such as a locked closet within a locked office or on a password protected computer in a 
locked office. At the end of the study these data will be electronically archived on a password 
protected computer or other electronic storage device. 

 
Protocol #851447– PRECISE 
Page 36 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
10.1.4 
Future Use of Stored Specimens and Data  
Samples are not stored for future use. 
10.1.5 
Source documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
10.1.6 
Case report forms 
The study case report form (CRF) is the primary data collection instrument for the study. 
All data requested on the CRF must be recorded. All missing data must be explained. If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”. If the item is not applicable to the individual case, write “N/A”. All entries should be 
printed legibly in black ink. If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
10.1.7 
Study monitoring, auditing, and inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g., source documents, regulatory documents, data collection   
instruments, study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g., diagnostic laboratory, etc.).  
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
10.1.8 
Safety Oversight 
The Principal Investigator and Co-Investigators will be ultimately responsible for assuring the 
security of all study related materials to minimize risk to participants. Safety data such AEs and 
SAE will be assessed and reviewed in the PGx arm every 3 months after enrollment begins. 

 
Protocol #851447– PRECISE 
Page 37 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
This study is expected to be classified as low risk by IRB. The intervention (PGx test) requires a 
self-collected buccal swab sample and thus poses limited risk compared to that experienced in 
daily life.  
10.1.9 
Clinical Monitoring 
There is no external sponsor for this study. The PI will not complete the Principal Investigator’s 
Compliance Assessment (PICA) form because this is a minimal risk research study. 
10.1.10 
Study Records Retention 
Study documents and records will be retained for at least 2 years after the last participant has 
completed the study. 
10.1.11 
Protocol Deviations 
The PI and the study team should document all scenarios where the protocol is not followed and 
provide, in particular: 
• Who deviated from the protocol 
• What was the deviation 
• When did the deviation occur 
• How did the deviation happen 
• What is the impact of the deviation 
• A root cause analysis of why the deviation occurred 
Not following the genotype guided dose recommendation is NOT considered a protocol 
deviation but will be recorded as one of the study outcomes.  
If the assessment results in a determination that any of the following are potentially affected, the 
deviation would be considered of significant impact: 
• having the potential to adversely affect subject safety; OR 
• increases risks to participants; OR 
• adversely affects the integrity of the data; OR 
• violates the rights and welfare of participants, OR 
• affects the subject’s willingness to participate in research.  
• there is a potential for an overall impact on the research that should be shared with the 
IRB for consideration and development of next best steps to address it 
10.1.12 
Publication and Data Sharing Policy 
This study will comply with the data sharing agreement. 

 
Protocol #851447– PRECISE 
Page 38 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
10.1.13 
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. 
10.2 Protocol Amendment History 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the principal investigator. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. The principal investigator will submit protocol amendments to the 
appropriate regulatory authorities. 
If in the judgment of, the sponsor, the IRB/IEC, and/or the investigator, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study participant, the currently approved 
written informed consent form will require similar modification. In such cases, informed consent 
will be renewed for subjects enrolled in the study before continued participation. 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
11/21/22 
Addition of contacting patients via phone 
for remote verbal or electronic consent. 
Also change of pharmacist “e-consult” to 
“consult”. 
We are missing eligible patients 
if/when their surgery is not 
confirmed during the surgical 
consultation visit. 
The pharmacist will enter a consult 
note in the chart instead of the e-
consult workflow. 
3.0 - 
Was reviewed 
by Office of 
Regulatory 
Affairs and 
returned by 
IRB 
1/17/23 
Addition of Penn Health for Women 
Radnor as a recruitment site, Survey 
Code letter (13.8), and PRECISE 
Recruitment flyer (13.13),   
We are adding Radnor as a 
recruitment site and created a 
recruitment flyer to help increase 
recruitment. The Survey code letter 
is to be mailed to the participant 
along with the pharmacist detailed 
note to patient summarizing results 
(13.7) 

 
Protocol #851447– PRECISE 
Page 39 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
Version 
Date 
Description of Change  
Brief Rationale 
3.0 
2/2/23 
Addition of Penn Health for Women 
Radnor as a recruitment site and Survey 
Code letter (13.8) 
We are adding Radnor as a 
recruitment site. The Survey code 
letter (13.8) was created to be 
mailed to the participant along with 
the already IRB-approved 
pharmacist detailed patient note 
that summarizes their results (13.7) 
4.0  
4/24/23 
Addition of sites, clarification of 
inclusion criteria, when the detailed 
letters will be sent to participant’s PCP, 
clarification of who is identifying 
participants, clarification that the survey 
sent to providers is optional, clarification 
that some baseline data will only be 
collected if available in the EHR, and 
updates to secondary endpoints to 
remove “in variant carriers”. 
Additional sites are being added to 
increase recruitment. Other changes 
are warranted to further clarify 
inclusion criteria, that certain data 
will only be collected if available, 
and who is identifying eligible 
participants. 
5.0 
8/29/23 
Removal of PICA requirement. To 
ensure participants receive their PGx 
results, the PGx results will be released 
to the EHR and patient after 9 months 
from enrollment if the participant has not 
scheduled surgery. 
This is a minimal risk research 
study and PICA is not required. 
Releasing results at 9 months will 
ensure that all participants will 
receive their PGx results. 
 
 
 
 
 
11 STUDY FINANCES 
11.1 Funding source 
This study is financed through a grant from the Penn Center for Precision Medicine. All PGx 
testing fees will be covered by this study. 
12 REFERENCES 
1. Crews, K. R. et al. Clinical Pharmacogenetics Implementation Consortium Guideline for 
CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin. Pharmacol. 
Ther. 110, 888–896. 

 
Protocol #851447– PRECISE 
Page 40 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
2. Theken, K. N. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline 
for CYP2C9 and Nonsteroidal Anti-inflammatory Drugs. Clin. Pharmacol. Ther. 108, 191–
200 (2020). 
3. Smith, D. M. et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 
intermediate and poor metabolizers: a pragmatic clinical trial. Genet. Med. Off. J. Am. Coll. 
Med. Genet. 21, 1842–1850 (2019). 
4. Thomas, C. D. et al. A hybrid implementation-effectiveness randomized trial of CYP2D6-
guided postoperative pain management. Genet. Med. 23, 621–628 (2021). 
5. Fingar, K. R., Stocks, C., Weiss, A. J. & Steiner, C. A. Most Frequent Operating Room 
Procedures Performed in U.S. Hospitals, 2003–2012: Statistical Brief #18. (2006). 
6. Gan, T. J. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J. 
Pain Res. 10, 2287–2298 (2017). 
7. ACOG Committee Opinion No. 750: Perioperative Pathways: Enhanced Recovery After 
Surgery. Obstet. Gynecol. 132, e120–e130 (2018). 
8. Obeng, A. O., Hamadeh, I. & Smith, M. Review of Opioid Pharmacogenetics and 
Considerations for Pain Management. Pharmacother. J. Hum. Pharmacol. Drug Ther. 37, 
1105–1121 (2017). 
9. Grosser, T., Theken, K. N. & FitzGerald, G. A. Cyclooxygenase Inhibition: Pain, 
Inflammation, and the Cardiovascular System. Clin. Pharmacol. Ther. 102, 611–622 (2017). 
10. 
ibuprofen [package insert]. New York, NY: Pharmacia & Upjohn Company; 2007. 
11. 
Klomp, S. D., Manson, M. L., Guchelaar, H.-J. & Swen, J. J. Phenoconversion of 
Cytochrome P450 Metabolism: A Systematic Review. J. Clin. Med. 9, (2020). 

 
Protocol #851447– PRECISE 
Page 41 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
12. 
Dunnenberger, H. M. et al. Preemptive Clinical Pharmacogenetics Implementation: 
Current programs in five United States medical centers. Annu. Rev. Pharmacol. Toxicol. 55, 
89–106 (2015). 
13. 
Zhu, Y. et al. A model-based cost-effectiveness analysis of pharmacogenomic panel 
testing in cardiovascular disease management: preemptive, reactive, or none? Genet. Med. 1–
10 (2020) doi:10.1038/s41436-020-00995-w. 
14. 
Chanfreau-Coffinier, C. et al. Projected Prevalence of Actionable Pharmacogenetic 
Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy 
Users. JAMA Netw. Open 2, e195345 (2019). 
15. 
Hicks, J. K. et al. Implementation of Clinical Pharmacogenomics within a Large Health 
System: From Electronic Health Record Decision Support to Consultation Services. 
Pharmacother. J. Hum. Pharmacol. Drug Ther. 36, 940–948 (2016). 
16. 
Herr, T. M. et al. Pharmacogenomic clinical decision support design and multi-site 
process outcomes analysis in the eMERGE Network. J. Am. Med. Inform. Assoc. JAMIA 26, 
143–148 (2018). 
17. 
Yeh, M.-L., Chang, Y.-J., Wang, P.-Y., Li, Y.-C. (Jack) & Hsu, C.-Y. Physicians’ 
responses to computerized drug–drug interaction alerts for outpatients. Comput. Methods 
Programs Biomed. 111, 17–25 (2013). 
18. 
Bright, D. et al. Pharmacist Consult Reports to Support Pharmacogenomics Report 
Interpretation. Pharmacogenomics Pers. Med. 13, 719–724 (2020). 
19. 
Dean, L. Irinotecan Therapy and UGT1A1 Genotype. 12. 

 
Protocol #851447– PRECISE 
Page 42 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
20. 
Wolkoff, A. W., Wolpert, E., Pascasio, F. N. & Arias, I. M. Rotor’s syndrome. Am. J. 
Med. 60, 173–179 (1976). 
21. 
Cicali, E. J. et al. How to Integrate CYP2D6 Phenoconversion Into Clinical 
Pharmacogenetics: A Tutorial. Clin. Pharmacol. Ther. 110, 677–687 (2021). 
22. 
McPherson, M. L. Demystifying Opioid Conversion Calculations: A Guide for Effective 
Dosing, 2nd Edition. (American Society of Health-System Pharmacists, 2018). 
23. 
Busse, J. W. et al. Guideline for opioid therapy and chronic noncancer pain. CMAJ Can. 
Med. Assoc. J. 189, E659–E666 (2017). 
24. 
Grond, S. et al. High-Dose Tramadol in Comparison to Low-Dose Morphine for Cancer 
Pain Relief. J. Pain Symptom Manage. 18, 174–179 (1999). 
25. 
Wilder-Smith, C. H., Schimke, J., Osterwalder, B. & Senn, H.-J. Oral tramadol, a μ-
opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. 
Ann. Oncol. 5, 141–146 (1994). 
26. 
naproxen [package insert]. Basildon, Essex: Atnahs Pharma; 2016. 
27. 
tramadol [package insert]. Gurabo, Puerto Rico: Janssen Ortho, LLC; 2008. 
28. 
oxycodone [package insert]. Stamford, CT: Purdue Pharma LP; 2018. 
13 
APPENDICES  
13.1 Schedule of Activities (SoA)  
Study Procedures 
Enrollment 
/ Baseline 
POD 
0 
POD 
1 
POD 
2 
POD 
3 
POD 
7 
POD 
14 
POD 
30 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
Buccal swab collection 
X 
 
 
 
 
 
 
 
Demographic data1 
X 
 
 
 
 
 
 
 

 
Protocol #851447– PRECISE 
Page 43 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
Study Procedures 
Enrollment 
/ Baseline 
POD 
0 
POD 
1 
POD 
2 
POD 
3 
POD 
7 
POD 
14 
POD 
30 
Diagnosis prompting surgical 
consultation 
X 
 
 
 
 
 
 
 
Prior medical history 
X 
 
 
 
 
 
 
 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
 
Routine physical exam3 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Pharmacogenetic test 
X 
 
 
 
 
 
 
 
Concomitant medications4 
X 
 
 
 
 
 
 
 
Clinical chemistry5 
X 
 
 
 
 
 
 
 
Creatinine clearance6 
X 
 
 
 
 
 
 
 
Self-reported numeric pain score7 
 
X 
X 
X 
X 
X 
X 
 
Number of doses of pain medication 
taken per day while hospitalized8 
 
X 
X  
X  
X  
X 
X 
 
Total number of doses of pain 
medication taken after discharge9 
 
 
 
 
 
X 
X 
 
Opioids administered while 
hospitalized10 
 
X 
X  
X  
X  
X 
X 
 
Naloxone administration during 
hospitalization11 
 
X 
X  
X  
X  
X 
X 
 
Adverse event assessment for 
analgesics (opioids & NSAIDS)12 
 
X 
X 
X 
X 
X 
X 
 
Patient Survey13 
 
 
 
 
 
 
 
X 
1. Age, race/ethnicity, gender 
2. Heart rate, blood pressure (POD 0, 1, 2, 3, 7, and 14 only during hospitalization) 
3. Height/weight 
4. Including dose, unit, frequency, route of administration and indication 
5. Creatinine, AST, ALT (within 30 days of scheduled gynecologic surgery if available) 
6. Using Cockcroft-Gault formula 
7. Using a 0-10 numeric pain scale (POD 1 and 2 only during hospitalization) 
8. Including daily calculated MME (POD 1 and 2 only during hospitalization) 
9. Outpatient prescriptions doses: After discharge to POD 3, POD 4-7, POD 8-14, including total calculated MME 
10. Names, doses, units, calculated MME, and dates/times 
11. Dose, unit, and date/time of administration 
12. See section 13.6.3 
13. See section 13.11 
 
13.2 CYP2D6 Phenoconversion 
CYP2D6 Phenoconversion21 
Steps: 
1. Obtain/calculate genotype-based CYP2D6 activity score 

 
Protocol #851447– PRECISE 
Page 44 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
2. Assign phenotype 
3. Multiple activity score by 0 (if taking a strong inhibitor) or 0.5 (if taking a moderate inhibitor) 
4. Use adjusted CYP2D6 activity score to determine new CYP2D6 phenotype 
CYP2D6 inhibitor category 
Medications 
Multiply Genotype Activity Score by: 
Strong inhibitors 
Bupropion 
Fluoxetine 
Paroxetine 
Quinidine 
Terbinafine 
0 
Moderate inhibitors 
Abiraterone 
Cinacalcet 
Duloxetine 
Lorcaserin 
Mirabegran 
0.5 
 
13.3 Morphine milligram equivalence 
Opioids (in mg except where specified) 
Equianalgesic conversions22 
Codeine (oral): Morphine (oral) 
6.7:1 
Fentanyl (IV in mcg): Morphine (oral) 
10:1 
Hydrocodone (oral): Morphine (oral) 
1:1 
Hydromorphone (oral): Morphine (oral) 
1:4 
Hydromorphone (IV): Morphine (oral) 
1:20 
Morphine (IV): Morphine (oral) 
1:3 
Oxycodone (oral): Morphine (oral) 
1:1.5 
Tramadol (oral): Morphine (oral)* 
10:123 
Mcg: micrograms 
*Equianalgesic ratios of oral tramadol to oral morphine range from 4:1 to 10:1.22–25 We have chosen to 
use a conservative conversion when converting tramadol to morphine equivalent doses.

 
Protocol #851447– PRECISE 
Page 45 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
13.4 Analgesic medication selection and dosing algorithm for CYP2C9 
 
 
 
 
 
 
 
 
 
 
 
 
* Contraindications and precautions: Severe allergic reaction to any NSAIDs, recent CABG, active GI bleed/ulcer, cerebrovascular bleeding, severe hepatic impairment, severe 
renal impairment (CrCl < 30 mL/min), hyperkalemia, severe uncontrolled heart failure, third trimester of pregnancy 
Major drug interactions:  Acemetacin, anticoagulants (including DOACs), corticosteroids, cyclosporine, lithium, loop diuretics (specifically in patients with HF or cirrhosis), 
methotrexate, micamorelin, mifamurtide, NSAIDs, phenylbutazone, pralatrexate, salicylates, SSRIs/SNRIs, sincalide, sodium phosphates, tenofovir, urokinase  
 
AS activity score; NSAID non-steroidal anti-inflammatory; CABG coronary artery bypass surgery; GI gastrointestinal; CrCl creatinine clearance; DOAC direct oral 
anticoagulants; HF heart failure; SSRI selective serotonin reuptake inhibitors; SNRI serotonin norepinephrine reuptake inhibitors 
 
ibuprofen10 naproxen26 
CYP2C9 
CYP2C9 normal metabolizer/intermediate 
metabolizer (AS ≥ 1.5) 
CYP2C9 intermediate metabolizer (AS = 1) 
CYP2C9 poor metabolizer 
Contraindications, precautions, 
drug interactions* 
• Use ibuprofen or 
NSAID of choice  
Avoid 
NSAID use 
Avoid 
NSAID use 
• Use naproxen (alternative NSAID 
not metabolized by CYP2C9) 
Avoid 
NSAID use 
• Use naproxen (alternative NSAID not 
metabolized by CYP2C9) 
Contraindications, precautions, 
drug interactions* 
Contraindications, precautions, 
drug interactions* 
No 
Yes 
No 
Yes 
No 
Yes 

 
Protocol #851447– PRECISE 
Page 46 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
13.5 Analgesic medication selection and dosing algorithm for CYP2D627 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Contraindications and precautions: Severe allergic reaction to opioid (recommendations for opioids in non-cross-reactive opioid subclasses will be made if applicable), severe 
hypotension, GI obstruction, paralytic ileus; seizure disorder (avoid tramadol, use caution with other opioids); MAOI in last 14 days; acute pancreatitis; use caution combining 
tramadol and other drugs that may reduce seizure threshold (neuroleptics) 
Major drug interactions (those italicized and bolded are specific to tramadol): SSRIs (C), SNRIs (C), TCAs, tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc), 
abametapir, alvimopan, azelastine, blonanserin, bromperidol, carbamazepine, chlormethiazole, use caution with other CNS depressants (including other opioids), dapoxetine, 
droperidol, eluxadoline, fexinidazole, flunitrazepam, fusidic acid, iobenguane, iohexol, iomeprol, iopamidol, kratom, lemborexant, linezolid, methylene blue, MAOIs, 
methotimeprazine, nefazodone,  nalmefene, naltrexone, orphenadrine, oxomemazine, oxybate salt products,  paraldehyde; phenobarbital, primidone, ropeginterferon alfa-2b, 
samidorphan, sincalide, suvorexant, zolpidem 
 
Chemical classes or opioids (cross sensitivity): Phenanthrenes: buprenorphine, butorphanol, codeine, dextromethorphan, hydrocodone, hydromorphone, levorphanol, 
methylnaltrexone, morphine, nalbuphine, naloxone, naltrexone, oxycodone, oxymorphone; Phenylpiperadines: alfentanil, fentanyl, meperidine, remifentanil, sufentanil; 
Diphenylheptanes: methadone, propoxyphene; Phenylpropyl amines: tramadol 
CI contraindication; DI drug interaction; GI gastrointestinal; MAOI monoamine oxidase inhibitor 
 
 
oxycodone28  tramadol27
CYP2D6 
CYP2D6 normal metabolizer 
CYP2D6 ultrarapid, intermediate, or 
poor metabolizer 
Contraindications, precautions, 
drug interactions to tramadol* 
Tramadol  
Use alternative 
opioid without 
CI or DI 
Contraindications, precautions, 
drug interactions to oxycodone* 
No 
Yes 
No 
Yes 
Oxycodone 
• Use alternative opioid without CI or DI 
• Avoid opioids metabolized by CYP2D6 
(i.e., codeine, tramadol, and hydrocodone) 

 
Protocol #851447– PRECISE 
Page 47 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
13.6 Medication information 
13.6.1 
Dosing information for oral analgesics 
Medication class 
Medication 
Initial dose 
Range 
Max/24 hours  
Opioids  
Oxycodone 
(IR)28 
5 mg PO Q4-6H prn 
5-10 mg PO Q4-6H 
 
Tramadol (IR)27 
50 mg PO Q4-6H prn 
25-100 mg PO Q4-
6H 
400 mg 
NSAIDs  
(Short-acting) 
Ibuprofen10 
200-400 mg PO Q4-
6H prn or scheduled 
200-800 mg PO Q4-
6H 
3200 mg 
Naproxen26 
500 mg once, 
followed by (250-
500mg PO Q12 or 
250 mg PO Q6-8H) 
prn or scheduled 
250-500 mg PO Q6-
12H 
1250 mg on day 1, 
then 1000 mg 
thereafter 
IR = immediate release; H = hours; Q = every 
 
13.6.2 
Dosing adjustments for clinical factors 
Medication CrCl 30-60 mL/min 
CrCl< 30 mL/min 
Hemodialysis 
Hepatic 
impairment 
Elderly > 75 
years 
Oxycodone 
50-75% of usual dose, 
no more frequent than 
Q6H 
50% of usual dose, no 
more frequent than Q8H 
50% of usual 
dose no more 
than Q8H 
33-50% of 
usual dose 
Tramadol 
Increase dosing interval 
to Q12H (max: 200 
mg/day) 
25 mg twice 
daily (max 100-
200 mg/day) 
Severe*: 50 
mg Q12H 
Max: 300 
mg/day 
Ibuprofen 
Use lowest effective 
dose 
</= 30 mL/min avoid 
use 
Naproxen 
Use lowest effective 
dose 
</= 30 mL/min avoid 
use 
*Child-Pugh class C 
CrCl creatinine clearance; Q = every; H = hours 
 
 
 

 
Protocol #851447– PRECISE 
Page 48 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
13.6.3 
Clinical adverse drug reaction profile 
Most common adverse drug reactions for opioids 
ADR 
Codeine 
Fentanyl 
Hydrocodone 
Hydromorphone 
Morphine 
Oxycodone 
Tramadol 
Abdominal pain 
X 
 
 
X 
 
X 
X 
Adrenal 
insufficiency 
X 
X 
X 
X 
 
X 
 
Apnea 
 
X 
 
X 
X 
 
 
Bradycardia 
 
X 
 
 
X 
 
 
Cardiovascular 
depression (severe) 
X 
X 
X 
X 
X 
X 
 
Constipation 
X 
 
X 
X 
X 
X 
X 
Diarrhea 
 
 
 
X 
 
 
X 
Dizziness 
X 
X 
X 
X 
X 
X 
X 
Dry mouth 
 
 
 
X 
 
X 
X 
Dysphoria 
X 
 
X 
X 
X 
 
 
Euphoria 
X 
 
 
X 
X 
 
X 
Flushing 
 
 
 
X 
X 
 
 
Headache 
 
 
 
 
X 
X 
X 
Hypertension 
 
X 
 
X 
 
 
 
Hypotension 
X 
X 
X 
X 
X 
X 
 
Laryngospasm 
 
X 
 
X 
 
X 
 
Light-headedness 
X 
 
X 
X 
X 
 
 
Nausea 
X 
X 
X 
X 
X 
X 
X 
Pruritis 
X 
X 
X 
X 
X 
X 
X 
Rash 
X 
X 
X 
X 
X 
X 
X 
Respiratory 
depression 
X 
X 
X 
X 
X 
X 
 
Rigidity 
 
X 
 
 
 
 
 
Sedation 
X 
X 
X 
X 
X 
 
 
Seizures* 
X 
X 
X 
X 
 
X 
X† 
SOB 
X 
 
 
 
 
 
 
Skeletal muscle 
rigidity 
 
X 
 
X 
 
 
 
Sweating 
X 
X 
 
X 
X 
X 
X 
Vomiting 
X 
X 
X 
X 
X 
X 
X 
Color Key: 
Serious ADRs: Included in boxed warning or 
warning/precaution section of PI 
Most common ADRs 
*Increased risk in patients with seizure disorders 
† Seizure risk is increased with concomitant use of SSRIs, TCAs, tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc), 
other opioids, MAO inhibitors, neuroleptics, or other drugs that reduce seizure threshold 
SOB shortness of breath; ADR adverse drug reaction 
 

 
Protocol #851447– PRECISE 
Page 49 of 62
 
Confidential and Proprietary Information of University of Pennsylvania 
 
Most common adverse drug reactions for non-steroidal anti-inflammatory drugs (NSAIDs)  
ADR 
Celecoxib 
Flurbiprofen 
Ibuprofen 
Ketorolac 
Meloxicam 
Naproxen 
Piroxicam 
Abdominal pain 
X 
X 
X 
X 
X 
X 
X 
Appetite () 
 
 
X 
 
 
 
 
Bleeding (risk) 
 
X 
X 
X 
X 
X 
X 
 Bleeding time 
 
X 
X 
X 
X 
X 
X 
Constipation 
 
X 
X 
X 
 
 
X 
CTE 
X 
X 
X 
X 
X 
X 
X 
Diarrhea 
X 
X 
X 
X 
X 
 
X 
Dizziness 
X 
 
X 
X 
X 
X 
X 
Dyspepsia 
X 
X 
 
X 
X 
X 
X 
Ecchymosis 
 
 
 
 
 
X 
 
Edema 
X 
X 
X 
X 
X 
X 
X 
Epigastric pain 
 
 
X 
 
 
 
 
Flatulence 
X 
X 
X 
X 
X 
X 
X 
GI bleed/ulcer 
X 
X 
X 
X 
X 
X 
X 
Headache 
 
X 
X 
X 
X 
X 
X 
Heartburn 
 
 
X 
X 
 
X 
X 
Hemoglobin () 
X 
X 
X 
X 
X 
X 
X 
Hyperkalemia 
 
X 
X 
X 
X 
X 
X 
Hypertension 
X 
X 
X 
X 
X 
X 
X 
Indigestion 
 
 
X 
 
 
 
 
Influenza-like Sx 
 
 
 
 
X 
 
 
Liver enzymes () 
X 
X 
X 
X 
X 
X 
X 
Nausea 
 
X 
X 
X 
X 
X 
X 
Pharyngitis 
X 
 
 
 
X 
 
 
Rash 
X 
 
X 
X 
X 
X 
X 
Renal dysfunction 
X 
X 
X 
X 
X 
X 
X 
Rhinitis 
X 
 
 
 
 
 
 
Sinusitis 
X 
 
 
 
 
 
 
Tinnitus 
X 
 
 
X 
 
X 
X 
URI 
X 
 
 
 
X 
 
 
Vomiting 
 
X 
X 
X 
X 
X 
 
Color Key: 
Serious ADRs: Included in boxed warning or 
warning/precaution section of  PI 
Most common ADR for all NSAIDs 
ADR adverse drug reaction; CTE cardiovascular thrombotic events (including myocardial infarction and stroke); PI package 
insert; Sx symptoms; URI upper respiratory tract infection

Page 50 
 
 
13.7 Pharmacist detailed note to patient summarizing PGx results  
Introduction: Pharmacogenetic (PGx) Testing  
Pharmacogenetic (PGx) tests are genetic tests that help predict how you will respond to some 
medications and the results help your medical team make decisions about which medications may work 
best for you. People have differences in these genes and this test helps to explain why people respond 
differently to the same medication. Differences in these genes can 1) increase the person’s risk of side 
effects to some medications or 2) decrease how well the medication will work for them.   
Key terms to consider when reviewing your PGx results:  
Gene: Each gene is a separate instruction guide for a protein that is needed for medications to work in the 
body. An example of a gene is CYP2C19.  
Allele: We all have two copies of each gene, one from each parent. A single gene copy is referred to as an 
allele, you have one allele from your mother and one from your father. The alleles are coded by a 
naming system using numbers and stars (*). An example of an allele for the CYP2C19 gene is *2.  
Genotype: Together a pair of alleles is called a genotype. Each gene allele may give the same or slightly 
different instructions. The genotype tells which two alleles you carry for each gene. An example 
genotype for the CYP2C19 gene is *1/*2.  
Phenotype: The phenotype predicts how well the proteins created from your two alleles for each gene 
will work. Each person can have a different phenotype for each gene. For the above example gene and 
genotype, CYP2C19 *1/*2, the phenotype would be intermediate metabolizer.   
The below figure is an example of how variations in these genes can impact how a person will respond to 
a medication.   
  
The first part of the report includes detailed information about each gene that was tested.  The second part 
has recommendations from the pharmacist to help you and your healthcare providers make choices about 
medications.  These recommendations may change in the future as new drugs are developed and as we 
learn more about gene-drug interactions.  
  

Page 51 
 
 
Part I: Gene results   
  
This section lists the actionable genes that were tested, which alleles are present in your body (genotype), 
and how your alleles are expected to affect drug metabolism and drug response (phenotype).    
  
Actionable Pharmacogenetic Results:  
  
Gene  
Genotype  
Phenotype  
CYP2B6  
  
  
CYP2C19  
  
  
CYP2C9  
  
  
CYP2C Cluster  
  
  
CYP2D6  
  
  
CYP3A5  
  
  
CYP4F2  
  
  
DPYD  
  
  
IFNL4  
  
  
HLA-A  
  
  
HLA-B  
  
  
NUDT15  
  
  
SLCO1B1  
  
  
TPMT  
  
  
UGT1A1  
  
  
VKORC1  
  
  
  
Normal Pharmacogenetic Results  
  
Gene  
Genotype  
Phenotype  
CYP2B6  
  
  
CYP2C19  
  
  
CYP2C9  
  
  
CYP2C Cluster  
  
  
CYP2D6  
  
  
CYP3A5  
  
  
CYP4F2  
  
  
DPYD  
  
  
IFNL4  
  
  
HLA-A  
  
  

Page 52 
 
 
HLA-B  
  
  
NUDT15  
  
  
SLCO1B1  
  
  
TPMT  
  
  
UGT1A1  
  
  
VKORC1  
  
  
  
Part II: Medication recommendations   
This section provides specific medication recommendations based upon your pharmacogenetic results. 
The recommendations reflect clinical practice guidelines at the time of this report. Discuss these results 
with your medical team, including a pharmacist, prior to starting new medications or making changes to 
your current medications.    
   
Use These Medications with Great Caution or  
Consider Alternatives   
   
• 
May have serious side effects   
• 
May have little to no drug response   
• 
May need a higher or lower dose of drug   
  
 
 
 
***  
 
Drug 
Name  
Gene(s)  
Common uses  
Clinical impact  
Recommendation (Intended for 
healthcare providers only)  
  
  
  
  
  
  
  
• 
May have some side effects  
• 
May have less than optimal drug response  
• 
May need a higher or lower dose of drug  
  
 
 
 
***  
 
Drug Name  
Gene(s)  
Common uses  
Clinical impact  
Recommendation (Intended 
for healthcare providers only)  
  
  
  
  
  
  

Page 53 
 
 
The above report summarizes your actionable genetic results.  Actionable means there is enough scientific 
evidence to make clinical decisions using these gene tests. The results will be placed into your electronic 
health record to assist your medical care team at Penn Medicine in prescribing decisions.    
  
The information in this report is for general educational purposes and is not intended to be a substitute for 
professional medical advice. Only a physician, pharmacist, or other healthcare provider should advise you 
on your prescribed medications.  
  
The lab only reports select variants but not all variants in the genes. It is possible that you may have 
variants that were not tested. The results of the genetic testing will not change, but the scientific 
knowledge surrounding the impact of these genes on drug response is always changing, so that in the 
future we will have more knowledge on how these may predict side effects or efficacy of medications. 
Visit https://cpicpgx.org/genes-drugs/ for up-to-date evidence.   
  
Many side effects of medications cannot be explained by currently known genetics factors. These genetic 
results are only one of the clinical components that your provider uses when selecting a medication and 
dose for you. Other factors such as drug interactions, lab results, age, sex, past medical history, weight, 
height, etc. are also important considerations.  
  
We recommend that you present this report to every doctor, physician assistant, nurse practitioner, and 
clinician you see, as well as your pharmacist. The pharmacogenetics pharmacist at Penn Medicine is 
available during regular business hours for questions regarding these test results.  You may contact the 
pharmacogenetics pharmacist or a genetic counselor through the Medical Genetics Clinic at (215) 662-
4740.  
  
Report completed by/Date:  
  
  
____________________________________/_________  
  
 
 
13.8  Survey Code Letter 
 
Hello ***,  
Thank you for participating in our research study called PhaRmacogEnetic-guided ChoIce of post-SurgEry 
analgesics (PRECISE). In this envelope you will find a detailed letter explaining your pharmacogenetic 
results.  
Additionally, an email was sent to *** on *** with directions for how to activate your Greenphire 
ClinCard (reloadable, prepaid card). A total of $*** has been added to this card for completing *** out 
of 3 text messages surveys after your surgery.  
  
We previously texted you a link to a survey on *** that you haven’t completed yet. If you complete this 
brief survey shown below, an additional $15.00 will be added to your card.   

Page 54 
 
 
  
Thank you,  
The PRECISE Research Study Team  
Contact: precise@pennmedicine.upenn.edu  
 
 
 
13.9 Pharmacist PGx-guided recommendations to providers consult note 
 
template  
Pharmacist Pharmacogenetic (PGx) Consultation  
  
*** is a ***-year-old *** who is scheduled to have *** on ***. He/She underwent pharmacogenetic testing using 
the OneOme RightMed test panel, ordered by *** on ***.  
 
Reason for consultation: Pharmacogenetic-guided postoperative pain medication recommendations. 
  
Medical history pertaining to this genetic result and pain medication recommendation (obtained from the 
EHR)    
*** 
  
Current medications 
*** 
 
Drug allergies/intolerances 
*** 
 
Pertinent lab results 
*** 
 
Pharmacogenetic results:  
Dr. ***, PharmD, a pharmacist with specialized training in pharmacogenomics reviewed the pharmacogenetic 
results. Only actionable pharmacogenomic results are listed in this note. To see an exclusive list of all 
pharmacogenes tested, refer to the OneOme lab report, easily found in the genomics tab of the EHR.  
 
• 
Gene genotype phenotype 

Page 55 
 
 
• 
Gene genotype phenotype 
 
Assessment/Plan: The below recommendations are for those drug-gene interactions (DGIs) where there is enough 
scientific evidence to support clinical decisions.  
 
General pharmacogenomic testing information. The lab only reports select variants but not all variants in the 
genes. It is possible that the patient may have variants that were not tested. The results of the genetic testing will not 
change, but the scientific knowledge surrounding the impact of these genes on drug response is always changing, so 
that in the future we will have more knowledge on how these may predict side effects or efficacy of medications. 
Many side effects of medications cannot be explained by currently known genetics factors. Visit 
https://cpicpgx.org/genes-drugs/ for up-to-date evidence.  
 
• 
Postoperative pain.  
• 
Postoperative nausea/vomiting. 
13.10 Text messaging script  
PhaRmacogEnetic-guided ChoIce of post-SurgEry analgesics (PRECISE) 
Text messaging script via RedCap for the survey and Twilio for SMS service on postop days 3, 
7, & 14 
 
Post-op Day 3 Text Message Script 
“Hello this is the PRECISE study team at Penn Medicine! You enrolled in this study prior to 
your gynecologic surgery. The goal of the PRECISE study is to understand if pharmacogenetic 
tests are useful to guide the choice of pain medication following surgery. We have a few 
questions for you. 
 
Text ‘YES’ if we can ask you a few questions about how you are managing your pain. Text 
‘STOP’ anytime to opt-out.  
Texting is not secure. Other people may be able to see information in text messages. By texting 
back ‘YES’ you are accepting this risk. Message & data rates may apply.” 
Question 1: 
How would you rate your pain over the past 24 hours? (From 0-10, 0 being no 
pain [please choose one number]) 
Question 2: 
Have you taken [narcotic_RX] for your pain after you were discharged from the 
hospital (at home)? [Y for yes or N for no].” 
LOGIC:  
 If yes, proceed to question 3 
 If no, proceed to question 5 
Question 3: 
“Please estimate how many pills of [narcotic_RX] you have taken after you were 
discharged from the hospital (at home)? Please text back a number.” 
Question 4:  
“How many pills of [narcotic_RX] are remaining in your bottle? Please text 
back a number.” 
Question 5: 
“Have you taken any of the following medications for your pain after you were 
discharged from the hospital (at home): acetaminophen (TYLENOL), ibuprofen 
(ADVIL/MOTRIN), or naproxen (ALEVE/NAPROSYN)? [enter 1 for 
acetaminophen (TYLENOL), 2 for ibuprofen (ADVIL/MOTRIN), 3 for 
naproxen (ALEVE/NAPROSYN), or 4 if you have taken a combination of these 
meds ].” 

Page 56 
 
 
Question 6: 
“Do you plan to continue taking medication to control your pain? [enter 1 for 
acetaminophen (TYLENOL), 2 for ibuprofen (ADVIL/MOTRIN), 3 for 
naproxen (ALEVE/NAPROSYN), 4 {narcotic_RX}, or 5 if you plan to take a 
combination of these meds ].” 
Final 
statement 
“Thanks! When you’re finished, it’s important to dispose of unused %narcotic%. 
You can do so at any Penn Pharmacy” 
 
 
Post-op Day 7 Text Message Script 
“Hello this is the PRECISE study team at Penn Medicine! You enrolled in this study prior to 
your gynecologic surgery. The goal of the PRECISE study is to understand if pharmacogenetic 
tests are useful to guide the choice of pain medication following surgery. We have a few 
questions for you. 
 
Text ‘YES’ if we can ask you a few questions about how you are managing your pain. Text 
‘STOP’ anytime to opt-out.  
Texting is not secure. Other people may be able to see information in text messages. By texting 
back ‘YES’ you are accepting this risk. Message & data rates may apply.” 
Question 1: 
How would you rate your pain over the past 24 hours? (from 0-10, 0 being no 
pain [please choose one number]) 
Question 2: 
Have you taken [narcotic_RX] for your pain in the last 4 days? [Y for yes or N 
for no].” 
LOGIC:  
 If yes, proceed to question 3 
 If no, proceed to question 5 
Question 3: 
“Please estimate how many pills of [narcotic_RX] you have taken in the last 4 
days? Please text back a number.” 
Question 4:  
“How many pills of [narcotic_RX] are remaining in your bottle? Please text 
back a number.” 
Question 5: 
“Have you taken any of the following medications for your pain in the last 4 
days: acetaminophen (TYLENOL), ibuprofen (ADVIL/MOTRIN), or naproxen 
(ALEVE/NAPROSYN)? [enter 1 for acetaminophen (TYLENOL), 2 for 
ibuprofen (ADVIL/MOTRIN), 3 for naproxen (ALEVE/NAPROSYN), or 4 if 
you have taken a combination of these meds ].” 
Question 6: 
“Do you plan to continue taking medication to control your pain? [enter 1 for 
acetaminophen (TYLENOL), 2 for ibuprofen (ADVIL/MOTRIN), 3 for 
naproxen (ALEVE/NAPROSYN), 4 {narcotic_RX}, or 5 if you plan to take a 
combination of these meds ].” 
Final 
statement 
“Thanks! When you’re finished, it’s important to dispose of unused %narcotic%. 
You can do so at any Penn Pharmacy” 
 
 
Post-op Day 14 Text Message Script 
“Hello this is the PRECISE study team at Penn Medicine! You enrolled in this study prior to 
your gynecologic surgery. The goal of the PRECISE study is to understand if pharmacogenetic 

Page 57 
 
 
tests are useful to guide the choice of pain medication following surgery. We have a few 
questions for you. 
 
Text ‘YES’ if we can ask you a few questions about how you are managing your pain. Text 
‘STOP’ anytime to opt-out.  
Texting is not secure. Other people may be able to see information in text messages. By texting 
back ‘YES’ you are accepting this risk. Message & data rates may apply.” 
Question 1: 
How would you rate your pain over the past 24 hours? (from 0-10, 0 being no 
pain [please choose one number]) 
 Question 2: 
Have you taken [narcotic_RX] for your pain over the past 7 days? [Y for yes or 
N for no].” 
LOGIC: 
 If yes, proceed to question 3 
 If no, proceed to question 5 
Question 3: 
“Please estimate how many pills of [narcotic_RX] you have taken in the past 7 
days? Please text back a number.” 
Question 4:  
“How many pills of [narcotic_RX] are remaining in your bottle? Please text 
back a number.” 
Question 5:  
“Have you taken any of the following medications for your pain in the last 7 
days: acetaminophen (TYLENOL), ibuprofen (ADVIL/MOTRIN), or naproxen 
(ALEVE/NAPROSYN)? [enter 1 for acetaminophen (TYLENOL), 2 for 
ibuprofen (ADVIL/MOTRIN), 3 for naproxen (ALEVE/NAPROSYN), or 4 if 
you have taken a combination of these meds ].” 
Question 6: 
“Do you plan to continue taking medication to control your pain? [enter 1 for 
acetaminophen (TYLENOL), 2 for ibuprofen (ADVIL/MOTRIN), 3 for 
naproxen (ALEVE/NAPROSYN), 4 {narcotic_RX}, or 5 if you plan to take a 
combination of these meds ].” 
Question 7: 
“Thank you so much! Just one more question for you. How many days did it take 
for your pain to improve after your procedure/surgery?” [please enter a number] 
Final 
statement 
“Thanks! When you’re finished, it’s important to dispose of unused %narcotic%. 
You can do so at any Penn Pharmacy” 
 
13.11 Provider survey – Pharmacogenetic testing  
Provider Pharmacogenomics (PGx) Questionnaire 
The intent of this questionnaire is to identify attitudes, interest, and knowledge of healthcare professionals regarding 
pharmacogenetic testing (PGx).  
 
This questionnaire should take you less than 10 minutes to complete. Thank you for your support. 
 
1. Number of years in practice.  
o 0 – 5 years  
o 6 – 10 years  
o 11 – 15 years  
o 16 – 20 years  

Page 58 
 
 
o 21+ years  
 
2. What is your profession?  
o Physician  
o Non-physician provider 
o Other 
 
3. What is your specialty/area of practice?  
o General gynecologic surgery 
o Gynecologic Oncology surgery 
o Other (please specify):  
 
4. State your gender. 
o Male  
o Female  
o Non-binary 
o Prefer not to say 
o Prefer to self-describe 
 
5. I have heard of pharmacogenetics or pharmacogenomics (PGx) before. 
o Yes 
o No 
 
6. How often do you order PGx tests to assist with medication selection or dosing?  
o Never  
o 1-5 times a year 
o 6-10 times a year 
o 11-25 times a year  
o More than 25 times a year  
o Not sure 
 
7. At some point in my practice, a patient has come to me with PGx test results. 
o Yes 
o No 
 
8. I believe gene-drug interactions (i.e., when a patient’s PGx results affect the metabolism of a drug) are as 
clinically important as drug-drug interactions. 
o Strongly agree  
o Agree  
o Neutral  
o Disagree  
o Strongly disagree  
 
9. I believe PGx testing can improve care for patients.  
o Strongly agree  
o Agree  
o Neutral  
o Disagree  
o Strongly disagree  

Page 59 
 
 
 
10. I am confident in my ability to use the results of PGx testing in prescribing medications.  
o Strongly agree  
o Agree  
o Neutral  
o Disagree  
o Strongly disagree  
 
11. PGx variations can impact the efficacy and/or safety of a medication.  Which of the following scenarios 
are you likely to order a PGx test before prescribing a medication (select all that apply): 
 If the PGx test can predict efficacy of the drug  
 If the PGx test can predict risk of side effects to the drug 
 If the PGx test can help to achieve the target therapeutic dose more quickly 
 If the Food & Drug Administration (FDA) labeling recommends PGx testing 
 
12. I am aware that FDA product labeling can contain PGx information, that helps clinicians apply PGx 
results in clinical practice.  
o I was aware of this 
o I was not aware of this 
 
13. If I had PGx test results for a patient, it would be helpful to consult with a pharmacist for their 
interpretation and recommendations on medication selection and dosing. 
o Strongly agree  
o Agree  
o Neutral  
o Disagree  
o Strongly disagree  
 
14. The following barrier(s) prevent me from using PGx in practice. (Select all that apply) 
 Access to a laboratory that can perform a PGx test 
 Access to clinical PGx specialists 
 Cost of the test or insurance coverage 
 Ethical concerns 
 Lack of inclusion of PGx data in society guidelines 
 Little training or experience with PGx 
 Turnaround time for the test results (estimate 1-2 weeks) 
 Other (please specify) 
 
 
15. In your opinion, what are effective methods to educate clinicians about PGx testing? (Select all that 
apply)   
 Case conference 
 Conference or symposium (half or full day) 
 Grand rounds or other types of in-house seminars 
 Online module 
 PGx training in school  
 PGx training in residency 
 Publication in scientific journals that I read regularly 
 Webinar 

Page 60 
 
 
 Other (Please specify) 
 PGx education is not necessary 
 
16. Please provide any additional comments or thoughts about PGx testing in the box below. 
 
13.12 Patient survey – Pharmacogenetic testing 
 
EXPERIENCE AND SATISFACTION WITH PHARMACOGENETIC 
TESTING IN GYNECOLOGIC SURGERY PATIENTS 
 
PLEASE COMPLETE THE SURVEY BELOW. THE SURVEY SHOULD TAKE ABOUT 
15 MINUTES TO COMPLETE. 
THANK YOU! 
 
1. First name: 
 
2. Last name: 
 
3. Please enter your age: 
 
4. What is the highest degree or level of school you 
have completed? 
o Less than high school 
o High school graduate (or 
GED) 
o Some college/university 
o College/university graduate 
o Post college/university 
degree 
o Choose not to respond 
5. How confident are you in filling out forms in a 
doctor’s office by yourself? 
o Extremely 
o Somewhat 
o A little bit 
o Not at all 
6. Have you ever had a bad reaction from a 
medication that led to stopping the medication or 
going to the hospital? 
o Yes 
o No 
o I am unsure 
7. How many different prescriptions do you take 
regularly? 
o 0 
o 1-2 
o 3-5 

Page 61 
 
 

 

 
o 6-10 
o 11 or more 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Strongly 
Agree 
Agree 
Unsure 
Disagree 
Strongly 
Disagree 
8. I understand the purpose of pharmacogenetic 
(PGx) testing. 
¡ 
¡ 
¡ 
¡ 
¡ 
9. The cheek swab for the PGx test was easy to 
perform.  
¡ 
¡ 
¡ 
¡ 
¡ 
10. My physician explained my PGx test results to 
me.  
¡ 
¡ 
¡ 
¡ 
¡ 
11. I understand the PGx test results that I received. 
¡ 
¡ 
¡ 
¡ 
¡ 
12. I am confused about my PGx test results. 
¡ 
¡ 
¡ 
¡ 
¡ 
13. Based on my PGx test results, I learned 
something new about the medications I am or was 
taking. 
¡ 
¡ 
¡ 
¡ 
¡ 
14. After having PGx testing, I am more confident 
that the pain medication I was prescribed worked 
better for me. 
¡ 
¡ 
¡ 
¡ 
¡ 
15. I think the PGx test results were helpful to my 
doctor when they decided what pain medication to 
give me. 
¡ 
¡ 
¡ 
¡ 
¡ 
16. I am satisfied with the PGx test. 
¡ 
¡ 
¡ 
¡ 
¡ 

Page 62 
 
 
17. I would recommend PGx testing to a family 
member or friend. 
¡ 
¡ 
¡ 
¡ 
¡ 
18. I would like to talk to a PGx specialist to further 
explain my results. 
¡ 
¡ 
¡ 
¡ 
¡ 
19. I am happy that I now know my PGx test results 
to help guide future medication choices. 
¡ 
¡ 
¡ 
¡ 
¡ 
20. I plan on sharing my PGx test results with all my 
healthcare providers to help in deciding what 
medication and dose to prescribe me. 
¡ 
¡ 
¡ 
¡ 
¡ 
21. How did you learn about your PGx test results? 
 
o In-person by my physician 
o In my online chart (My Penn Medicine) 
o By another healthcare professional 
o I don’t remember 
o I didn’t learn about my PGx results