A Depression and Opioid Pragmatic Trial in Pharmacogenetics
Phase: NA
Conditions: Depression
Sponsor: Duke University

 
 
A Depression and Opioid Pragmatic Trial in Pharmacogenetics 
(ADOPT PGx) 
 
          NCT04445792 
 
Principal Investigators: 
Julie A. Johnson, Pharm. D. 
Larisa Cavallari, Pharm. D. 
Josh F. Peterson, MD, MPH 
Kerri Cavanaugh, MD MHS 
Todd C. Skaar, Ph.D. 
Paul R. Dexter, MD 
Statistical Investigator: Hrishikesh Chakraborty, DrPH 
NIH Program Officer: Simona Volpi, PhD 
 
 
 
 
 
Funded by: National Human Genome Research 
Institute 
Version Number: Final v2 
11 February 2020 
Amendment 1: 28 April 2020 
Amendment 2: 03 June 2020 
Amendment 3: 17 August 2020 
Amendment 4: 20 November 2020 
Amendment 5:  17 June 2021 
Amendment 6: 24 August 2023 
Amendment 7:  27 September 2023 
Amendment 8: 23 May 2024 

Page 2 of 72 
 
 
 
PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/ 
Affected Section(s) 
Summary of Revisions Made 
Approval Date 
Blinding Section 4.2 
UF Pharmacy Call Center personnel 
administration of the final 6 month 
survey may reveal study arm 
randomization 
5/18/2020 
Interventions/Treatments 
Section 7.1 
Recent FDA update of strong and 
moderate inhibitors, Appendix C 
5/18/2020 
Interventions/Treatments 
Section 7.1, Table 2 
CYP2D6 allele to activity 
score 
Allele *10 activity value change 
6/15/2020 
Interventions/Treatments 
Section 7.1, Table 3 
CYP2D6 phenotype by 
Activity Score 
Inferred CYP2D6 phenotype, 
Intermediate metabolizer, definition 
differences from current CPIC 
guidelines and may be different from 
what appears in the lab reported 
phenotypes 
6/15/2020 
Interventions/Treatments 
Section 7.1, Table 5 CDS 
summary for acute and 
chronic pain treatments 
Phenotype - normal defined as activity 
score >0.75 and ≤ 2.0 
Phenotype - intermediate defined as 
activity score >0 and ≤ 0.75 
6/15/2020 
Data Collection from 
CMS and State Medicaid 
Agencies Table 8 Data 
Collection Schedule 
Adjustments to trial arm collection time 
points 
6/15/2020 
Analysis of the Primary 
Endpoint 10.4 
Text added for pediatric depression T 
score conversions 
6/15/2020 
Cover Page 
Added Principal Investigators, 
Larisa Cavallari, Pharm. D. and 
Sara Van Driest, MD. PhD. 
9/15/2020 

Page 3 of 72 
 
PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/ Affected 
Section(s) 
Summary of Revisions Made 
Approval Date 
Randomization 4.1 
Removed text: … and revealed after 
baseline data are collected so study 
assignment does not impact the 
baseline survey 
responses. 
9/15/2020 
Safety Assessment and 
Monitoring 8 
Deleted text…This is an observational 
study that does not include a drug or 
device 
intervention. 
9/15/2020 
Analysis of the Primary 
Endpoint 10.4 
Depression – text deleted 
…Pediatric depression T- scores will be 
converted to adult depression T-scores 
using a published crosswalk linking the 
scores from the two surveys. 
 
Added text: Pediatric depression T-
scores will be transformed to the adult 
scale using a published crosswalk 
for a combined analysis. 
9/15/2020 
Specimen Collection Section 
7.4 
Clarification that DNA specimen 
collection should be done after 
consenting and completed prior to 
randomization 
12/22/2020 
Throughout the Document 
Removal of Quick Inventory of 
Depressive Symptomatology (QIDS) 
depression scale and replaced with 
Patient Health Questionnaire-8 (PHQ-8) 
depression scale. 
7/2/2021 
Protocol Synopsis-Inclusion 
Criteria  
Section 1 
Inclusion Criteria  
Section 5.1 
Acute Pain:  
• 
Removal of “Elective/planned surgery 
patients with an upcoming pre-surgery 
visit” 
• 
Removal of “as this is the minimum 
age at which proposed outcome 
measures (PROMIS) are validated 
without parent proxy” at age inclusion 
• 
Added clarifying text for targeted 
opioids for Elective/planned surgery 
types  
 
Chronic Pain: 
• 
Added clarifying text for primary 
7/2/2021 

Page 4 of 72 
 
clinics definition and for treatment of 
chronic pain with specific opioids 
• 
Removed medical diagnosis codes 
for pain diagnosis, and symptoms 
 
Depression:  
• 
Removal of “as this is the minimum 
age at which proposed outcome 
measures (PROMIS) are validated 
without parent proxy” at age inclusion 
• 
Added clarifying text for psychiatry 
and primary clinics definition and 
depression diagnosis 
• 
Removed medical diagnosis codes 
for depression 
Protocol Synopsis-Exclusion 
Criteria  
Section 1  
Exclusion Criteria  
Section 5.2 
Trial Wide:  
• 
Include “incarcerated” as an exclusion 
example for “Are institutionalized or too
ill to participate (i.e. mental or nursing 
home facility) 
• 
Removal of “Plan to move out of the 
area within 6 months of enrollment” 
 
Acute Pain:  
• 
Removal of “Plan to move out of the 
area within 6 months of enrollment” 
• 
Removal of “Adults with a similar, 
previous surgery in whom pain 
control is well defined and a genotype 
guided approach would not likely be 
followed” 
 
Chronic Pain: 
• 
Addition of “Plan to move out of the 
area within 6 months of enrollment” 
• 
Addition of “Currently taking daily 
opioids other than tramadol, codeine 
or hydrocodone 
 
Depression:  
• 
Addition of “Plan to move out of the 
area within 6 months of enrollment” 
• 
Removal of medical diagnosis codes 
for psychotic, neurocognitive, 
cognitive developmental delay or 
disability, seizure and bipolar 
disorders 
• 
Removal of antipsychotic medications 
• 
Removal of “Depression secondary to 
substance abuse disorder or general 
medical condition” 
7/2/2021 

Page 5 of 72 
 
Protocol Synopsis-Secondary 
Endpoints  
Section 1  
Secondary Endpoints  
Section 3.2 
Depression:  
• 
Updated the secondary endpoints 
using PHQ-8 depression scale 
 
Provider Recruitment and 
Assent  
Section 6.1 
Acute Pain: 
• 
Refined the text:  “Providers with a 
predominant use of codeine, tramadol 
and hydrocodone for pain control 
before and during the 10-day primary 
endpoint may be approached by 
qualified study personnel. Providers 
will be notified per site institutional 
guidelines that their patients may be 
contacted by study site recruiters to 
participate.  Surgical procedures 
where there is persistent pain at 
the10-day primary endpoint should be 
prioritized for inclusion in the study.” 
 
Chronic Pain:  
• 
Removed text “approached by 
qualified study personnel, and notified 
that their patients will be contacted by 
study site recruiters to participate.” 
• 
Added text: ““may be approach by 
qualified personnel. Providers will be 
notified per site institutional 
guidelines that their patients may be 
contacted by study site recruiters to 
participant.” 
 
Depression: 
• 
Removed text “They then will be 
notified that their patients will be 
contacted by study site recruiters to 
participate.” 
• 
Added text “and may be approached 
by qualified study personnel, and 
given the opportunity to participate as 
a   study provider. Providers will be 
notified per site institutional 
guidelines that their patients may be 
contacted by study site recruiters to 
participate.” 
7/2/2021 

Page 6 of 72 
 
Baseline Participant 
Assessments  
Section 7.2 
Baseline:  
• 
Removed text “baseline data will be 
collected” 
• 
Added text “survey data will be 
collected” 
 
Past Medical History:  
• 
Removed text “in the medical record.” 
• 
Added text: See MOP for details.” 
 
Baseline medication: 
• 
Added text “the EHR and/or 
participant self-report.” 
7/2/2021 
Follow-up Participant 
Assessment All Trials  
Section 7.3  
All Trials: Medications: 
• 
Removed text “patient surveys at the 
primary endpoint time points: at 
baseline, 10-days and 1-month, 3-
months and 6-months for the acute 
pain participants, and baseline, 1-
month, 3-months and 6-months for 
the chronic pain and depression 
participants.” 
• 
Added text ““patient surveys at 
baseline and the primary endpoint 
time points: 10-days for Acute Pain 
and 3-months for Depression and 
Chronic pain.” 
 
Acute Pain:Opioid Consumption 
Questionnaire: 
• 
Removed text  
o “the date the prescription was 
filled”  
o “Study participants will also be 
asked to read the tablet strength 
from their prescription bottle but 
this will be verified by local study 
coordinators by reviewing the 
EHR for the prescription written.” 
 
Depression:  
• 
Removed reference text to the QIDS: 
“Quick Inventory of Depressive 
Symptomatology: A 16 item survey 
completed by the participant 
assessing depression symptoms[38]. 
This survey will be administered at 
baseline, 3 months, and 6 months 
post return of results. 
• 
Added reference text for the PHQ-8: 
“Patient Health Questionnaire-8 – An 
7/2/2021 

Page 7 of 72 
 
8 item survey completed by the 
participant assessing depression 
symptoms over the last two weeks. 
This survey will be administered at 
baseline, 3 months, and 6 months 
post return of results[38]. 
Data Collection from 
Electronic Health Record 
Section 7.8 
• 
Removed text: “Data from the local 
EHR will be used to assess 
participant’s medications, medication 
changes, medication 
discontinuations, and, if available, 
reasons for medication 
discontinuations”  
• 
Added text: “Data collected from the 
local EHR will include prescription 
information and encounters including 
clinic visits, hospitalizations, and 
emergency department visits and 
associated diagnoses” 
7/2/2021 
Table 8. Data Collection 
Schedule 
• 
Updated the Data Collection Timing 
for the Acute Pain and Immediate 
Chronic Pain and Depression arms. 
Including timings for Delayed Chronic 
Pain and Depression arms 
• 
Updated the data collection schedule 
for the Assessment of Prescriptions 
7/2/2021 
Safety Assessment and 
Monitoring-Events of Interest 
Section 8.2 
Redefined the text to:  
• 
“Participant reported emergency 
department visits and hospitalizations 
will be collected in the 1, 3, and 6-
month follow-up participant surveys. 
EHR will be used as an additional 
source for emergency department 
visits and hospitalizations, up to 
approximately 12 after the last patient 
is randomized. For the details of 
collecting EHR data, see Protocol 
section 7.8 and MOP. EHR results 
will be sent to the CC via secure data 
transfer and formatted for data 
analyses.” 
7/2/2021 
Statistical Analysis Plan and 
Sample Size: Analysis of 
Secondary Endpoints 
Section 10.5 
Depression: 
• 
Added text “and achieving 5% 
reduction in PHQ-8 scores “and 
“PHQ-8 scores” 
7/2/2021 

Page 8 of 72 
 
Data Management: Data 
Entry and Record Keeping 
Section 11.1 
• 
Removed text: “automatically “ and 
“To verify the accuracy of automatic 
import of results into the participant’s 
records, laboratories will also transfer 
raw data in whatever format produced 
locally to the CC via secure file 
transfer after the first patient sample 
has been processed and at other 
intervals as described in the MOP.” 
• 
Added text: “The accuracy of the 
import of laboratory results will be 
verified by comparing the results 
recorded in the study database to an 
external record of the result for a 
subset of the study participants. See 
MOP for details.” 
7/2/2021 
Data Management: Data 
Element Definitions 
Section 11.2 
Depression Remission: 
• 
Added text: B. Whether or not the 
PHQ-8 scores are ≤ 4, which is 
equivalent to depression severity 
being none-mild.” 
 
• 
Added term definition: “Depression 
(PHQ-8) score: The sum of the 
responses to the PHQ-8 survey, 
range from 0 to 24.” 
 
• 
Removed text in Opioid Usage: “and 
post discharge inpatient opioid usage 
immediate post-surgery collected 
from EHR queries” 
7/2/2021 
References 
Removed reference for QIDS depression 
scale and added in reference for PHQ-8 
depression scale. 
7/2/2021 
Title page; Protocol Version 
and Amendment Tracking; 
Investigator Statement; 
Abbreviations; Protocol 
Synopsis;  
• 
Reformatted the entire document and 
updated page numbers 
• 
Title page updates and PI names 
• 
Protocol Version and Amendment 
Tracking -- Added Amendment 6 
change information 
• 
Investigator_Statement–updated 
protocol version date 
• 
Abbreviations corrected typo 
• 
Protocol Synopsis – Study Population 
updated the enrollment numbers to 
reflect the update milestones 
8/30/23 

Page 9 of 72 
 
Updates found in Protocol 
Clarification Memo #2-
28Aug2021 in Protocol 
Synopsis, Study Population, 
and Inclusion/Exclusion 
Criteria Section 5 and Study 
Procedures 
• 
Updated Inclusion criteria for 
Depression: 
o Remove “the last” from 
“Evidence of depressive 
symptoms for at least the last 
3 months based on patient 
interview or documentation in 
electronic health records” 
• 
Updated Exclusion criteria:  
o Add to Trial wide: Any other 
medical, behavioral, or 
developmental condition that 
in the opinion of the 
investigator may confound 
study data/assessments 
o Add to Chronic Pain: Include 
“for treatment of pain” to 
“Currently taking daily opioids 
other than tramadol, codeine, 
or hydrocodone for treatment 
of pain” 
o Add to Chronic Pain: Include 
“Using a pain pump” 
• 
Updated text for baseline participant 
assessments in Section 7.2 
 
Updates found in Protocol 
Clarification Memo #3-
22Oct2021 in Protocol 
Synopsis-Inclusion/Exclusion 
Criteria and section 5.2 
Exclusion Criteria 
• 
Updated Exclusion criteria: removal 
of “Undergoing a laparoscopic 
surgery” 
8/30/23 
Section 7 Study Procedures 
• 
Section 7.1 Interventions/Treatments: 
Table 2 Corrected a typo in the table 
• 
Section 7.2: Baseline medications-
Simplified the text by removing 
“Additionally, participant prescription 
and over the counter medications 
may be collected using patient 
surveys.” And adding “See MOP for 
details.” 
• 
Section 7.3: Follow-up Participant 
Assessments All Trials Medications: 
Removed “prescription and over the 
counter” 
• 
Section 7.4: Specimen Collection- 
corrected verb tense. 
• 
Section 7.8: Data Collection from the 
Electronic Health Record-corrected 
text from “baseline” to “time-zero”. 
• 
Section 7.9 Table 8. Data Collection 
Schedule-- Reverted the Table 8 to 
8/30/23 

Page 10 of 72 
 
the prior version—removed the 
specific timing from the last 
amendment 
Section 8: Safety Assessment 
and Monitoring 
• 
Revised the language to reflect what 
type of Adverse Device Effect (ADE) 
and unanticipated Adverse Device 
Effect (UADE) events to be reported 
to the IRB based on the trial 
regulated under an Abbreviated 
Investigational Device Exemption. 
• 
Section 8.2: Event of Interest: 
clarified the text to “EHR may be 
used…” and the timing of the data  
collection 
8/30/23 
Section 9: Medicare and 
Medicaid Claims Data 
Collection and Analysis 
• 
Added in clarifying text for the 
Medicare and Medicaid data 
collection and analysis. 
8/30/23 
Section 10: Statistical 
Analysis Plan and Sample 
Size 
• 
Section 10.1: Sample Size 
Determination: Added language to 
define the mITT population and 
updated the enrollment numbers to 
reflect the update milestones 
• 
Table 9: Sample size calculations: 
updated the numbers 
8/30/23 
Title page; Protocol Version 
and Amendment Tracking; 
Investigator Statement; 
• 
Title page updates 
• 
Protocol Version and Amendment 
Tracking -- Added Amendment 7 
change information 
• 
Investigator Statement–updated 
protocol version date 
10/9/23 
Section 6.3: Participant 
Discontinuation/Withdrawal 
from the Study 
• 
Removal of “that is ≥ 3 months”. 
10/9/23 
Title page; Protocol Version 
and Amendment Tracking; 
Investigator Statement; 
• 
Title page updates 
• 
Protocol Version and Amendment 
Tracking -- Added Amendment 8 
change information 
• 
Investigator Statement–updated 
protocol version date 
 
Throughout the Document 
• 
Corrected 4 instances of ADOPT-
PGx to ADOPT PGx 
 

Page 11 of 72 
 
Section 10.6: Other Planned 
Analyses 
• 
Added a couple of primary research 
exploratory analyses 
• 
Updated exploratory endpoints or 
comparison of endpoints 
• 
Updated sub-groups  
 
Section 12.3: Confidentiality 
and Privacy 
• 
Updated language to reflect what is 
occurring in the study. Removed the 
text: and all identifiers, data, and 
keys will be placed in separate, 
password protected/encrypted files 
and each file will be stored in a 
different secure location. 
 
Section 12.4: Publication and 
Data Sharing Polices 
• 
Updated language from “The de-
identified and anonymized data” to 
“The de-identified or anonymized 
data” 
 

Page 12 of 72 
 
 
 
 
INVESTIGATOR STATEMENT 
 
 
By signing below, I agree to the conditions relating to this trial as set out in this 
protocol, Amendment 8 dated 23 May, 2024.  
 
I agree to conduct this clinical trial according to Good Clinical Practice (ICH GCP) and European 
Regulatory Requirements. 
 
I fully understand that any changes instituted by me without previous discussion with the IGNITE PTN 
Coordinating Center or their designated representative constitute a violation of the protocol. 
 
I agree to adhere to the protocol in all circumstances other than where necessary to protect the well- 
being of the subject. 
 
Principal Investigators’ Signatures 
 
Name:  
 
 
Signature: 
Date:  
 
 
 
Name:  
 
 
Signature: 
Date:  
 
 
 
Name:  
 
 
Signature: 
Date:  
 
 
 
Name:  
 
 
Signature: 
Date:  
 

Page 13 of 72 
 
 
 
ABBREVIATIONS 
 
 
ADOPT PGx 
A Depression and Opioid Pragmatic Trial in Pharmacogenetics 
AE 
Adverse event 
CC 
Coordinating center 
CDS 
Clinical decision support 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Centers for Medicare and Medicaid Services 
CPIC 
Clinical Pharmacogenetics Implementation Consortium 
CRF 
Case Report Form 
DCRI 
Duke Clinical Research Institute 
DEA 
Drug Enforcement Administration 
DoB 
Date of birth 
DSMB 
Data Safety Monitoring Board 
EHR 
Electronic Health Record 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICD-10 
The International Classification of Diseases, 10th Revision, 
Procedure Coding System 
IGNITE PTN 
Implementing Genomics in Practice Pragmatic Trials Network 
IM 
Intermediate metabolizer 
LOS 
Length of stay 
M/M 
Medicare/Medicaid 
MED 
Morphine Equivalent Doses 
MME 
Morphine Milligram Equivalents 
MOP 
Manual of Operations 
NM 
Normal metabolizer 
PGx 
Pharmacogenetics 
 

Page 14 of 72 
 
PHQ-8 
Patient Health Questionnaire-8 
PI 
Principal investigator 
PM 
Poor metabolizer 
PROMIS 
Patient Reported Outcome Measurement System 
RM 
Rapid metabolizer 
ROR 
Return of results 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SIA Score 
Silverman Integrated Analgesic Score 
SOP 
Standard operating procedure 
SSN 
Social security number 
SSRI 
Selective serotonin reuptake inhibitors 
UM 
Ultra-rapid metabolizer 

Page 15 of 72 
 
 
 
 
 
TABLES 
Table 1. Genes to be tested and drugs with CPIC recommendations 
29 
Table 2. CYP2D6 allele to activity score 
30 
Table 3. CYP2D6 phenotype by Activity Score 
30 
Table 4. CYP2C19 phenotype by genotype 
30 
Table 5. CDS summary for acute and chronic pain treatments 
31 
Table 6. CDS summary for antidepressant medications 
32 
Table 7. PGx panel genes and drugs with CPIC recommendations 
33 
Table 8. Data collection schedule 
39 
Table 9. Sample size calculations 
45 
FIGURES 
Figure 1. ADOPT PGx Trial Design 
22 

Page 16 of 72 
 
 
 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS 
11 
2. 
INTRODUCTION 
18 
2.1 
Background, Significance, and Rationale 
18 
2.2 
Aims and Objectives of the Study 
20 
3. 
ENDPOINTS 
21 
3.1 
Primary Endpoint(s) 
21 
3.2 
Secondary Endpoints 
21 
4. 
Study Arms & Design 
22 
4.1 
Randomization 
23 
4.2 
Blinding 
23 
5. 
STUDY POPULATION 
24 
5.1 
Inclusion Criteria 
24 
5.2 
Exclusion criteria 
24 
6. 
RECRUITMENT AND ENROLLMENT PROCEDURES 
26 
6.1 
Provider Recruitment and Assent 
26 
6.2 
Participant Consent Process 
26 
6.3 
Participant Discontinuation/Withdrawal from the Study 
26 
6.4 
Lost to Follow-Up 
27 
6.5 
Risk 
27 
6.6 
Benefit 
27 
6.7 
Costs to the Participants 
28 
6.8 
Compensation to Participants 
28 
7. 
STUDY PROCEDURES 
29 
7.1 
Interventions/Treatments 
29 
7.2 
Baseline Participant Assessments 
33 
7.3 
Follow-up Participant Assessments 
34 
7.4 
Specimen Collection 
37 
7.5 
Specimen Transfer and Genetic Testing Procedures 
37 
7.6 
Return of Results 
37 
7.7 
Clinical Decision Support Systems 
37 
7.8 
Data Collection from the Electronic Health Record 
38 
7.9 
Data Collection from CMS and State Medicaid Agencies 
38 

Page 17 of 72 
 
8. 
SAFETY ASSESSMENT AND MONITORING 
40 
8.1 
Medication Side Effects 
40 
8.2 
Events of Interest 
40 
8.3 
Data Safety Monitoring Board 
40 
8.4 
Early Termination and Participant Discontinuation 
40 
9. 
MEDICARE AND MEDICAID CLAIMS DATA COLLECTION AND ANALYSIS 
41 
9.1 
Rationale 
41 
9.2 
Data Collection 
41 
10. 
STATISTICAL ANALYSIS PLAN AND SAMPLE SIZE 
42 
10.1 
Sample Size Determination 
42 
10.2 
General Statistical Methods 
44 
10.3 
Population for Analyses 
44 
10.4 
Analysis of the Primary Endpoint 
44 
10.5 
Analysis of the Secondary Endpoints 
45 
10.6 
Other Planned Analyses 
46 
10.7 
Interim Analyses 
48 
10.8 
Handling of Missing Data 
49 
10.9 
Multiplicity 
49 
11. 
DATA MANAGEMENT 
50 
11.1 
Data Entry and Record Keeping 
50 
11.2 
Data Element Definitions 
50 
11.3 
Database Management and Quality Control of Data 
51 
11.4 
Database Lock and Study Close Out 
51 
11.5 
Data Sharing 
52 
12. 
ETHICAL AND HUMAN SUBJECTS CONSIDERATIONS 
53 
12.1 
Institutional Review Board/Ethics Committee Review 
53 
12.2 
Use and Disclosure of Protected Health Information (HIPAA) 
53 
12.3 
Confidentiality and Privacy 
53 
12.4 
Publication and Data Sharing Policies 
53 
13. 
PROTOCOL DEVIATIONS AND VIOLATIONS 
54 
REFERENCES 
55 
14. 
APPENDICES 
58 
14.1 Appendix A. SIA Score Background and Rationale 
58 
14.2 Appendix B. Table of Minimum Required Variants 
60 

Page 18 of 72 
 
14.3 Appendix C. CYP2D6 Inhibitors as defined by the FDA guidance on drug interactions 
61 

Page 19 of 72 
 
1. 
PROTOCOL SYNOPSIS 
 
Protocol Title 
A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT- 
PGx) 
US IND Number 
Grant Number 
 
Product/Intervention 
Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or 
depression therapy 
 
 
 
 
 
 
 
 
 
Objectives 
Acute Pain: 
● To determine the effect of genotype-guided therapy on pain control and use 
of DEA schedule II opioids in post-surgical participants 
Chronic Pain: 
● To determine the effect of genotype-guided therapy on pain control in 
chronic pain participants 
Depression: 
● To determine the effect of genotype-guided selection and dosing of 
antidepressants on control of depression in participants with ≥3 months of 
depressive symptoms who require new or revised therapy 
All Trials: 
● To determine the effect of genotype-guided therapy for opioids, 
antidepressants, and optional additional, CPIC gene-drug pairs on overall 
well-being 
● To determine the effect of genotype-guided therapy for opioids, 
antidepressants, and optional additional, CPIC gene-drug pairs on 
healthcare utilization 
 
 
 
Study Design 
ADOPT PGx is comprised of three separate trials, Acute Pain, Chronic Pain, and 
Depression. Each trial is a prospective, multicenter, two arm randomized pragmatic 
trial. For all trials, participants will be randomized in a 1:1 ratio to immediate 
pharmacogenetic testing and genotype-guided therapy (Intervention arm) or 6- 
month delayed testing on participants receiving standard care (Control arm). In 
each trial, the primary outcome comparison will be between the intervention group 
(i.e. immediate testing) and control group (i.e. delayed testing) in the subset of 
participants with actionable phenotypes, within each study. 
 
 
Rationale for Study 
Design 
Pain and depression are conditions that impact substantial proportions of the US 
population and have challenges associated with identifying the right therapy while 
minimizing adverse effects or opioid addiction. There is evidence that both opioid 
and antidepressant prescriptions can be guided by pharmacogenetics (PGx) data 
based on existing guidelines from the Clinical Pharmacogenetics Implementation 
Consortium (CPIC). Using such an approach, a recent single site Pragmatic 
Clinical Trial (PCT) demonstrated that among CYP2D6 poor (PM) and intermediate 
 

Page 20 of 72 
 
 
metabolizers (IM), there was greater improvement in pain control in the genotype- 
guided arm compared to usual care arm[1]. Similarly, existing studies of PGx 
tailored antidepressant therapy suggest that the genotype-guided approach is 
superior to usual care in remission and/or response rates, however these studies 
are small and often industry-sponsored. 
A broader trial is needed to determine the importance of PGx testing and genotype 
guided therapy for improving symptom management (i.e. pain control or control of 
depression symptoms), DEA schedule II opioid use, well-being, and overall 
healthcare utilization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population 
Acute Pain 
Randomized Population 
Approximately 1730* participants with planned/elective surgery who are 
anticipated to start a pain control medication with existing CPIC guidelines after 
their surgery 
 
Analytical Population 
Approximately 304 participants from the randomized population who have an 
actionable phenotype defined as CYP2D6 IM or PM (i.e. CYP2D6 activity score ≤ 
0.75) 
 
Chronic Pain 
Randomized Population 
Approximately 985* participants see in primary care or pain specialty clinics who 
are already prescribed or anticipated to be prescribed tramadol, codeine, or 
hydrocodone for pain control. 
 
Analytical Population 
Approximately 268 participants from the randomized population who have an 
actionable phenotype defined as CYP2D6 IM or PM (i.e. CYP2D6 activity score ≤ 
0.75) 
 
Depression 
Randomized Population 
Approximately 1540* participants seen in primary care or psychiatry clinics who are 
already prescribed or anticipate to be prescribed an SSRI with existing CPIC 
guidelines 
 
Analytical Population 
Approximately 542 participants from the randomized population who have an 
actionable phenotype, defined as a CYP2D6 PM or ultra-rapid metabolizer (UM), 
or a CYP2C19 PM, rapid metabolizer (RM), or UM 
 
*Subject to change based on the actionable phenotype rates and missing data. 
Number of Sites 
11 sites with approximately 60-80 clinics 
Duration of Subject 
Participation: 
Up to one year from consent to end of follow-up 

Page 21 of 72 
 
Description of 
implementation of 
intervention (e.g., 
The intervention for ADOPT PGx is the immediate return of PGx testing results to 
the participant’s healthcare provider. 
 
dose, schedule, etc.) 
The PGx testing is comprised of Clinical Laboratory Improvement Amendments 
(CLIA) validated, panel-based genetic testing of two required genes, CYP2D6 and 
CYP2C19. The resulting CYP2D6 genotypes will be converted to enzymatic 
activity scores and the activity scores converted to metabolizer phenotypes after 
also taking strong and moderate CYP2D6 enzyme inhibitor drug interactions into 
account. The CYP2C19 genotypes will be converted to metabolizer phenotypes. 
The results of the PGx test will be returned to the healthcare providers using 
standard site-specific laboratory return of results methods, a static report with both 
interpretation and recommendations, and where possible, interruptive clinical 
decision support (CDS) alerts within the electronic healthcare system. Both the 
static report and interruptive alerts will guide health care providers towards 
medications best suited to the participant. 

Page 22 of 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria: 
Acute Pain 
● Age ≥ 8 years 
● English speaking or Spanish speaking 
● Elective/planned surgery types with planned or anticipated to be treated 
with tramadol, hydrocodone, or codeine pain management at an enrolling 
site, which may include  orthopedic surgeries (e.g. arthroplasty, spine, 
etc.), open abdominal surgery, or cardiothoracic surgery and others 
Chronic Pain 
● Age ≥ 18 years 
● English speaking or Spanish speaking 
● Seen at primary care clinics (such as, but not limited to, Internal  
Medicine, Family Medicine or Pediatrics) or patients seen in 
pain-relevant specialty clinics 
● History of pain for at least the last 3 months 
● Currently treated or being considered for treatment with 
tramadol, hydrocodone, or codeine to improve pain 
management 
Depression 
● Age ≥ 8 years 
● English speaking or Spanish speaking 
● Patients followed at psychiatry clinics or primary care clinics at an 
enrolling site (such as, but not limited to, Internal Medicine, Family 
Medicine, or Pediatrics) 
● Documentation of depression and/or provider report of depression 
● Evidence of depressive symptoms for at least 3 months based on patient 
interview or documentation in electronic health records 
● Recent initiation of SSRI therapy, recent revised SSRI therapy, or 
anticipated need for revised or new SSRI therapy per health care provider  
 

Page 23 of 72 
 
 
Exclusion Criteria 
Trial-wide: 
● Life expectancy less than 12 months 
● Are too cognitively impaired to provide informed consent and/or complete 
study protocol 
● Are institutionalized or too ill to participate (i.e. mental or nursing home 
facility or incarcerated) 
● Have a history of allogeneic stem cell transplant or liver transplant 
● People with prior clinical pharmacogenetic test results for genes relevant for 
the study in which they will enroll (CYP2D6 for the pain studies and CYP2D6 
or CYP2C19 for depression) or already enrolled in an ADOPT PGx trial 
● Any other medical, behavioral, or developmental condition that in the opinion 
of the investigator may confound study data/assessments 
Acute Pain 
● Receiving chronic opioid therapy, defined as use of opioids on most days 
for >3 months 
Chronic Pain 
● Plan to move out of the area within 6 months of enrollment 
● Undergoing treatment for an active cancer diagnosis 
● Currently taking daily opioids other than tramadol, codeine or hydrocodone 
for treatment of pain 
● Using a pain pump 
Depression 
● Plan to move out of the area within 6 months of enrollment 
● Have active psychosis or diagnosed psychotic disorders (schizophrenia, 
schizoaffective disorder, delusional disorder, psychotic depression, 
substance induced psychosis, schizophreniform disorder) 
● Have dementia or other neurocognitive disorders due to any cause, such 
as Alzheimer’s disease, vascular/subcortical, lewy body disease, 
frontotemporal lobar degeneration 
● Have cognitive developmental delay and/or cognitive disability, including 
autism spectrum disorders (Note: ADHD is not an exclusion criteria) 
● Has a seizure disorder 
● Have bipolar disorder 
 
 
 
 
 
Primary Endpoint 
Acute Pain: Silverman Integrated Analgesic Assessment (SIA) score (a composite 
of pain and opioid usage) at 10 days post-surgery in participants who are 
genetically or pheno-converted CYP2D6 IM or PM 
Chronic Pain: Pain control, defined as change in the composite pain intensity score 
from baseline to 3-months in participants who are genetically or pheno-converted 
CYP2D6 IM or PM 
Depression: Depression symptom control, defined as change in PROMIS 
depression 8A scores from baseline to 3-months in genetically or pheno-converted 
CYP2D6 UM/PM or CYP2C19 UM/RM/PM 

Page 24 of 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary Endpoints 
Acute Pain: 
● Pain intensity at 10 days post-surgery 
● Opioid usage at 10 days post-surgery 
● Prescription pain medication misuse score 3 months post-surgery 
● Mobility score 1-month post-surgery 
● Opioid persistence 6 months post-surgery 
Chronic Pain: 
● Pain reduction magnitude at 3-month follow-up, relative to baseline 
● Achievement of clinically significant pain reduction (30%) by 3-month 
follow-up, relative to baseline 
● Prescription pain medication misuse score at 3-month follow-up 
Depression: 
● Change in PHQ-8 scores between baseline and 3 months 
● Achieve 50% reduction in PHQ-8 scores at 3 months, relative to baseline 
● Medication side effects severity burden at 3 months 
● Participant medication adherence at 3 months 
● Achieve remission at 6 months defined as PROMIS depression score ≤ 16 
● Achieve remission at 6 months, defined as PHQ-8 score ≤ 4 
All Trials: 
● Overall well-being at 6 months in all randomized participants 
● Concordance between metabolizer phenotype and prescribed medication 
● Sub-domains of the PROMIS 43 survey: pain interference, physical 
function, sleep disturbance, social role and activities functioning, fatigue, 
anxiety, and depression at 6-month follow-up 
 
 
Statistical Analyses 
Acute Pain: 
● The effect of genotype guided opioid therapy on pain control will be 
determined by comparing the 10-day post-surgery SIA scores of the 
Intervention arm participant with CYP2D6 IM or PM phenotypes to the 10- 
day post-surgery SIA scores of the Control arm participant with CYP2D6 IM 
or PM phenotypes using a two-sided t-test or a two-sided Mann Whitney 
 

Page 25 of 72 
 
 
test, as appropriate, with a two-sided type 1 error rate of 0.049 
● Similarly, the effect of genotype guided opioid therapy on all secondary 
endpoints will be compared between the Intervention arm CYP2D6 IM or 
PM phenotype and the Control arm CYP2D6 IM or PM phenotype using a 
two-sided t-test or a two-sided Mann Whitney test 
● Additional analyses will include time trends in primary and secondary 
endpoints, subset analyses, covariate adjustments, and exploratory 
healthcare utilization and cost effectiveness analyses 
Chronic Pain: 
● The effect of genotype guided opioid therapy on pain control will be 
determined by comparing the change in baseline to 3-month follow-up 
composite pain scores of the Intervention arm participants with CYP2D6 IM 
or PM phenotypes to the change in baseline to 3-month follow-up 
composite pain scores of the Control arm participants with CYP2D6 IM or 
PM phenotypes using a two-sided t-test with type 1 error rate of 0.049 
● Similarly, the effect of genotype guided opioid therapy on all chronic pain 
secondary endpoints will be compared between the Intervention arm 
CYP2D6 IM or PM subgroup and the Control arm CYP2D6 IM or PM 
subgroup using either a two-sided t-test or a test of two proportions, as 
appropriate. 
● Additional analyses will include time trends in primary and secondary 
endpoints, subset analyses, covariate adjustments, and exploratory 
healthcare utilization and cost effectiveness analyses 
Depression: 
● The effect of genotype guided antidepressant therapy on depression 
symptoms will be determined by comparing the 3-month follow-up 
composite depression scores of the Intervention arm participant subgroup 
with CYP2D6 UM or PM or CYP2C19 UM, RM, or PM phenotypes to the 3- 
month follow-up composite depression scores of the Control arm participant 
subgroup with CYP2D6 UM or PM or CYP2C19 UM, RM, or PM 
phenotypes using a two-sided t-test with type 1 error rate of 0.049 
● Similarly, the effect of genotype guided antidepressant therapy on all 
depression secondary endpoints will be compared between the Intervention 
arm CYP2D6 or CYP2C19 UM, RM or PM subgroup and the Control arm 
CYP2D6 or CYP2C19 UM, RM, or PM subgroup using either a two-sided t- 
test, a two-sided Mann Whitney test, or a test of two proportions, as 
appropriate. 
● Additional analyses will include time trends in primary and secondary 
endpoints, subset analyses, covariate adjustments, and exploratory 
healthcare utilization and cost effectiveness analyses 
All Trials: 
● Overall well-being of all Intervention participants will be compared to the 
overall well-being of all Control participants at 6-month follow-up using 
ANOVA, adjusting for baseline differences in the two groups 
● The effect of genotype guided therapy on concordance between phenotype 
and prescribed medication will be compared between Intervention and 
Control participants from the metabolizer phenotypic subgroups specified 
 

Page 26 of 72 
 
 
for each trial’s primary endpoint. 
● Additional analyses will include time trends, subset analyses, and covariate 
adjustments analyses 

Page 27 of 72 
 
 
2. 
INTRODUCTION 
 
2.1 Background, Significance, and Rationale 
Study Rationale 
Pain and depression are conditions that impact substantial proportions of the US population. Finding 
safe and effective drug therapies for both conditions is challenging. In the case of treatment for acute 
and chronic pain, the challenge is finding effective therapy while minimizing adverse effects or opioid 
addiction (and the ensuing consequences). For depression, there are few clinically relevant predictors 
of successful treatment leading to multiple trials of inadequate therapy for some patients. Both opioid 
and antidepressant prescriptions can be guided by pharmacogenetics (PGx) data based on existing 
guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC). A pilot study 
conducted during IGNITE-1, in patients with chronic pain supports the potential benefit of a genotype- 
guided approach to pain therapy.[1] Existing studies of tailored antidepressant therapy are small and 
often industry-sponsored but suggest the genotype-guided approach is superior to usual care. We 
propose a randomized pragmatic clinical trial that enrolls patients into three PGx-guided therapy 
scenarios: acute post-surgical pain, chronic pain, and depression. For each scenario, participants will 
be randomized to genotype-guided drug therapy versus usual approaches to drug therapy selection 
(hereafter referred to as usual care). Changes in patient reported outcomes representing pain and 
depression control using standard PROMIS scales define the primary endpoints. Secondary analyses 
include safety endpoints, changes in overall well-being, and economic impact represented by 
differences in healthcare utilization and cost effectiveness. 
Background and Significance 
Acute and chronic pain represents the most prevalent and expensive public health condition in the U.S., 
affecting an estimated 100M Americans with annual costs to society estimated at $635B dollars.[2, 3] 
This exceeds the combined costs of cancer, AIDS and heart disease.[3] Opioids have become a 
mainstay of treatment for chronic pain, yet analgesic responses to opioids are widely variable in both 
acute and chronic pain.[4, 5] Opioid prescribing rates have more than tripled since 1999, with 65 in 100 
people getting an opioid prescription in 2016, and nearly 215M opioid prescriptions dispensed.[6, 7] 
Nearly half of all opioid prescriptions originate in primary care, and approximately 35% are from 
surgeons.[8] 
 
Tramadol, codeine, hydrocodone, and oxycodone comprise the vast majority of opioids prescribed in 
the U.S.[9] Codeine and tramadol are dependent on bioactivation by the CYP2D6 enzyme to morphine 
and O-desmethyltramadol, respectively, which have 200-fold greater affinity for the µ-opioid receptor 
than their parent compounds. CYP2D6 genotype has important relevance for response to codeine and 
tramadol. Specifically, 5-10% of individuals are poor metabolizers (PMs), with no active CYP2D6 
enzyme secondary to frameshift mutations (*3, *6), splicing defects (*4), or complete gene deletion (*5). 
As a result, PMs are unable to generate the active metabolites of codeine and tramadol and may derive 
no pain relief from these drugs.[10] Another 2-11% are intermediate metabolizers (IMs), with 
significantly impaired enzyme activity secondary to having both a nonfunctional and a reduced function 
CYP2D6 allele and may derive little pain relief from codeine and tramadol. At the opposite extreme, 
approximately 1-2% of individuals are ultra-rapid metabolizers (UMs) with CYP2D6 gene 
duplication/multiplication. UMs are at increased risk for toxic concentrations of active opioid 
metabolites, with reports of life-threatening toxicity and death with codeine or tramadol.[11-15] 
Hydrocodone and oxycodone undergo similar metabolism via CYP2D6 to compounds with 10- to 40- 
fold higher receptor affinity, respectively, and recent data support CYP2D6 genotype as an important 
contributor to hydrocodone efficacy, though risk exists for both drugs in those with UM phenotypes.[1] 

Page 28 of 72 
 
Guidelines support CYP2D6 genotype-guided use of opioid analgesics, but this is rarely done in clinical 
practice.[10] In a single center PCT[1], CYP2D6 genotype-guided prescribing led to improved pain 
control in PMs and IMs compared to a traditional pain management approach. We now propose a multi- 
center PCT in which we will make recommendations based on CYP2D6 genotype and CYP2D6 
enzyme inhibitor drug interactions that can convert individuals to PM or IM phenotypes. In PM, IM and 
UM we will recommend avoidance of hydrocodone, tramadol and codeine, and for normal metabolizers 
(NM), tramadol will be recommended as the preferred opioid, given its opioid and non-opioid 
mechanisms and purported lower risk for misuse.[16, 17] One study suggested the potential for abuse 
and dependence with tramadol in patients with chronic non-cancer pain was significantly less than for 
hydrocodone, and not different from that of non-opioid analgesics.[16] 
 
The prevalence of major depressive disorder ranges from 5 to 10% in primary care, and it can be as 
high as 37% after critical care hospitalizations and surgeries.[18] SSRI prescriptions have increased 
5.8-fold between 1991 and 2011.[19] Response to SSRIs and other antidepressants depends on 
numerous factors, but pharmacokinetic adjustments based on drug-drug interactions, renal and hepatic 
function, and pharmacogenomic variants within CYP2D6 and CYP2C19 play a substantial role in 
interindividual drug response.[20] 
 
Existing clinical trials of PGx-guided treatment of depression have been primarily industry-sponsored 
and often investigate proprietary treatment algorithms.[21] One open label, non-randomized study 
demonstrated significantly improved depression outcomes in 227 adults with major depressive disorder 
(MDD) treated with PGx-guided prescribing of psychotropic medications relative to unguided 
participants.[22] Another 12-week randomized, double-blind trial of 144 adults with MDD receiving PGx- 
guided prescribing reported a 2.52-fold greater chance of remission of depressive symptoms. A 
randomized clinical trial of 685 adults with anxiety and depression identified significantly improved 
outcomes relative to controls in patients diagnosed with depression or anxiety using pharmacogenetic- 
guided medication selection.[23] A meta-analysis of randomized controlled trials of pharmacogenetic 
tests and depressive symptom remission concluded that individuals receiving treatment of depression 
with pharmacogenetic-guided decision support tools were 1.71 (95% CI: 1.17-2.48; p = 0.005) times 
more likely to achieve symptom remission relative to individuals who receive treatment as usual.[24] 
Another industry-sponsored, randomized, double-blind prospective trial with only 51 study subjects (26 
pharmacogenetic-guided versus 25 unguided) reported a trend toward improved clinical outcomes in a 
10-week trial. PGx-guided participants with depression had greater than double the likelihood of 
response and remission. Mean percent improvement in depressive symptoms was higher for the PGx- 
guided group over Treatment as Usual (TAU). PGx-guided treatment doubled the likelihood of response 
in patients with treatment resistant depression.[25] A more recent double-blind randomized controlled 
trial of 316 adults with MDD failed to report a difference in sustained response within a 12-week period. 
However, the PGx-guided treatment group had a higher responder rate compared to treatment as 
usual.[26] 
 
While the above clinical trials suggest improved depression outcomes with use of pharmacogenomic- 
guided management of psychotropic medications when treating major depression in outpatient 
psychiatric practices, the majority of the trials were small and sponsored by industry. Importantly, a 
large, definitive trial with non-proprietary drug selection algorithms has not yet been published. Three of 
the six most commonly used SSRIs (sertraline, citalopram, and escitalopram) require functional 
CYP2C19 enzyme activity for their hepatic inactivation in vivo, and CPIC recommends dose reduction 
in the setting of a CYP2C19 poor metabolizer phenotype (to reduce probability of side effects) and 
alternative drug in the setting of a CYP2C19 ultra-rapid or rapid phenotype (to reduce the probability of 
pharmacotherapy failure).[27] Two additional common antidepressants (fluvoxamine, paroxetine) are 
oxidized by CYP2D6, one of the most polymorphic of all human enzymes. For the present investigation, 

Page 29 of 72 
 
PGx-guided antidepressant selection will follow CPIC guidelines for CYP2D6 and CYP2C19 
phenotypes with regard to the selection or dosing of antidepressants. 
 
2.2 Aims and Objectives of the Study 
Our rationale for examining a genotype-guided approach to acute and chronic pain management is 
based on the importance of CYP2D6 for the bioactivation of tramadol, codeine, and hydrocodone and 
data from a pilot study supporting improved pain control in IM/PMs in the genotype-guided arm who are 
taking these drugs at baseline. Similarly, the rationale for examining a genotype-guided approach to 
depression medication therapy is based on the demonstrated role of CYP2D6 in the bio inactivation 
and CYP2C19 oxidation of select, commonly used SSRIs. Secondly, data from industry sponsored 
trials support the hypothesis of improved symptom control in a genotype-guided arm. 
 
Acute Pain: Determine if a genotype-guided approach to acute post-surgical pain therapy leads to 
improved pain control compared to usual care, as defined by a decrease in the SIA score. Secondarily, 
we will evaluate whether this approach leads to reduced use of DEA Schedule II opioids and reduced 
pain intensity. 
 
Chronic Pain: Determine if a genotype-guided approach to pain therapy in participants with at least 3 
months of chronic pain leads to improved pain control compared to usual care. 
 
Depression: Determine if genotype-guided dosing or selection of antidepressants among participants 
with at least 3 months of depressive symptoms who require new or revised antidepressant therapy 
leads to improved control of depression, compared to usual care. 

Page 30 of 72 
 
 
3. 
ENDPOINTS 
 
3.1 
Primary Endpoint(s) 
Acute pain: The primary endpoint for the acute pain study is the SIA score, a composite of pain and 
opioid usage, at 10 days post-surgical procedure. See Appendix A for the SIA score rationale. 
 
Chronic pain: The primary endpoint for the chronic pain study is change in composite pain intensity 
score, assessed using the PROMIS pain intensity survey, from baseline to 3 months post return of 
genetic testing results to the provider. 
 
Depression: The primary endpoint for the depression study is change in depression score, assessed 
using the PROMIS Emotional Distress - Depression 8b survey (adults) or PROMIS pediatric depressive 
symptoms (pediatric), from baseline to 3 months post return of genetic testing results to provider. 
 
3.2 Secondary Endpoints 
Secondary endpoints include: 
 
All Trials 
1. Overall well-being at 6-month follow-up 
2. Sub-domains of overall well-being: pain interference, physical function, sleep disturbance, social 
role and activities functioning, fatigue, anxiety, and depression at 6-month follow-up 
3. Concordance between metabolizer phenotype and prescribed medication 
 
Acute pain 
1. Pain intensity at 10 days post-surgery 
2. Opioid usage at 10 days post-surgery 
3. Prescription pain medication misuse score at 3-months post-surgery 
4. Mobility at 1-month post-surgery 
5. Opioid persistence 6 months post-surgery 
 
Chronic pain 
1. Pain reduction magnitude at 3-month post return of genetic testing results to provider, relative to 
baseline 
2. Proportion of participants achieving clinically significant pain reduction (30% reduction from 
baseline) at 3-months post return of genetic testing results to provider 
3. Prescription pain medication misuse at 3-months post return of genetic testing results to 
provider 
 
Depression 
1. Change in PHQ-8 score between baseline and 3 months 
2. Achieve 50% reduction in PHQ-8 scores at 3 months, relative to baseline 
3. Medication side effects severity burden at 3 months 
4. Participant medication adherence at 3 months 
5. Achieve remission at 6 months, defined as PROMIS depression score ≤ 16 
6. Achieve remission at 6 months, defined as PHQ-8 score ≤ 4 

Page 31 of 72 
 
 
 
4. 
Study Arms & Design 
This is a prospective, multicenter, subset analysis of 1:1 randomized Intervention (immediate PGx 
testing and genotype-guided opioid or SSRI therapy with clinical decision support) vs. Control (usual 
care with delayed PGx testing) pragmatic, open label clinical trial (Figure 1). The three trials are 1) 
genotype-guided opioid therapy among post-surgical acute pain participants (Acute Pain, Figure 1A), 2) 
genotype-guided opioid therapy among chronic pain participants (Chronic Pain, Figure 1B), and 3) 
genotype-guided SSRI therapy in participants with depression (Depression, Figure 1C). Trial-specific 
outcomes will be compared between participants in the intervention arm and control arms who have an 
actionable phenotype. Actionable phenotypes are defined as CYP2D6 IM and PMs (i.e. CYP2D6 
activity score ≤ 0.75) for the acute pain and chronic pain trials and CYP2C19 UM, RM and PMs or 
CYP2D6 UM and PMs for the depression trial. 
 
 
 
Figure 1. ADOPT PGx Trial Design 
Intervention participants are denoted by blue boxes and blue lines, control participants are denoted by orange 
boxes and orange lines. Return of results are denoted with black outlines, endpoint comparison groups 
(actionable phenotypes in the control and intervention arms) are denoted with red outlines, and * denote timing of 
the primary endpoint collection. Time 0 denotes the time from which the follow-up assessment timing begins. 

Page 32 of 72 
 
4.1 Randomization 
After participants provide informed consent/assent, participants will be randomized in a 1:1 allocation to 
the Intervention (i.e. immediate PGx testing and genotype-guided opioid or SSRI therapy with clinical 
decision support) and Control (i.e. usual care with delayed PGx testing) arms. Randomization will be 
stratified by trial and site or clinic with a random block size within each site or clinic. We anticipate 
variability in patient populations between recruiting sites or clinics and aim to balance the intervention 
assignments within the site or clinic unit. Additionally, the randomization for the chronic pain trial will be 
stratified by presence/absence of depression, and the randomization for the acute pain and depression 
trials will be stratified by pediatric/adult. 
 
The randomization scheme will be generated by an unblinded statistician. Randomization assignments 
will be generated in real time in REDCap at the Coordinating Center. 
 
4.2 
Blinding 
ADOPT PGx randomization assignments will not be blinded to the participants or their providers but will 
be masked to the UF call center personnel who may be administering some of the participants follow- 
up surveys. Due to the nature of the intervention, it is impossible to completely mask participants and 
providers from the pharmacogenetic testing and return of results, hence participants, providers, and 
local study personnel will not be blinded. While the UF call center personnel administering follow-up 
surveys will be masked from the results and randomization, study-arm specific questions in the final (6 
month) survey may reveal study arm randomization. Additionally, participants may volunteer to reveal 
their randomization or PGx testing results. If the randomization or phenotype is revealed to the call 
center, prior to administering the 6 month surveys, it will be documented in the database. 

Page 33 of 72 
 
 
5. 
STUDY POPULATION 
5.1 Inclusion Criteria 
Acute Pain 
● Age ≥ 8 years 
● English speaking or Spanish speaking 
● Elective/planned surgery types with planned or anticipated to be treated with tramadol, 
hydrocodone, or codeine pain management at an enrolling site, which may include orthopedic 
surgeries (e.g. arthroplasty, spine, etc.), open abdominal surgery, or cardiothoracic surgery and 
others 
 
Chronic Pain 
● Age ≥ 18 years 
● English speaking or Spanish speaking 
● Seen at primary care clinics at an enrolling site (such as, but not limited to, 
Internal Medicine, Family Medicine, Pediatrics) or seen in pain-relevant 
specialty clinics 
● History of pain for at least the last 3 months 
● Currently treated or being considered for treatment with tramadol, 
hydrocodone, or codeine to improve pain management 
Depression 
Age ≥ 8 years 
● English speaking or Spanish speaking 
● Patients followed at psychiatry clinics or primary care clinics at an enrolling site (such as, 
but not limited to, Internal Medicine, Family Medicine, or Pediatrics) 
● Documentation of depression and/or provider report of depression 
● Evidence of depressive symptoms for at least 3 months based on patient interview or 
documentation in electronic health records  
● Recent initiation of SSRI therapy, recent revised SSRI therapy, or anticipate need for revised or 
new SSRI therapy per health care provider  
 
5.2 Exclusion criteria 
Trial-wide: 
● Life expectancy less than 12 months 
● Are too cognitively impaired to provide informed consent/assent and/or complete study protocol 
● Are institutionalized or too ill to participate (i.e. mental or nursing home facility or incarcerated) 
● Have a history of allogeneic stem cell transplant or liver transplant 
● People with prior clinical pharmacogenetic test results for genes relevant for the study in which 
they will enroll (CYP2D6 for the pain studies and CYP2D6 or CYP2C19 for depression) or 
already enrolled in an ADOPT PGx trial 
● Any other medical, behavioral, or developmental condition that in the opinion of the 
investigator may confound study data/assessments 
 
Acute Pain 
 
● Receiving chronic opioid therapy, defined as use of opioids on most days for >3 months 
 

Page 34 of 72 
 
Chronic Pain 
● Plan to move out of the area within 6 months of enrollment 
● Undergoing treatment for an active cancer diagnosis 
● Currently taking daily opioids other than tramadol, codeine or hydrocodone for treatment of pain 
● Using a pain pump 
 
Depression 
● Plan to move out of the area within 6 months of enrollment 
● Have active psychosis or diagnosis of a psychotic disorder (schizophrenia, 
schizoaffective disorder, delusional disorder, psychotic depression, substance induced 
psychosis, schizophreniform disorder) Have dementia or other neurocognitive disorders 
due to any cause, such as Alzheimer’s disease, vascular/subcortical, lewy body, 
frontotemporal lobar degeneration 
● Have cognitive developmental delay and/or cognitive disability, including autism spectrum 
disorders (Note: ADHD is not an exclusion criteria) 
● Has a seizure disorder 
● Have bipolar disorder

Page 35 of 72 
 
 
6. 
RECRUITMENT AND ENROLLMENT  PROCEDURES 
Outlined below are suggested strategies for recruitment and enrollment. It is anticipated that each site 
will need to optimize the strategies that work best for the clinic and patient population and are in 
accordance with local regulations and procedures. Strategies utilized will be documented for each 
recruiting site (see MOP for details). Sites shall maintain local recruitment logs per local policies and 
share aggregated data with the CC. 
 
6.1 Provider Recruitment and Assent 
Acute Pain: Providers with a predominant use of codeine, tramadol, and hydrocodone for pain control 
before and during the 10-day primary endpoint may be approached by qualified study personnel. 
Providers will be notified per site institutional guidelines that their patients may be contacted by study 
site recruiters to participate.  Surgical procedures where there is persistent pain at the 10-day primary 
endpoint should be prioritized for inclusion in the study. 
 
Chronic Pain: Primary care providers, pain clinic providers, and/or anesthesiologists specializing in pain 
control who treat patients meeting eligibility criteria will be identified, and may be approached by 
qualified study personnel.  Providers will be notified per site institutional guidelines that their patients 
may be contacted by study site recruiters to participate. 
 
Depression: Primary care providers and psychiatric providers who manage the care of eligible patients 
will be identified, and may be approached by qualified study personnel, and given the opportunity to 
participate as a   study provider. Providers will be notified per site institutional guidelines that their 
patients may be contacted by study site recruiters to participate. 
 
6.2 Participant Consent Process 
Pre-screened participants that meet the inclusion criteria will be asked to provide an informed 
consent/assent. 
 
Original informed consent documents will be maintained at the site. Copies of the signed informed 
consent will be given to the participant. The consenting process can be remote, via a phone or 
electronically if approved by the reviewing IRB. 
 
6.3 
Participant Discontinuation/Withdrawal from the Study 
Participants may stop participating and withdraw from the study at any time. All information and data 
collected up until that point will be used in the study. 
 
If a participant wishes to withdraw consent, they should contact study staff. A participant may also 
revoke HIPAA authorization and must provide the revocation in writing. Study staff may attempt to 
obtain a reason for withdrawal from the participant and record it in the study database. 
 
In the acute pain trial, the principal investigators or clinical site investigators may withdraw a participant 
from the study for any of these reasons: 
● Participant does not have the surgery within 12 months of study enrollment 
● Participant has the surgery at a healthcare system that is different from where the participant 
enrolled 
● Participant's surgery is scheduled for a date after the close of the enrollment period for 
that clinical site 
● Participant is unable to have the surgery for other medical reasons 

Page 36 of 72 
 
6.4 Lost to Follow-Up 
Participant status of lost to follow-up will be minimized and retention maximized through various 
mechanisms to collect study survey responses. The following options will be available: in person, 
via phone, or a web-based link, text or email. Study staff should confirm the best contact 
information for the participant at each study encounter. 
 
Additionally, data collected from the EHR and Medicare and Medicaid claims data (see Section 9 
for details) will be robust to missing data due to participants that are lost to follow up. 
 
6.5 
Risk 
The potential risks described below are minimal and reasonable in relation to the potential benefit for 
genotype-guided therapy to improve the management of pain and depression and reduce the pain and 
depression burden to society. 
 
Blood Draw 
The risks of a blood draw include pain, bruising, and the slight possibility of infection at the place of 
needle insertion. Some people feel dizzy or may faint during or after a blood draw. 
 
Off FDA label use of antidepressants 
In the depression trial, specifically in the pediatric population, the standard practice of medicine may 
include use of antidepressants that are currently not FDA approved to treat depression in pediatrics. 
Use of drugs not labeled for use in pediatrics, but prescribed by their treating physician, is not a risk 
due to study participation. 
 
Prescription Changes 
It is possible that the PGx-PGx-recommended drug therapy change may lead to worse pain control or 
worse control of depression symptoms, though the likelihood is that is no different than with the usual 
trial and error approach typically used for defining pain management or antidepressant therapy. 
Pharmacogenetic information is expected to lead to safer and more effective drug therapy, and the 
ultimate prescribing decision in this study will be left to the physicians. Thus, there are no anticipated 
risks with basing therapy on pharmacogenetic test results and our preliminary data support a clinical 
benefit, not risk. 
 
Genetic Information Privacy 
The risks of study participation are primarily those related to genetic studies, including risks related to 
confidentiality surrounding the genetic information and the chance that the genetic information could in 
some way expose the participant to increased risk regarding employment or that future life, health, 
disability or long-term care insurance providers could potentially use this genetic information to deny, 
limit or raise rates for insurance coverage. The Genetic Information Nondiscrimination Act (GINA) 
makes it illegal for health insurance companies, group health plans, and most employers to discriminate 
based on genetic information, but other insurers may still use genetic information to discriminate. The 
pharmacogenetics examples included in our study are only known to be associated with drug response, 
which is unlikely to lead to insurance discrimination as long as effective, alternative therapies are 
available, as they are for all gene-drug pairs included in this study. 
 
6.6 
Benefit 
Study participation may not directly benefit participants of the study especially those who do not have 
an actionable phenotype. It is possible however that those individuals who have an actionable 
phenotype may benefit from this study. 
 

Page 37 of 72 
 
Improved drug therapy 
The genotype information could lead to improved drug therapy management for select participants. For 
example, CYP2D6 genotype may help to identify participants unlikely to respond to codeine, tramadol, 
or hydrocodone or who are at high risk for toxicity with these opiates plus oxycodone. This could lead to 
prescribing of alternative opiates or other non-opioid therapies more likely to reduce pain without 
compromising participant safety. In addition, through improved pain management and use of lower 
potency opioids in individuals expected to respond well to these drugs based on genotype, the study 
may indirectly have positive impacts on the opioid crisis by helping to reduce the individual participant 
opioid burden. 
 
Similar to the above, potential benefits exist for the SSRIs based on more appropriate dosing or 
selection of an alternative antidepressant. Finally, participants may benefit from optimized therapy for 
other drugs that may have recommendations based on the panel-based pharmacogenetic testing. 
 
Though the study participants that are randomized to the usual care/control arm have no potential to 
derive benefit during their participation in the clinical trial, when they complete the 6-month follow-up, 
they will have their genotype recorded in the EHR, whereby it could be used to guide any future 
relevant therapies. 
 
6.7 Costs to the Participants 
The cost of clinical genotyping and collection of PRO outcomes will be covered by the clinical trial. The 
cost of their drug therapy will not be covered by the trial since they would be prescribed a medication 
regardless of participation in the trial. However, taking part in this study may lead to added costs to the 
participant, specifically the costs of their care, including the physician-prescribed drug therapy, which 
will generally be covered by the participant’s insurance (if insured), and will not be covered by the 
study. 
 
6.8 
Compensation to Participants 
Participants will be reimbursed for their time and effort, prorated by study completion. Sites will follow 
local policies and procedures for amount, timing of, and mechanism for issuing compensation to 
participants. Participants may be reimbursed for travel or parking expenses per institutional specific 
policies. 

Page 38 of 72 
 
 
 
7. 
STUDY PROCEDURES 
An overview of the study procedures to be followed is presented in this section. Recruiting sites will 
receive training on the protocol and MOP before site activation for enrollment. 
 
7.1 Interventions/Treatments 
The intervention, genotype-guided pain or depression therapy, is intended to reflect the practices and 
procedures that are likely to be implemented if PGx testing were to be integrated into standard clinical 
practice. The intervention has two technical components: the PGx panel testing and the clinical 
decisions support/clinical recommendations for providers, described below. The participant and 
provider facing components of the intervention include the following: 
 
Patient Participants 
● The return of the PGx testing results to the participant’s medical record that is analogous to 
typical lab results. Participants may discuss their results with their provider. 
 
Providers 
● The return of PGx testing results to the participant’s provider via standard site-specific 
laboratory return of results methods 
● Clinical decision support will be provided to all providers, how that is provided may vary. At least 
one of the two options below that includes drug-drug interactions, is required. 
a. A static report/consult note with interpretation of the genetic testing results and drug- 
drug interactions, and treatment recommendations 
b. Where possible, a provider prescribing alert for actionable phenotypes, triggered when a 
relevant opioid or SSRI medication is ordered that indicates the participant’s genetic 
results and/or metabolizer phenotype, the predicted phenotype (i.e. efficacy of various 
opioid or SSRI medications), other considerations, and treatment recommendations 
 
PGx Panel Testing 
 
For all trials, the PGx testing panel includes two required genes: CYP2C19 and CYP2D6. The list of 
drugs with responses affected by these genes that will be the focus of recommendations in the trial are 
found in Table 1. Reflecting the pragmatic nature of the trial, there may be site to site variability in the 
testing of specific variants due to site-specific institutional approvals. The minimal required set of 
CYP2C19 and CYP2D6 variants are listed in Appendix B. 
 
Table 1. Genes to be tested and drugs with CPIC recommendations 
 
Genes 
Drugs 
CYP2C19 
citalopram, escitalopram, sertraline 
CYP2D6 
codeine, oxycodone, tramadol, hydrocodone, fluvoxamine, paroxetine 
 
CYP2D6 phenotypes will be inferred based on the activity scoring system as shown in Table 2 and 
Table 3. The activity score value of each allele (Table 2) is added together to determine the total 
activity score for the diplotype. The activity scores are converted to phenotypes per Table 3. The IM 
phenotype will be defined as an activity score of >0 to 0.75, not >0.75 to 1.0. As there is debate about 

Page 39 of 72 
 
how to define the IM phenotype, we will have an a priori analysis plan to determine whether participants 
in the usual care arm with an activity score of >0.75 to 1 (who we will define as NM) have worse pain 
control or depressive symptoms than NMs with an activity score > 1 to 2. If an allele is duplicated, and it 
is unknown which allele is duplicated, then the AS may be a ranged number, resulting in a ranged 
phenotype. If the ranged phenotype is NM-UM, the individual will be treated clinically as is if they were 
a UM. 
 
Table 2. CYP2D6 allele to activity score 
Alleles 
Activity value+ 
*1, *2 
1 
*9, *14, *17, *29, *41 
0.5 
*10 
0.25 
*3, *4, *5, *6, *7, *8 
0 
+ Lab reported results may use older versions of CPIC guidelines for activity value definitions 
 
 
Table 3. CYP2D6 phenotype by Activity Score 
 
Inferred CYP2D6 phenotype 
CYP2D6 activity score (AS) 
UM 
> 2.0 
NM 
>0.75 to 2.0 
IM* 
>0 to 0.75 
PM 
0 
*This phenotype definition differences from current CPIC guidelines and may be different from 
what appears in the lab reported phenotypes 
CYP2C19 phenotypes will be inferred from the genotypes, as shown in Table 4. 
Table 4. CYP2C19 phenotype by genotype 
 
Inferred CYP2C19 phenotype 
Example CYP2C19 genotypes 
UM 
*17/*17 
RM 
*1/*17 
NM 
*1/*1 
IM 
*1/*2,*1/*3, *2/*17, *3/*17 
PM 
*2/*2, *2/*3, *3/*3 

Page 40 of 72 
 
The CYP2C19 metabolizer phenotype and the CYP2D6 metabolizer phenotypes and/or activity scores 
will be included in the PGx testing report generated by the laboratory, which is then returned to the 
provider and deposited in the EMR, where available. 
 
Clinical Decisions Support / Clinical Recommendations 
 
Acute and Chronic Pain 
Standardized clinical consult notes with or without pharmacogenetics expert consultations will be 
generated based on the genotype-inferred phenotype, and in the case of drugs including CYP2D6 
guidance, will include consideration of drug interactions. 
 
For CYP2D6, those taking concomitantly a strong CYP2D6 inhibitor (as defined by FDA guidance on 
drug interactions[28]) will be considered to have been pheno-converted to a PM and recommendations 
will be consistent with that for a PM. Examples of strong inhibitors include, but are not limited to: 
bupropion, fluoxetine and paroxetine. Moderate inhibitors include, but are not limited to: duloxetine 
and mirabegron and reduce CYP2D6 activity scores by 50%, and thus the inferred phenotype will be 
based on the genotype activity score x 0.5. Activity scores that align with a given phenotype, and which 
will ultimately will be based on genotype and drug interaction data, are shown in Tables 2 and 3. A full 
list of strong and moderate inhibitors can be found in Appendix C. 
 
While we will not be including oxycodone as a drug on which we will make recommendations in IMs 
and PMs, based on UF data and other data in the literature that make the importance of CYP2D6 for 
the pain response unclear, there are data that suggest that CYP2D6 UMs can have significant toxicities 
(especially respiratory depression).[1, 29-31] Thus, oxycodone will be a drug for which we will make 
strong recommendations about avoiding use in UMs. 
Using a standardized consult note/CDS or pharmacogenetics expert consultation, recommendations 
will be made to avoid tramadol, hydrocodone, or codeine in PMs, IMs, and UMs and to use an 
alternative opioid (e.g. morphine, hydromorphone) or non-opioid (e.g. NSAID), as noted in Table 5. 
Consideration of tramadol as the first line opioid will be recommended for NMs. While not part of the 
primary hypothesis, for safety reasons, avoidance of oxycodone will also be recommended in UMs. 
 
Additionally, where possible, the CDS will include a provider alert for actionable phenotypes, triggered 
when a relevant opioid medication is ordered that indicates the participant’s genetic results, the 
predicted phenotype, other considerations, and treatment recommendations. 
 
Table 5. CDS summary for acute and chronic pain treatments 
 
 Treatment 
CYP2D6 Phenotypes 
Ultra-rapid 
Normal to 
Ultra-Rapid 
Normal* 
Intermediate** 
Poor 
Tramadol 
Avoid 
Avoid 
Preferred opioid 
Avoid 
Avoid 
Codeine 
Avoid 
Avoid 
Acceptable 
Avoid 
Avoid 
Hydrocodone 
Avoid 
Avoid 
Acceptable 
Avoid 
Avoid 
Oxycodone 
Avoid 
Avoid 
Acceptable 
Acceptable 
Acceptable 
*Defined as activity score >0.75 and ≤ 2.0 
**Defined as activity score >0 and ≤ 0.75 

Page 41 of 72 
 
Depression 
Clinical decision support in the form of computerized alerts, standardized clinical consult notes, and/or 
pharmacist consultations will be generated to guide prescribers on dosing or selection of SSRIs or 
selection of alternate antidepressants based on predicted phenotype. Recommendations on drug 
choice and starting dose will be made in accordance with CPIC guidelines and/or FDA label information 
for paroxetine, fluvoxamine, citalopram, escitalopram, and sertraline, as outlined in Table 6. Drug-drug 
interactions leading to pheno-conversion will be incorporated into recommendations. For CYP2D6, 
concomitant use of a strong inhibitor (listed above) will result in a predicted phenotype of poor 
metabolizer, and the effect of concomitant moderate inhibitor (listed above) will be estimated by 
multiplying the CYP2D6 activity score by 0.5. 
 
Table 6. CDS summary for antidepressant medications 
 
CYP2D6 Phenotypes 
Ultra-rapid 
Normal to 
Ultra-rapid 
Normal 
Intermediate 
Poor 
Paroxetine 
Avoid 
Avoid 
Acceptable 
Acceptable 
Avoid or 50% Dose 
Reduction* 
Fluvoxamine 
No 
recommend 
ation 
No 
recommend 
ation 
Acceptable 
Acceptable 
Avoid or 25-50% Dose 
Reduction* 
CYP2C19 Phenotypes 
Ultra-rapid and Rapid 
Normal 
Intermediate 
Poor 
Citalopram 
Avoid 
Acceptable 
Acceptable 
Avoid or 50% 
Reduction** 
Escitalopram 
Avoid 
Acceptable 
Acceptable 
Avoid or 50% 
Reduction* 
Sertraline 
Monitor for Non-response 
Acceptable 
Acceptable 
Avoid or 50% 
Reduction* 
* Dose reductions refer to starting dose of medication; Avoid refers to recommendation to switch to a drug not predominantly 
metabolized by the listed drug metabolizing enzyme. No recommendation refers to a scenario where CDS is not triggered but 
the drug is also not offered as an alternative given the phenotype. 
** Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the 
risk of QT prolongation 

Page 42 of 72 
 
Context of the intervention implementations 
Reflecting the pragmatic nature of the clinical trial, the intervention may be implemented in 
environments in which there are existing PGx testing and CDS. The PGx testing may be completed as 
part of larger, CLIA validated, PGx panel that include optional gene-drug pairs (Table 7). Additionally, 
clinical decision support may be in place for the study gene-drug pairs as well as other CPIC drug-gene 
pairs and/or other drugs affected by the study genes. 
 
Table 7. PGx panel genes and drugs with CPIC recommendations 
 
Genes 
Drugs 
CYP2C19 
(Required) 
amitriptyline, clopidogrel, clomipramine, doxepin, imipramine, trimipramine, voriconazole, 
omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole 
CYP2D6 
(Required) 
amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, ondansetron, 
trimipramine, tropisetron 
CYP2C9 
warfarin, phenytoin 
CYP3A5 
Tacrolimus 
SLCO1B1 
Simvastatin 
TPMT 
azathioprine, mercaptopurine, thioguanine 
NUDT15 
azathioprine, mercaptopurine, thioguanine 
VKORC1 
Warfarin 
CYP4F2 
Warfarin 
 
 
7.2 Baseline Participant Assessments 
All study participants will complete baseline surveys for demographics and participant reported 
outcomes (PROs) (see Table 8 for details). These data will be collected by the study coordinator in 
person or alternatively by using telephone, email, or text. 
 
Baseline data will be collected for the Chronic Pain and Depression trials following consent, for the 
Acute pain trial, survey data will be collected before surgery. The type of surgery information will be 
collected after the completed procedure. 
 
Participant demographics – including but not limited to age, sex, gender, race, Hispanic/Latino ethnicity 
(Yes or no), and smoking status will be administered at baseline as a survey. 
 
Past medical history – A snapshot of the participant’s medical history. See MOP for details. 
 
Baseline medications - Participant medications will be collected through the EHR and/or participant 
self-report. See MOP for details. 

Page 43 of 72 
 
7.3 Follow-up Participant Assessments 
The event that starts the post-intervention data collection timing are as follows. 
 
Acute Pain: 
● Date of surgery (intervention and control arms) 
Chronic Pain and Depression: 
● Intervention arm: When the pharmacogenetics results are returned to the provider and 
deposited in the EMR 
● Control arm: At date of DNA sample collection plus one week, where one week reflects the 
average time from sample collection to returning the results to the EHR 
● Note: There will be variability in time the results are returned to provider and when 
genotype-guided therapy is delivered to the participant, time from results being available to 
the next provider-participant interaction (e.g. email, clinic visit, new prescription order, phone 
visit, etc.) will be recorded by study personnel. 
 
Post intervention assessment collection may be done by the University of Florida College of 
Pharmacy Call Center. The center agents will be trained survey collectors*, using an IRB approved 
telephone script. The collected survey responses will be entered into the study database. If preferred, 
the participant will have the option to complete the study follow-up survey by a URL link sent by text 
(to mobile phone) or email and captured in REDCap database 
 
In the event that the call center is unable to reach a participant, local study coordinators may contact 
participants to facilitate completion of the follow-up surveys. 
 
Data will be collected in the following timeframes*: 
● Acute pain: 10 days, 1 month, 3 months, and 6 months post-surgery 
● Chronic pain and depression: 1-month, 3 months, and 6 months post return of results for the 
intervention arm, and post baseline assessments for the control arm. 
 
*See MOP for call center agents and survey collection interval windows 
 
All Trials 
PROMIS 43 – Adults (≥ 18 years of age) will complete a 43-question survey assessing well-being and 
sub domains: pain interference, physical function, sleep disturbance, social role and activities 
functioning, fatigue, anxiety, and depression.[32] This survey will be administered to adult participants 
at baseline, 1-month, 3-months, and 6-months post-surgery (acute pain), or baseline, 1-month, 3- 
months, and 6-months post return of results (chronic pain, depression). 
 
PROMIS pediatrics 37 – Pediatric study participants (ages 8-17) will complete a 37-question survey 
assessing pediatric well-being and sub domains: pain interference, physical function, sleep disturbance, 
social role and activities functioning, fatigue, anxiety, and depression. This survey will be administered 
to pediatric participants at baseline, 1-month, 3-months, and 6-months post-surgery (acute pain), or 
baseline, 1 month, 3 months, and 6 months post return of results (depression). 
 
Health care utilization – Survey of the number of significant cost driver health care encounters (e.g. 
hospitalizations, clinic visits, etc.). This survey will be administered to participants at 10-day, 1-month, 
3-months, and 6-months post-surgery (acute pain), or baseline, 1-month, 3-months, and 6-months post 
return of results (chronic pain, depression). 

Page 44 of 72 
 
Medications - Participant medications will be collected using patient surveys at baseline and the 
primary endpoint time points:  10-days for Acute Pain and  3-months for Depression and Chronic pain.  
 
Productivity loss – Survey of loss of work the time and pay lost due to the participant’s depression or 
pain. This survey will be administered to participants at 1-month, 3-months, and 6-months post-surgery 
(acute pain), or 1-month, 3-months, and 6-months post return of results (chronic pain, depression). 
 
Acute Pain: 
PROMIS Numeric Rating Scale - Pain Intensity - An 11-point numeric scale ranging from 0 (no pain) to 
10 (worst possible pain) for average pain. This survey will be administered to all participants at 
baseline, 10 days, 1-month, 3-months, and 6-months post-surgery. 
 
PROMIS pain intensity scale – A participant completed 3-question survey of average pain over the last 
7 days, worst pain over the last 7 days, and current pain. Each question is on a 1-5 integer scale, the 
higher the value, the more intense the pain. This survey will be administered to all participants at 
baseline, 10 days, 1-month, 3-months, and 6-months post-surgery. 
 
Opioid consumption questionnaire – A participant completed survey of pain prescription medication 
consumption, including the type of opioid pain medication, number of pills dispensed, if a refill has 
been obtained, and the number of pills left for each opioid pain medication selected. This survey will 
be administered to all participants at 10 days and 1-month post- surgery.   
 
PROMIS prescription medication mis-use scale - A participant completed survey of prescription 
medication misuse over the past 3 months. The survey is comprised of 7 questions on a 5-point ordinal 
scale of never/rarely/sometimes/frequently/almost always or not at all/a little bit/somewhat/quite a 
bit/very much[33]. This survey will be administered at baseline, 3-months, and 6-months post-surgery. 
 
PROMIS Item Bank v2.0 Mobility – A participant completed survey of the participant’s level of difficulty 
in completing different physical activities such as standing unassisted, walking, and sprinting or 
activities that their health currently limits. The survey is comprised of 15 questions, each answered on a 
5-point scale ranging from without difficulty to unable to do, or not at all through cannot do[34]. This 
survey will be administered at baseline, 10 days, 1-month, 3-months, and 6-months post-surgery to the 
adult participants. 
 
PROMIS Pediatric Mobility – Short Form 8a – A participant completed 8 item survey of difficulty in 
completing different physical activities such as getting up from the floor, standing on tiptoes, and ability 
to do sports and exercises that their peers can complete [35]. The survey will be administered at 
baseline, 10 days, 1-month, 3-months, and 6-months post-surgery to the pediatric participants. 
 
Acute pain specific health care utilization – A participant completed survey of hospital length of stay for 
the surgical admission, administered at 10 days post-surgery. 
 
Opioid side effects – A participant completed survey of common opioid side effects experienced and 
the extent to which those side effects bothered the participant. This survey will be administered at 
baseline, 10 days, 1-month, 3-months, and 6-months post-surgery. 
Opioid persistence - Whether or not the participant had an opioid prescription refill 90 – 180 days post- 
surgery. This survey will be administered to participants at 6 months post-surgery. 
 
Chronic Pain: 
PROMIS pain intensity scale – A participant completed 3-question survey of average pain over the last 
7 days, worst pain over the last 7 days, and current pain. Each question is on a 1-5 integer scale, the 

Page 45 of 72 
 
higher the value, the more intense the pain. This survey will be administered at baseline, 1 month, 3 
months, and 6 months post return of results. 
 
PROMIS prescription pain medication mis-use scale - A participant completed survey of prescription 
medication misuse over the past 30 days. The survey is comprised of 7 questions on a 5-point ordinal 
scale of never/rarely/sometimes/frequently/almost always or not at all/a little bit/somewhat/quite a 
bit/very much[33]. This survey will be administered at baseline, 3 months, and 6 months post return of 
results. 
 
PROMIS emotional distress depression 8b survey - A participant completed eight question survey 
assessing frequency of depression symptoms over the past 7 days[36]. This survey will be 
administered at baseline, 1 month, 3 months, and 6 months post return of results to the adult 
participants. 
 
Opioid side effects – A participant completed survey of common opioid side effects experienced and 
the extent to which those side effects bothered the participant. This survey will be administered at 
baseline, 3 months, and 6 months post return of results to the adult participants. 
 
 
Depression: 
PROMIS emotional distress depression 8b survey - A participant completed eight question survey 
assessing frequency of depression symptoms over the past 7 days[36]. This survey will be 
administered at baseline,1 month, 3 months, and 6 months post return of results to the adult 
participants. 
 
PROMIS Pediatric Depressive Symptoms Short Form 8a- A pediatric (ages 8-17 years) participant 
completed eight question survey assessing frequency of depression symptoms over the past 7 
days[37]. This survey will be administered at baseline, 3 months, and 6 months post return of results to 
the pediatric study participants . 
 
Patient Health Questionnaire-8 – An 8 item survey completed by the participant assessing 
depression symptoms over the last two weeks. This survey will be administered at baseline, 3 
months, and 6 months post return of results[38]. 
 
Antidepressant side effects – A participant completed survey of relevant antidepressant side effects. 
This survey will be administered at baseline, 1 month, 3 months, and 6 months post return of results. 
 
 
Voils Medication Adherence - A participant completed three question survey, 5-point scale survey 
assessing participant medication adherence[39]. This survey will be administered to depression trial 
participants at baseline, 1 month, 3-months and 6 months post return of results. 
 
All of the PROMIS® surveys can be found online[40]. 

Page 46 of 72 
 
7.4 Specimen Collection 
DNA sample collection can be whole blood by venipuncture, saliva, buccal swab, or mouthwash, 
whichever is most appropriate for the site or study participant preference. The sample collection can 
occur in person or by mailed kits after consenting.  
 
Once sample collection is completed, participants are randomized to a trial Control or Intervention 
arm. All DNA sample types and collection processes are detailed in the MOP. 
 
 
7.5 Specimen Transfer and Genetic Testing Procedures 
All collected specimens will be clearly marked with two patient identifiers (CLIA requirement). Samples 
from the Intervention arm participants will be processed, using analytically validated PGx testing 
procedures (see Table 1 for gene and variant list). For Control arm samples, designated laboratories 
will either extract DNA after sample receipt, and store the DNA for later analysis or store the sample 
and extract DNA after the Control participant has completed the 6-month follow-up assessment. After 
the Control participant has completed the 6-month follow-up assessment, Control Arm samples will be 
processed using analytically validated procedures. Details of sample storage and transport will be 
presented in the MOP. 
 
7.6 Return of Results 
The designated laboratory will transfer participant genetic testing results to the EHR. Genetic results 
will be imported into the study database. Providers will be notified of participant results via standard 
site-specific laboratory return of results methods, a static report/consult note with interpretation and 
treatment recommendations, and, where possible, a CDS within the EHR as described in Sections 7.1 
and 7.7. 
 
After their participation in the trial is complete, the PGx testing results will be actively returned to the 
participants. The PGx testing results that are returned to the participant will follow current FDA 
guidance. 
 
7.7 
Clinical Decision Support Systems 
Providers will be notified of participant results via standard site-specific laboratory return of results 
methods, a static report/consult note with both interpretation and treatment recommendations, and, 
where possible, a just in time alert within the electronic health system. Sites will work with their 
institutional information technology departments to set up provider alerts for actionable PGx 
phenotypes when a relevant opioid or SSRI medication is ordered. Provider alerts will indicate the 
participant’s genetic results, the predicted phenotype (e.g. efficacy of various opioid or SSRIs), and 
prescribing recommendations. 
 
Continuing on the health IT collaborative efforts established in IGNITE I through CDSKB 
(http://cdskb.org), all participating sites will seek to harmonize their CDS logic, recommendations, and 
provider alerts using a framework of required and optional elements for both the static report and the 
just in time alert. However, due to the pragmatic nature of the trial, the many involved research sites, 
and variations in local CDS policies, it is anticipated that there will be differences in CDS 
implementation details, but all sites will ensure that providers are alerted to the PGx test results and 
associated significance. Details of the alerts will be provided in the MOP. 

Page 47 of 72 
 
7.8 Data Collection from the Electronic Health Record 
Data collected from the local EHR will include prescription information and encounters including clinic 
visits, hospitalizations, and emergency department visits and associated diagnoses for the study 
interval time-zero through six-month follow up. Sites will extract data using prespecified programmatic 
algorithms, site-developed algorithms, and/or manual chart abstractions. EHR query results will be 
sent to the IGNITE PTN CC via secure data transfer and formatted for consistency across sites. 
Details for the  EHR elements and transfer process will be provided in the MOP. 
 
7.9 Data Collection from CMS and State Medicaid Agencies 
 
Medicare and Medicaid claims data from CMS and state Medicaid agencies will be used to assess 
health care utilization, costs, and medications among participants covered by either Medicare or 
Medicaid. Claims made in the period of 12 months prior to surgery (acute pain) or return of results 
(chronic pain, depression) through 6 months following those events will be collected. See Section 9 
and the MOP for additional details. Schedule of Activities and Timeframe for Collection of Endpoints 
Table 8. Data collection schedule 
Data collection schedule, method of data collection, and timing 
Outcome 
Data 
source/instrument 
Baseline 
10 d ± 3 d 
1 mo. ± 7 d 
3 mo. ± 14 d 
6 mo. ± 14 d 
Pain Assessments 
Pain intensity 
PROMIS Pain intensity 
scales 
AP, CP 
AP 
AP, CP 
AP, CP* 
AP, CP 
Pain intensity 
PROMIS Numeric Rating 
Scale - Pain Intensity (NPRS) 
AP 
AP* 
AP 
AP 
AP 
Daily opioid dose 
& type of opioid 
use 
Average daily mg morphine 
equivalents (MED) since 
discharge use of opioids: 
tramadol/ codeine vs others 
AP* 
AP 
Opioid use 
disorder 
PROMIS - Prescription pain 
medication misuse subscale 
AP, CP 
AP, CP 
AP, CP 
Mobility 
PROMIS mobility 
AP 
AP 
AP 
AP 
AP 
Depression Assessments 
Depressive state 
PROMIS Emotional Distress - 
Depression 8b survey 
CP, D 
CP, D 
CP, D* 
CP, D 
Depressive state 
Patient Health 
Questionnaire-8 
depression scale 
D 
D 
D 
Participant Medications 
Assessment of 
prescriptions 
Custom survey/EHR 
AP, CP, D 
AP 
 
CP, D 
 
Assessment of 
filled prescriptions 
Medicaid and Medicare billing 
records for 12 months prior to 
time 0 through 6 months after 
time 0 
AP, CP, D 
 

Page 48 of 72 
 
Adherence 
Voils Medication Adherence 
D 
D 
D 
D 
SSRI AE Survey 
Custom survey 
D 
D 
D 
D 
Opioid side effect 
survey 
Adapted medication side 
effect survey (SPACE) 
AP, CP 
AP 
AP, CP 
AP, CP 
AP, CP 
Opioid 
persistence 
Custom survey 
AP 
Participant Actions 
Interaction with 
provider 
Participant visits 
CP, D 
Interaction with 
test result 
Custom survey 
AP, CP, D 
Quality of life and well being 
Past Medical 
History 
Participant visits/custom 
survey 
AP, CP, D 
Well-being 
PROMIS43/PROMIS Peds37 
AP, CP, D 
AP, CP, D 
AP, CP, D 
AP, CP, D 
Healthcare Utilization and Costs 
Medicare/Medicai 
d billing records 
Medicaid and Medicare billing 
records for 12 months prior to 
time 0 through 6 months after 
time 0 
AP, CP, D 
LoS 
LoS for index admission 
AP 
ED/urgent care & 
inpatient visits 
Participant reported visits 
AP, CP, D 
AP, CP, D 
AP, CP, D 
Outpatient visits 
Participant reported primary 
care & pain clinic visits 
AP, CP, D 
AP, CP, D 
AP, CP, D 
Outpatient visits 
Long-term care or in-patient 
rehab days, home healthcare 
days 
AP 
AP 
AP 
Productively Loss 
Survey of lost work time and 
income 
AP, CP, D 
AP, CP, D 
AP, CP, D 
 
Abbreviations: CP – chronic pain, AP – acute post-surgical pain, D-depression, ED – emergency department, EHR – electronic health record; LoS – length of stay; 
PT – physical therapy 
*Denote primary endpoints 

Page 49 of 72 
 
 
8. 
SAFETY ASSESSMENT AND MONITORING 
ADOPT PGx is a prospective, multicenter, subset analysis of 1:1 randomized Intervention (immediate 
PGx testing and genotype-guided opioid or SSRI therapy with clinical decision support) vs. Control 
(usual care with delayed PGx testing) pragmatic, open label clinical trial. It is regulated under an 
Abbreviated Investigational Device Exemption (IDE). The genotyping-guided therapy is the device 
and classified as a minimal risk to the welfare of the enrolled participants. Only Adverse Device Effect 
(ADE) events suspected to be related to the specimen collection, laboratory assay genotyping 
results, and phenoconversion recommendations from the Best Practice Alerts (BPAs)/Consult notes 
will be reported to the IRB. Reportable ADEs or unanticipated Adverse Device Effect (UADEs) events 
including unanticipated study related deaths will be collected in the study database per IRB reporting 
policies. See the MOP for more details. 
 
The IRB reporting timeline requirements are: 
● Immediately (within 24 hours) upon learning of an unanticipated study-related death. Study 
personnel will notify the IRB via phone or email by providing a brief summary of the event; then 
within 1 week (5 business days), study personnel should submit report to IRB 
● Within 5 business days for unanticipated events 
● Within 10 business days for any other problem or event 
 
 
8.1 Medication Side Effects 
Participant reported medication side effects will be collected in the baseline and follow-up surveys. The 
opioid medication side effects that will be surveyed include: problems with sleep; nausea, gas or 
indigestion; constipation or diarrhea; and dizziness or balance problems. The SSRI medication side 
effects that will be surveyed include: fatigue, change in weight, GI upset, sedation/somnolence, anxiety, 
insomnia, irritability/hostility, and sexual dysfunction. 
 
8.2 Events of Interest 
Participant reported emergency department visits and hospitalizations will be collected in the 1, 3, and 
6-month follow-up participant surveys. EHR may be used as an additional source for emergency 
department visits and hospitalizations, up to approximately 12 months after the last patient is 
randomized, i.e. through completion of the 6 month-follow up activities. For the details of collecting 
EHR data, see Protocol section 7.8 and MOP. EHR results will be sent to the CC via secure data 
transfer and formatted for data analyses.  
 
8.3 Data Safety Monitoring Board 
The DSMB, appointed by the NHGRI, will be responsible for providing recommendations regarding the 
conduct of the study and guidance to ensure the safety and well-being of participants. The DSMB will 
meet semi-annually. A DSMB Charter will be developed detailing the procedures to be followed. A Data 
and Safety Monitoring Plan and a separate DSMB statistical analysis plan (SAP) will be developed in 
collaboration with the IGNITE PTN, IGNITE PTN CC, and NHGRI, and enacted by the DSMB. 
 
8.4 Early Termination and Participant Discontinuation 
Early termination considerations will generally apply only to emerging issues of major concern, or 
problems with trial conduct that suggest the trial could not be completed successfully with a reliable 
conclusion in a feasible time frame. 
 
The site investigator, sponsor or institution may stop involvement of any participant in this research 

Page 50 of 72 
 
study at any time without their consent. This may be because the research study is being stopped, the 
instructions of the study team have not been followed, the investigator believes it is in the participant’s 
best interest, or for any other reason. If specimens or data have been stored as part of the research 
study, they too may be destroyed without participant consent. 

Page 51 of 72 
 
 
9. 
MEDICARE AND MEDICAID CLAIMS DATA COLLECTION AND ANALYSIS 
 
9.1 
Rationale 
The economic analyses will be conducted from the perspective of the payer with the primary goal to 
provide cost-effectiveness data that can inform reimbursement decisions for genotyping. Reporting 
metrics will include: 
1. Average costs for each study arm, considering overall cost to the payer and select services 
directly relevant to the acute pain, chronic pain, and depression groups 
2. Differences in cost utility between the intervention arm, considering overall cost to the payer and 
select services directly relevant to the acute pain, chronic pain, and depression groups 
3. Incremental cost-effectiveness ratio (ICER), i.e., the incremental change in cost per unit 
improvement of effectiveness. 
All metrics will be ascertained over a 6-month follow-up period with the assumption that beneficial 
effects of genotype-guided therapy are fully realized within this time period and that the control arm 
participants have not yet developed any cross-over effects from the 6-month delayed testing. 
 
In a population of mixed payer types, collecting actual costs for all participants is not feasible. 
Therefore, costs will be obtained from Medicare and Medicaid claims data and imputed or cross-walked 
to the other payer types. Based on data in the National Inpatient Sample, 53% and 4% of knee and 
59% and 4% of hip arthroplasties were reimbursed by Medicare and Medicaid, respectively. For chronic 
pain participants, data from the University of Florida suggest 40% and 20% are covered by Medicare 
and Medicaid, respectively. Thus, considering enrollment gaps, at least 60% of the study population is 
anticipated to have claims data, from which comprehensive cost analyses can be performed and 
extrapolated to the entire cohort. Major cost drivers associated with pain and depression will be 
ascertained from the participant using validated resource questionnaires, and verified through 
secondary claims data whenever possible. 
 
9.2 Data Collection 
Data for this specialized analysis will come from these sources: 
1. Participant report of healthcare utilization (e.g. emergency department, urgent care, office) for 
all participants, these will focus on high-cost items and/or items that are expected to be 
sensitive to the intervention 
2. Medicare claims data for Medicare enrollees 
3. Medicaid claims data for Medicaid enrollees 
 
Participant reported visits: Participant reported assessment for health care utilization is previously 
described in section 7.3. 
Medicare claims data: For Medicare enrollees in fee-for-service (FFS) plans or Medicare Advantage, 
clinical groups will ascertain Medicare claims data (Part A-D) directly from the Centers for Medicare and 
Medicaid Services (CMS). 
Medicaid claims data: For Medicaid enrollees, clinical groups will ascertain claims data from their 
states’ Medicaid agencies directly. 
 
To ensure full adjudication, requests to Medicare/Medicaid for claims data will be timed to occur 
between 6-12 months after the end of the 6-months follow-up of the last enrolled patient. Claims data 
will also be requested for one year before trial enrollment up to 6 months thereafter. 

Page 52 of 72 
 
The procedure for obtaining claims data will require a database linkage step – mapping the participant 
study ID to the Medicare/Medicaid identifiers. The data linkage will rely on social security number (SSN) 
or Medicare ID and date of birth (DoB), which can be collected in two possible ways: 
1. Both SSN and/or Medicare ID and DoB are collected as part of the trial by the recruiting site 
2. One or both variables are extracted from the medical record of the participating health center by 
a healthcare data security officer or the local equivalent, on behalf of the study team 
 
For 2020-2024 Medicare data, we will have three groups:(1) Clinical Trial Participants: To achieve our 
goals to understand the effects of a genotype-guided approach, we will have all Medicare beneficiaries 
who participated in the ADOPT PGx clinical trial and enrolled in the trial. (2) Controls- a standardized 
national cohort based on the 5% sample of beneficiaries who did not participate the clinical trial but had 
similar characteristics with beneficiaries who participate the clinical trial (received opioids or 
antidepressants). We will further require beneficiaries to have at least 2 months of Part D and at least 2 
months of FFS in the year that they received the opioid or antidepressant. (3) Controls – a cohort of 
beneficiaries from Florida, New York, North Carolina, Tennessee, South Dakota, and Indiana (the states 
in which the clinical sites are located), pulled from the 100% sample, in which the beneficiaries did not 
participate the clinical trial but have similar characteristics with beneficiaries who participate the clinical 
trial received opioids or antidepressants). We will further require beneficiaries to have at least 2 months 
of Part D and at least 2 months of FFS in the year that they received the opioid or antidepressant. The 
clinical trial participants will be used to evaluate the effects of immediate vs delayed pharmacogenetic 
testing and genotype-guided pain or depression therapy on health care utilization, healthcare costs, and 
cost-effectiveness. We will further compare the Medicare beneficiaries among the trial enrollees to large 
random sample of beneficiaries who take pain medications to compare demographics and clinical 
characteristics to explore representativeness of the trial sample, making inferences about generalizability 
of the results. 
 
For 2020-2024 Medicaid data, we will have two groups: (1) Clinical Trial Participants: we will have all 
Medicaid beneficiaries who participated in the ADOPT PGx clinical trial and enrolled in the trial. (2) 
Controls- a cohort of beneficiaries from Florida, New York, North Carolina, Tennessee, South Dakota, 
and Indiana (the states in which the clinical sites are located), in which the beneficiaries did not 
participate the clinical trial but have similar characteristics with beneficiaries who participate the clinical 
trial received opioids or antidepressants). We will further require beneficiaries to have at least 2 months 
of FFS in the year that they received the opioid or antidepressant. 
 
For the Controls for Medicare and Medicaid beneficiaries, waiver of consent forms and HIPPA waiver of 
authorization will be obtained as the analyses of health care utilization and costs are retrospective in 
nature. It will be impracticable to obtain authorization from this population sample as patient contact 
information is unavailable.  
 
Costs imputation 
The Medicare/Medicaid (M/M) claims will be used to impute healthcare utilization and costs for 
participants who are enrolled in other plans or not insured as follows. First, the subset of the study 
participants with both the participant reported set of medical encounters and M/M claims data will be 
identified. In this subgroup, claims data and self-report data will be used to derive extrapolation factors 
for total healthcare utilization and cost across all study participants. Additionally, for participants in other 
plans or uninsured, we will use M/M data to assign average cost to each of the self-reported items. 
 
 
10. 
STATISTICAL ANALYSIS PLAN AND SAMPLE SIZE 
 
10.1 Sample Size Determination 

Page 53 of 72 
 
All trials power analyses are based on a modified intent to treat analysis, comparing the subset of 
intervention participants with have an actionable phenotype to the subset of control participants with an 
actionable phenotype. Effect sizes used to estimate power are based on prior studies of pain and 
depression pharmacogenetic testing and described below for each trial and shown in Table 8. Several 
steps were taken to generate a conservative sample size estimate. First, the power requirement was 
set to 90%. Second, sample sizes are adjusted for a 10% drop-out (for which UF has data from several 
studies that this is a good estimate). Third, slightly smaller effect sizes than what was observed in prior 
studies was used. Finally, sample size calculations are based on an alpha of 0.049, to allow one interim 
analysis with an alpha of 0.001 in each study. 
Due to the study design and the delay in the control arm to obtaining the genotyping results required 
determine the actionable phenotype subgroup assignment, it is not feasible to directly monitor the 
number of randomized participants in the actionable subgroup for the enrollment stopping rule. 
Alternatively, the observed trial specific actionable phenotype percentages and the corresponding trial 
specific total enrollment targets will be used to identify when enrollment can conclude for a fully 
powered mITT study.  
 
Acute Pain 
In the University of Florida’s pilot acute pain study, the difference between study arms in SIA score was 
–38.55 with a SD of 93.5, for a standardized effect size of 0.412. Assuming a reduced standardized 
effect size of 0.375, 304 participants with an actionable phenotype per group, 152 from the intervention 
arm and 152 from control arm, are required to achieve 90% power for a two-sided two-sample t-test. 
Preliminary data from the University of Florida’s acute pain study indicates the proportion of participants 
with an actionable phenotype, genotypic or pheno-converted CYP2D6 IM or PM, will be approximately 
18%. After adjusting for the subset anticipated to have an actionable phenotype, 845 participants 
completing all assessments, per group, are required to achieve 90% power in the sub-group analysis 
(1678 total). Assuming 10% drop out or lost to follow-up and 7% of participants not going on to surgery, 
a total of 2020 randomized participants is required to sufficiently power this study. Factoring in 
variability in the proportion that are IMs or PMs (15% to 24%), 1516 to 2424 randomized subjects  would 
be need to achieve 90% power in the mITT analysis. 
 
Chronic Pain: In the University of Florida’s prior chronic pain study, the difference between study arms 
in composite pain score was 0.6 with a SD of 1.4, for a standardized effect size of 0.43. The same 
effect size was observed when assessing 3-month changes in pain scores. Assuming a standardized 
effect size of 0.40, 268 participants within the specified subgroup, 134 from the intervention arm and 
134 from control arm, are required to achieve 90% power for a two-sided two-sample t-test. Preliminary 
data indicate the proportion of participants with an actionable phenotype will be 30-35%; 10-15% of 
participants with an actionable genotype-based phenotype (CYP2D6 IM or PM) and an additional 20% 
with a pheno-converted PM/IM based on drug-drug-gene interactions. After adjusting for the subset 
anticipated to have an actionable phenotype, 447 participants completing all assessments, per group, 
are required to achieve 90% power in the sub-group analysis (894 total). Assuming 10% drop out or 
lost to follow-up, a total of 994 randomized participants is required to sufficiently power this study. 
Factoring in variability of the proportion of randomized population that are IMs or PMs (24-33%), 906 
to 1244  randomized subjects would be need to achieve 90% power in the mITT analysis. 
 
Depression: 
In prior studies of depression, the difference between study arms in PROMIS 8a T-scores was –6.7 
with a SD of 10, for a standardized effect size of -.67. For the purposes of power analysis, a 4-point 
change is considered the minimally important difference representing a response to therapy that is 
congruent with the predicted CYP enzyme phenotype compared to the response to therapy which 

Page 54 of 72 
 
conflicts with the phenotype. 
Preliminary data from published studies indicate the proportion of participants with an actionable 
phenotype (CYP2C19 PM, RM, UM or CYP2D6 PM or UM, or pheno-converted CYP2D6 PM or UM) 
will be 40%. However, due to the distribution of study-related antidepressants in primary care and 
behavioral health settings, an estimated 67% of the participants with an actionable phenotype are 
anticipated to also have a study-related dosing or drug selection intervention. In other words, the 
analytic group of CYP2DC UM, PM, or CYP2C19 UM, RM, or PM phenotypes will represent a mixture 
of participants that may have a clinically meaningful change in depression due to being prescribed a 
study-relevant antidepressant and participants that may have changes in depression typical of the 
standard of care arm since they are not being prescribed a study-relevant antidepressant. In accounting 
for this population mixture, we incorporated a dilution factor of 67% into the clinically meaningful effect 
size projection and assume the effective difference of 0.28, representing a 2.8-point change to the T- 
score. We will need 542 modified intent to treat participants, 271 in each arm, to detect a standardized 
effect size of 0.28 with 90% power. After adjusting for the subset anticipated to have an actionable 
phenotype (i.e. 40%), 678 participants completing all assessments, per group, are required to achieve 
90% power in the mITT analysis (1356 total). After accounting for 90% retention, 754 participants from 
the intervention arm and 754 participants from control arm (1508 total) are required to achieve 90% 
power for a two-sided two-sample t-test. Factoring in variability for the on the mITT proportion of the 
randomized population (40-60%), 1006-1508 randomized subjects would be needed to achieve 90% 
power in the mITT analysis. 
 
 
Table 9. Sample size calculations 
Sample size calculations for each trial, assuming an alpha of 0.049 to allow for one interim analysis 
Study 
Assumed 
Actionable 
Phenotype 
Total N 
Completed 
N (90% 
assumed) 
Intervent 
ion 
Usual 
Care 
Interventi 
on: 
Actionabl 
e 
Phenotyp 
e 
Usual 
Care: 
Actionabl 
e 
Phenotyp 
e 
Effect 
Size 
Power 
Acute Pain 
(CYP2D6 
IM/PM) 
18% 
(15%-24%) 
2,020 
(2424- 
1516) 
1,690* 
(2028 
- 
1268) 
 
845 
(1014 
- 634) 
845 
(1014 - 
634) 
152 
152 
0.375 
90.00% 
Chronic Pain 
(CYP2D6 
30%  
(24% - 33%) 
994 
(906 -
1244) 
894 
(814-
1118) 
447 
(407-
559) 
447 
(407-
559) 
134 
134 
0.4 
90.00% 
 
IM/PM) 
Depression 
(CYP2D6 or 
CYP2C19 
PM/UM) 
40% 
(up to 60%) 
1,508 
(1006) 
1,356  
(904) 
678 
(452) 
678 
(452) 
271 
271 
0.28 
90.00% 
Total 
4,522 
3,940 
1,970 
1,970 
557 
557 
*Accounts for an additional 7% of participants not completing surgery 
 
 
10.2 General Statistical Methods 
A detailed statistical analysis plan will be developed for each trial (acute pain, chronic pain, and 

Page 55 of 72 
 
depression) and contained in a separate document. Prior to analysis, each trial study population details, 
including the number randomized, in each treatment arm, and lost to follow-up will be described. 
Baseline participant characteristics will be summarized as means, standard deviations, medians, and 
25th, 75th percentiles for continuous variables, and as counts and percentages for categorical variables. 
Model assumptions will be examined prior to analysis and transformations implemented, if necessary, 
to more adequately meet the assumptions. Unless otherwise stated, hypotheses will be tested as two- 
sided with a significance level of 0.05. 
 
 
10.3 Population for Analyses 
Acute pain 
Participants randomized who have an actionable phenotype, specifically participants who are 
genotypically or pheno-converted CYP2D6 IM or PMs (i.e. CYP2D6 activity score ≤ 0.75). 
 
Chronic pain 
Participants randomized who have an actionable phenotype, specifically participants who are 
genotypically or pheno-converted CYP2D6 IM or PMs (i.e. CYP2D6 activity score ≤ 0.75). 
 
Depression 
Participants randomized who have an actionable phenotype, specifically participants who are 
genotypically or pheno-converted CYP2D6 PM or UMs or CYP2C19 PM, RM, or UMs. 
 
 
10.4 Analysis of the Primary Endpoint 
Acute Pain 
To determine the effect of genotype-guided drug therapy on pain control in acute pain participants, we 
will conduct a subset analysis comparing SIA scores at 10-days post-surgery in the Intervention group 
subset with CYP2D6 IM or PM phenotypes to the Control group subset with CYP2D6 IM or PM 
phenotypes. Participants that have other CYP2D6 phenotypes will not be included. The 10-day post- 
surgery SIA scores of the Intervention CYP2D6 IM/PM group will be compared to the 10-day post- 
surgery SIA scores of the Control CYP2D6 IM/PM group using a two-sided two-sample t-test or Mann 
Whitney test, as appropriate, with a type 1 error of 0.049. This primary analysis will be conducted as a 
modified intent-to-treat analysis, with participants analyzed and endpoints attributed according to the 
treatment arm to which the participants were randomized, regardless of subsequent crossover or post- 
randomization medical care. 
 
Chronic Pain 
To determine the effect of genotype-guided drug therapy on pain control in chronic pain participants, we 
will conduct a subset analysis comparing change in pain intensity score from baseline to 3-month 
follow-up in the Intervention group subset with CYP2D6 IM or PM phenotypes to the Control group 
subset with CYP2D6 IM or PM phenotypes. Participants that have other CYP2D6 phenotypes will not 
be included. The baseline to 3-month change in pain intensity of the Intervention CYP2D6 IM/PM group 
will be compared to the baseline to 3-month change in pain intensity of the Control CYP2D6 IM/PM 
group using a two-sided two-sample t-test or Mann Whitney test, as appropriate, with a type 1 error of 
0.049. This primary analysis will be conducted according to modified intent-to-treat design, with 
participants analyzed and endpoints attributed according to the treatment arm to which the participants 
were randomized, regardless of subsequent crossover or post-randomization medical care. 
 
Depression 
To determine the effect of genotype-guided drug therapy on depression symptoms in depression 

Page 56 of 72 
 
participants, we will conduct a subset analysis comparing change in depression T-scores from baseline 
to 3-month follow-up in the Intervention group subset with either CYP2D6 PM or UM or CYP2C19 PM, 
RM or UM phenotypes to the Control group subset with CYP2D6 PM or UM or CYP2C19 PM, RM, or 
UM phenotypes. Participants that have other CYP2D6 or CYP2C19 phenotypes will not be included. 
Pediatric depression T-scores will be transformed to the adult scale using a published crosswalk for a 
combined analysis. The baseline to 3-month change in depression T-scores of the Intervention 
CYP2D6 PM/UM or CYP2C19 PM/RM/UM group will be compared to the baseline to 3-month change 
in depression T-scores of the Control CYP2D6 PM/UM or CYP2C19 PM/RM/UM subgroup using a two- 
sided two-sample t-test with a type 1 error of 0.049. This primary analysis will be conducted according 
to a modified intent-to-treat design, with participants analyzed and endpoints attributed according to the 
treatment arm to which the participants were randomized, regardless of subsequent crossover or post- 
randomization medical care. 
 
10.5 Analysis of the Secondary Endpoints 
All Trials 
To determine the effect of genotype-guided drug therapy on overall well-being and the well-being sub- 
domains (pain interference, physical function, sleep disturbance, social role and activities functioning, 
fatigue, anxiety, and depression) in acute pain, chronic pain, and depression participants, we will 
conduct an intent to treat analysis, comparing the well-being (or sub-domain) T-scores from the 6- 
month follow-up assessments in the Intervention group compared to the control group using a two- 
sided two-sample t-test or Mann Whitney test, as appropriate, stratified by participant population (acute 
pain, chronic pain, depression), with a type 1 error of 0.05. 
 
Acute Pain 
The effect of genotype-guided opioid therapy on secondary endpoints pain intensity, opioid usage, 
opioid misuse score, and mobility score will be assessed by comparing the Intervention group subset 
with CYP2D6 IM or PM phenotypes to the Control group subset with CYP2D6 IM or PM phenotypes 
using a two-sided two-sample t-test or Mann Whitney test, as appropriate, with a type 1 error of 0.05. 
The effect of genotype guided opioid therapy on the secondary endpoint opioid persistence will be 
assessed by comparing the Intervention group subset with CYP2D6 IM or PM phenotypes the Control 
group subset with CYP2D6 IM or PM phenotypes using a test of two-proportions with an alpha of 0.05. 
Participants with other CYP2D6 phenotypes will not be included in these analyses. 
 
Chronic Pain 
The effect of genotype-guided opioid therapy on secondary endpoints pain intensity reduction and 
opioid misuse score will be assessed by comparing the Intervention group subset with CYP2D6 IM or 
PM phenotypes to the Control group subset with CYP2D6 IM or PM phenotypes using a two-sided two- 
sample t-test or Mann Whitney test, as appropriate, with a type 1 error of 0.05. The effect of genotype 
guided opioid therapy on the secondary endpoint clinically significant pain reduction, defined as a 30% 
decrease, will be assessed by comparing the Intervention group subset with CYP2D6 IM or PM 
phenotypes the Control group subset with CYP2D6 IM or PM phenotypes using a test of two- 
proportions with an alpha of 0.05. Participants that have other CYP2D6 phenotypes will not be included 
in these analyses. 
 
Depression 
The effect of genotype guided antidepressants therapy on the secondary endpoint depression 
remission and achieving 5-% reduction in PHQ-8 scores will be assessed by comparing the 
Intervention group subset with CYP2D6 UM or PM or CYP2C19 UM, RM, or PM phenotypes the 

Page 57 of 72 
 
Control group subset with CYP2D6 UM or PM or CYP2C19 UM, RM, or PM phenotypes using a test of 
two-proportions with an alpha of 0.05. The effect of genotype guided antidepressants therapy on the 
secondary endpoints, medication adherence, PHQ-8 scores, and medication side effect severity 
burden, will be assessed by comparing the Intervention group subset with CYP2D6 UM or PM or 
CYP2C19 UM, RM, or PM phenotypes the Control group subset with CYP2D6 UM or PM or CYP2C19 
UM, RM, or PM phenotypes using a two-sided Mann Whitney test with an alpha of 0.05. Participants 
that do not have metabolizer phenotypes will not be included in these analyses. 
 
10.6 Other Planned Analyses 
 
Exploratory endpoints or comparisons of endpoints that will be considered: 
• 
Medication side effects  
• 
Comparisons of measures of depression and/or pain 
• 
Provider actions taken after CDS alerts 
Sub-groups that will be considered: 
● All randomized participants 
● Metabolizer phenotypes: UMs, RMs, NMs, IMs, and PMs. 
● CYP2D6 or CYP2C19 activity scores 
● Pediatric participants 
● Adult participants 
● “Per-protocol” - participants with both an actionable phenotype and concordance between the 
recommended medication/dosage and the prescribed medication and/or dosage 
● Participants with an actionable phenotype, a discordant medication at baseline, and a 
concordant medication at the end of the study 
● Stratified by medication, medication class and/or medications combinations 
● Stratified by demographic characteristics (e.g. age, sex, gender and/or race) 
● Stratified by type and/or design of CDS implemented 
● Stratified by institution, enrolling site, and/or practice setting specialty (e.g. psychiatry, primary 
care, etc.) 
● And other relative combinations of the above sub-groups 
 
In addition to the primary research exploratory analyses, we will also analyze the uptake and utilization 
of the clinical decision support (CDS) tools that were created and its role in any medication changes 
made by providers. We will examine the impact of the CDS tools on various primary and secondary 
outcomes. We may also describe the development of the CDS tools, with a specific focus on the 
automated phenoconversion calculations implemented by some sites. As part of these analyses, we may 
collect and/or include the following data points: socio-demographics, health care characteristics (i.e. 
comorbidities), site ID, clinical group ID, CDS related data points (i.e. alert ID, CDS name, CDS alert 
type, date triggered, provider action), prescriber specialty, medication details (i.e. triggering medications, 
medication or dose changes, medication concordance/discordance), genotype and phenoconversion 
results.  
 
We will also analyze reach, adoption, and implementation of the trial and PGx testing. We will examine 
enrollment and screening information, missing data rates, visit completion information. We will also 
analyze patient preferences for contact and survey administration, in addition to survey completion 
information 
 
 
Specified analyses: 
All Trials 

Page 58 of 72 
 
Medication side effects. The frequency and severity of medication side effects within each trial and trial 
arm will be summarized using standard descriptive statistics for discrete data (counts and 
percentages). 
 
Acute Pain 
Trends in endpoints. In addition to the primary and secondary endpoints described above, we will 
compare the time trends in the endpoints: pain scores, opioid usage, opioid misuse score, and mobility 
score at baseline, 1, 3, and 6 months among the CYP2D6 IM or PM subgroup, using a repeated- 
measures mixed effect model or generalized repeated-measures mixed effect model, as appropriate. 
Since participants are randomized to Intervention and Control groups and not to the CYP2D6 IM or PM 
subgroup within Intervention and Control groups, there could be important differences in baseline 
characteristics between the two groups. For these reasons, we will conduct covariate-adjusted 
repeated measures mixed models that will account for differences in baseline characteristics that differ 
between the Intervention – CYP2D6 IM or PM subgroup and the Control – CYP2D6 IM or PM 
subgroup. Potential baseline characteristics may include age, sex, income, education, insurance, 
surgical procedure type. We will select the appropriate covariance matrix (e.g. compound symmetry, 
autoregressive, unstructured, or other covariance structure) based on the data. 
 
Difference within the NM group. In the control arm participants, we will compare pain scores in 
participants with a CYP2D6 activity score >0.75 – 1 to participants with an activity scores >1-2 using a 
two-sided two-sample t-test or Mann Whitney test, as appropriate, with a type 1 error of 0.05. 
Additionally, we will use linear regression to adjust for differences in baseline characteristics. 
 
Chronic Pain 
Trends in endpoints. In addition to the primary and secondary endpoints described above, we will 
compare the time trends in the endpoints: pain control, pain reduction, clinically significant pain 
reduction, and opioid misuse score at baseline, 1, 3, and 6 months among the CYP2D6 IM or PM 
subgroup, using a repeated-measures mixed effect model or generalized repeated-measures mixed 
effect model, as appropriate. Since participants are randomized to Intervention and Control groups and 
not to the CYP2D6 IM or PM subgroup within Intervention and Control groups, there could be important 
differences in baseline characteristics between the two groups. For these reasons, we will conduct 
covariate-adjusted repeated measures mixed models that will account for differences in baseline 
characteristics that differ between the Intervention – CYP2D6 IM or PM subgroup and the Control – 
CYP2D6 IM or PM subgroup. Potential baseline characteristics may include age, sex, income, 
education, insurance, and medical conditions. We will select the appropriate covariance matrix (e.g. 
compound symmetry, autoregressive, unstructured, or other covariance structure) based on the data. 
 
Difference within the NM group. In the control arm participants, we will compare pain scores and pain 
control in participants with a CYP2D6 activity score >0.75 – 1 to participants with an activity scores >1- 
2 using a two-sided two-sample t-test or Mann Whitney test, as appropriate, with a type 1 error of 0.05. 
Additionally, we will use linear regression to adjust for differences in baseline characteristics. 
 
Depression 
Trends in endpoints. In addition to the primary and secondary endpoints described above, we will 
compare the time trends in the endpoint depression symptom scores at baseline, 1, 3, and 6 months 
among the CYP2D6 PM or UM or CYP2C19 UM, RM or PM subgroup, using a repeated-measures 
mixed effect model. Since participants are randomized to Intervention and Control groups and not to 
the CYP2D6 PM or UM or CYP2C19 UM, RM or PM subgroup within Intervention and Control groups, 
there could be important differences in baseline characteristics between the two groups. For these 

Page 59 of 72 
 
reasons, we will conduct covariate-adjusted repeated measures mixed models that will account for 
differences in baseline characteristics that differ between the Intervention – CYP2D6 PM or UM or 
CYP2C19 UM, RM or PM subgroup and the Control – CYP2D6 PM or UM or CYP2C19 UM, RM or PM 
subgroup. Potential baseline characteristics may include age, sex, income, education, insurance, 
medical conditions. We will select the appropriate covariance matrix (e.g. compound symmetry, 
autoregressive, unstructured, or other covariance structure) based on the data. 
 
Difference within the NM group. In the control arm participants, we will compare depression scores and 
depression control in participants with a CYP2D6 activity score >0.75 – 1 to participants with an activity 
scores >1-2 using a two-sided two-sample t-test or Mann Whitney test, as appropriate, with a type 1 
error of 0.05. Additionally, we will use linear regression to adjust for differences in baseline 
characteristics 
Cost Effectiveness 
Healthcare costs: In the Medicare fee-for-service or Medicaid enrollees, log-transformed overall 
expenditures (between index visit and 6 months follow-up) will be compared using a 2-sample t-test 
between the study arms (after ensuring that the variances in the log-scale are equal). Alternatively, cost 
comparisons will be made using appropriate regression models such as generalized linear models. For 
all participants, regardless of insurance type, we will estimate and aggregate participant-reported 
healthcare utilization during follow-up and assign cost for each item based on unit weighted mean cost 
estimates from the Medicare/ Medicaid data. 
 
Within the Medicare/Medicaid population, we will compare estimated cost differences between 
genotype-guided and usual care based on billing records versus participant report to further validate the 
cost comparisons for the entire population. Cost for the index hospitalization for surgery participants will 
not be included in the cost estimate, but we will compare length of stay between groups as reference 
for hospitals regarding potential cost savings in capitation-based reimbursement schemes. All costs will 
be converted to 2021 $US using the chain-weighted Consumer Price Index (CPI). 
 
Finally, we will compare the Medicare/Medicaid beneficiaries among our trial enrollees to a larger 
random sample of beneficiaries in the participating states and compare demographic and key clinical 
characteristics to explore representativeness of our study sample, evaluate the impact of attrition and 
loss to follow-up and make inferences about the generalizability of our results. 
 
Cost utility: For the cost-utility analysis, the PROMIS-43 responses will be converted into utilities using 
previously validated crosswalks.[41] Cost and quality adjusted life year (QALY) estimates, adjusted for 
clustering within site and baseline utility for QALYs, will be obtained using appropriate regression 
models such as generalized linear models. The analysis of maximum likelihood parameter estimates 
will allow us to capture differences in cost and QALYs between the intervention arm and control arm of 
the trial. The Incremental cost-effectiveness ratio (ICER) will be calculated from costs and QALY. A 
bootstrapping approach will be used to characterize sampling uncertainty and calculate confidence 
intervals (CI) around the ICER estimate (2.5thand 97.5thpercentiles corresponding to the lower and 
upper bounds of the CI, respectively). This sampling uncertainty will be summarized using cost- 
effectiveness acceptability curves. 
 
Details of these statistical analyses, along with other exploratory analyses will be described in the study 
SAP. 
 
10.7 Interim Analyses 
A single specified interim analysis is planned for each trial. To account for repeated significance testing 
of the accumulating data, the group sequential method of Lan and DeMets will be used as a guide for 

Page 60 of 72 
 
interpreting this interim analysis. Monitoring boundaries for the primary endpoint will be based on a 
two-sided symmetric O’Brien-Fleming type spending function with an overall two-sided significance 
level of α=0.05. The O’Brien-Fleming approach requires large critical values early in the study but 
relaxes (i.e., decreases) the critical value as the trial progresses. 
 
Acute Pain 
The interim analysis of the acute pain primary endpoint will compare SIA scores at 10 days post- 
surgery among participants with CYP2D6 IM or PM phenotypes in the Control arm to participants with 
CYP2D6 IM or PM phenotypes in the intervention arm. 
 
Chronic Pain 
The interim analysis of the chronic pain primary endpoint, pain control at 3 months post return of PGx 
testing result to providers, will be compared between the participants with CYP2D6 IM or PM 
phenotypes in the Control arm and the participants with CYP2D6 IM or PM phenotypes in the 
intervention arm. 
 
Depression 
The interim analysis of the depression primary endpoint, depression control at 3 months post return of 
PGx testing result to providers, will compare the participants with CYP2D6 PM/UM or CYP2C19 PM, 
RM and UM phenotypes in the Control arm to the participants with CYP2D6 PM/UM or CYP2C19 
PM/RM/UM phenotypes in the intervention arm. 
 
The primary analysis is a modified intent to treat design and the analytical subgroup is defined by the 
results of the PGx testing. Because the drug metabolizer phenotypes for participants in the Control arm 
is determined around the time of the 6-month follow up assessments for all trials (Acute Pain, Chronic 
Pain, and Depression), only participants that have completed their 6-month assessments will be 
included in the interim analysis. To account for the delays in receiving genetic testing results, the 
interim analysis will be targeted to occur when approximately 50% of the participants have completed 
their 6-month assessments. If the interim analysis does not propose stopping for efficacy (p-value 
<0.0003 and the intervention has the larger reduction in the primary endpoints), then the conditional 
power to detect a significant result at the end of the trial will be estimated. The conditional power will be 
presented to the DSMB to facilitate discussion of whether the trial should be stopped for futility. 
 
10.8 Handling of Missing Data 
For all primary and secondary statistical analyses described above, multiple imputation will be used for 
all missing values except those due to participant death. To ensure that the missing at random 
assumption for multiple imputation is valid, we will compare baseline pain or depression scores and 
other patient characteristics in those lost to follow up to participants retained on their randomization 
assignment. We will also do sensitivity analyses where we compare results obtained with multiple 
imputation to those obtained without imputation. Missing values due to death will not be imputed and 
will therefore not be included in the analyses. For exploratory repeated measures analyses, missing 
data are easily handled as long as the missing at random assumption is valid. However, the missing at 
random assumption cannot be tested. Accordingly, for exploratory analyses using repeated measures 
mixed models, we will also conduct a sensitivity analysis where missing values are imputed using 
multiple imputation. The results with and without multiple imputation will be compared. More complete 
details of the handling of missing values under different circumstances will be described in the SAP. 
 
10.9 Multiplicity 
With the primary and various secondary endpoints that have been outlined, there is a multiplicity of 
analyses to be performed, which leads to an increased probability that at least one of the comparisons 
could be "significant" by chance. Adjusting for the effects of the repeated significance testing for the 

Page 61 of 72 
 
multiplicity of secondary endpoints would require that very small significance levels be used for every 
comparison. Therefore, rather than adjusting for multiple comparisons, we will be conservative in the 
interpretation of the analyses, considering the degree of significance, and looking for consistency 
across endpoints. The nominal (unadjusted) p-value for each comparison will be reported to aid in the 
overall interpretation. We have also prespecified the primary and secondary outcome variables to avoid 
over-interpretation of strictly exploratory comparisons. 

Page 62 of 72 
 
 
11. 
DATA MANAGEMENT 
 
11.1 Data Entry and Record Keeping 
ADOPT PGx data sources include: data collected from participant surveys, genetic testing results, data 
from the EHR, and CMS billing records. Data will be entered into a REDCap database maintained by 
the CC by trained and qualified personnel at each clinical site for baseline and follow-up assessments 
and by the UF call center for follow-up assessments. Site staff will receive training on the use of the 
REDCap database. After staff are trained, they will receive a unique user identification and password 
to access data entry forms for their site. Access codes should not be shared and are non-transferable. 
 
Laboratories will transfer genetic testing results to the IGNITE PTN CC and follow standard site-specific 
return of results procedures for providers. The genotype and result (i.e. metabolizer phenotype) for 
each participant will then be  imported to the participant’s study database record from laboratory 
produced output files. The accuracy of the import of laboratory results will be verified by comparing the 
results recorded in the study database to an external record of the result for a subset of the study 
participants. See MOP for details. 
 
Sites will extract the relevant data from their EHR (see Section 7.7) and transfer of those data to the 
IGNITE PTN CC following procedures that will be specified in the MOP. Briefly, sites will be given a list 
of trial-specific information to extract for their ADOPT PGx participants, a common format that data 
should be converted to, and procedures for secure file transfer to the CC. 
 
11.2 Data Element Definitions 
Clinically significant pain reduction: Whether or not the pain reduction score is ≤ 0.7. If the pain 
reduction score is ≤0.7, clinically significant pain reduction is achieved, if pain reduction scores is > 0.7, 
clinically significant pain reduction is not achieved. 
 
Depression symptom control: The change in the PROMIS Emotional Distress - Depression 8b or 
PROIMIS pediatric Depression 8a survey depression score from baseline to time t. 
 
Depression remission: A. Whether or not the summed raw PROMIS emotional distress depression 
8b survey responses are <= 16, which is equivalent to the participant responding “rarely” or “never” 
to most or all of the PROMIS emotional distress - depression 8b survey questions. B. Whether or not 
the PHQ-8 scores are ≤ 4, which is equivalent to depression severity being none-mild.  
 
 
 Depression (PHQ-8) score: The sum of the responses to the PHQ-8 survey, range from 0 to 24. 
 
Depression (T) score: The T-score converted summed responses to the PROMIS emotional distress 
depression 8b survey. The T-score conversion is centered around 50 with standard deviation of 10. 
 
 
Depression severity: The depression score converted to depression severity (none, mild, moderate, 
severe) based on the scoring guide for the PROMIS emotional distress depression 8b survey. 
 
Medication adherence: The scored responses to the Voils Medication Adherence survey. 
 
Medication concordance: Whether or not the medication the participant is prescribed after the 
intervention is concordant with the participants CYP2D6 and, for the depression trial, CYP2C19 
phenotype. 

Page 63 of 72 
 
 
Medication side effects severity burden: (Depression only) The sum of the scored severity (none = 0, 
mild = 1, moderate = 2, severe = 3) for common SSRI side effects. 
 
Opioid misuse score: The T-score converted summed responses to the PROMIS prescription 
medication misuse 7a survey. The T-score conversion is centered around 50 with standard deviation 
of 10. 
 
Opioid persistence: Defined as ≥1 opioid prescription refill between 90 days and 180 days after the 
surgical procedure. 
 
Opioid usage: The average daily morphine equivalents in mg (MED) in past 7 days. MEDs will be 
calculated using data from the opioid usage survey. 
 
Overall well-being: Defined as the T-score converted summed responses to the PROMIS 43/PROMIS 
37 pediatrics survey. The T-score conversion is centered around 50 with standard deviation of 10. 
 
Pain control: The difference in pain intensity score at follow-up time t and the baseline pain intensity 
score. 
 
Pain intensity score: The mean of average pain in the last 7 days, current pain, and worst pain in the 
last 7 days. Average pain, current pain, and worst pain will be collected using the 3-question PROMIS 
pain intensity scale. 
 
Pain reduction score: The ratio of the pain intensity score (derived from the PROMIS pain intensity 
survey) at follow-up time t to the baseline pain intensity score. 
 
Silverman integrative analgesic assessment (SIA) score: This is an integrated measure of pain and 
opioid usage, calculated as follows: pain and opioid usage are ranked, the ranks are converted to 
percentiles and linearly transformed such that the scores are centered at 0 and range -100 to 100. The 
pain scores and opioid usage transformed percentiles are summed to generate the SIA score that 
ranges -200 to 200. Negative values indicate low pain with minimal opioid usage, while positive values 
indicate higher pain with higher opioid usage. See Appendix A for additional details and supporting 
rationale. 
 
11.3 Database Management and Quality Control of Data 
The IGNITE PTN CC will develop and manage the ADOPT PGx study database and perform internal 
database quality-control checks. The CC will conduct data audits throughout the course of the trial. 
These audits are intended to identify data errors, protocol deviations, failure of standardization, missing 
data, or inconsistencies. Any out-of-range values and missing or inconsistent key variables are flagged 
and addressed/answered at the site in real time during the data entry process. 
 
The CC will periodically perform additional data quality checks in SAS. Clinical sites may also be given 
regular feedback directly to discuss issues identified by QC assessments. 
 
11.4 Database Lock and Study Close Out 
The end of the study is defined as the completion of the final participant follow-up. The designated 
central clinical research monitor with oversight by the CC will coordinate participating site close-out 
process according to the Clinical Monitoring Plan (See MOP). The CC will follow the database lock 
process in the study Data Management Plan. 

Page 64 of 72 
 
11.5 Data Sharing 
In accordance with the NIH Genomic Data Sharing policy, https://grants.nih.gov/grants/guide/notice- 
files/NOT-HG-19-024.html deidentified genotypes, linked phenotype, and clinical outcome data, 
excluding Medicare or Medicaid claims data, will be deposited in an NIH-designated data repository. 
 
12. 
ETHICAL AND HUMAN SUBJECTS CONSIDERATIONS 
 
12.1 Institutional Review Board/Ethics Committee Review 
This study will be initiated after all required documentation has been reviewed and approved by the 
central IRB according to national and international regulations. All participating sites will be required to 
have central IRB approval prior to activation. The CC will be responsible for the coordination of all IRB 
activities. 
 
12.2 Use and Disclosure of Protected Health Information (HIPAA) 
For clinical trial sites, an authorization for the use and disclosure of protected health information (PHI) 
under the HIPAA Privacy Rule [45 CFR § 164.102 et seq] will be obtained from every trial participant 
prior to, or at the time of, enrollment. HIPAA Authorization may either be a separate form or included in 
the study ICF, dependent upon local requirements. It will be presented to, and signed by, the subject at 
the same time as the Informed Consent Form (ICF). See Section 6.4 Participant Consent Process . 
 
12.3 Confidentiality and Privacy 
Participant confidentiality will be maintained throughout the clinical study in a way that ensures the 
information can always be tracked back to the source data. For this purpose, a unique subject 
identification (ID number) will be used that allows identification of all data reported for each subject. 
Subject information collected in this study and all records will be kept confidential and the subject’s 
name will not be released by study staff at any time. 
 
Clinical data will be entered into a data entry system provided by the CC. The data system includes 
password protection and internal quality checks, such as automatic range checks to identify data that 
appear inconsistent, incomplete, or inaccurate. All data collection and storage devices will be password 
protected with a strong password and all sensitive research information on portable devices will be 
encrypted. Access to identifiable data will be limited to members of the study team. If it is necessary to 
use portable devices for initial collection of identifiers, the data files will be encrypted and the identifiers 
moved to a secure system as soon as possible. The portable device(s) will be locked up in a secure 
location when it is not in use. 
 
12.4 Publication and Data Sharing Policies 
The IGNITE PTN will have a Publications and Presentations Committee (PPC) with the primary 
responsibility for coordinating, monitoring, and reviewing all publications and presentations resulting 
from IGNITE PTN studies. In addition, the PPC will oversee the review, approval, and supervision of 
the secondary analyses and ancillary studies that are conducted within the Network. The goal of the 
PPC is to facilitate dissemination of the maximum amount of information from these studies in a 
scientifically sound and ethically responsible fashion in accordance with the unique nature of the 
IGNITE PTN mission. The IGNITE PTN Coordinating Center will draft a PPC charter in collaboration 
with NHGRI, PPC, and the IGNITE PTN which specifies the publication policies and procedures. The 
primary outcomes from each trial, Acute Pain, Chronic Pain, Depression, will be published as separate 
publications. 
 
The sharing of datasets will be performed per DCRI SOPs and requirements for NIH policy for data 

Page 65 of 72 
 
sharing, and guidelines for NIH Data Set Preparation. The de-identified or anonymized data, 
excluding Medicare and Medicaid claims data, and documentation in standardized formats will be 
made available in an NIH-designated data repository for sharing to the larger scientific community. 
Requested unrestricted data may be made available after database lock to parties who sign a data 
sharing agreement, which stipulates that data must be: 1) used solely for research purposes, 2) 
properly acknowledged in resulting publications, 3) kept confidential and inaccessible to third parties, 
and 4) destroyed or returned after analyses are completed. Additionally, users must agree not to use 
data to identify individual participants. 
 
13. 
PROTOCOL DEVIATIONS AND VIOLATIONS 
A protocol deviation is defined as an event where the Investigator or site personnel did not conduct the 
study according to the protocol or the Investigator Agreement. A protocol violation is an intentional act 
in which the protocol is not followed. (See Protocol Section 8 for IRB reporting timelines) 
 
Protocol deviations and violations will be reported to the IRB if it affects 
● subject rights and welfare 
● affects subject safety 
● affects the integrity of study data 
● affects the subject's willingness to continue in the study 
● is specifically requested by a government agency, internal/external auditor, medical monitor, or 
the IRB. 

Page 66 of 72 
 
 
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Orliaguet, G., et al., A case of respiratory depression in a child with ultrarapid CYP2D6 
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Adams, E.H., et al., A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone 
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Taylor, W.D., Clinical practice. Depression in the elderly. N Engl J Med, 2014. 371(13): p. 
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Noordam, R., et al., Identifying genetic loci associated with antidepressant drug response with 
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Singh, A.B., Improved Antidepressant Remission in Major Depression via a Pharmacokinetic 
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Winner, J.G., et al., A prospective, randomized, double-blind study assessing the clinical impact 
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Page 69 of 72 
 
 
14. 
APPENDICES 
 
14.1 APPENDIX A. SIA SCORE BACKGROUND AND RATIONALE 
For the primary endpoint, we propose to use a composite score that captures both opioid consumption 
(MED) and pain intensity. This is based on preliminary data from a University of Florida (UF) pilot study 
in which CYP2D6 genotype-guided opioid prescribing after arthroplasty surgery was compared to a 
usual care approach (ClinicalTrials.gov Identifier: NCT03534063). While not powered to detect 
differences in clinical endpoints, preliminary results from 174 patients showed similar pain intensity at 2- 
week post-surgery between genotype-guided and usual care groups, but significantly lower MMEs in 
the genotype-guided group. The combination of lower opioid consumption with similar pain intensity 
indicates better pain control in the genotype-guided arm. However, assessing opioid consumption and 
pain intensity as two separate variables fails to characterize the inter-individual differences in opioid use 
as pain intensity changes over time, which is why we believe a composite endpoint that integrates the 
two is justifiable. 
 
The Silverman Integrating approach (SIA) score has been shown to provide superior statistical power 
with appropriate control of type 1 error compared to methods that integrate pain score and post- 
operative opioid consumption.[1, 2] When comparing the SIA score between genotype-guided and 
usual care arms in the UF study described above, the score indicated lesser pain despite fewer opioids 
consumed in the genotype-guided arm compared with greater pain despite more opioids consumed in 
the usual care group (p=0.07). To date, at least 11 clinical trials have used the SIA score in the post- 
operative setting.[3-13] While the majority utilized patient-controlled analgesia pumps, a pain expert at 
UF proposes the SIA score applicability warrants consideration in an acute post-surgical pain 
population. The SIA score is referenced in recommendations by the Initiative on Methods, 
Measurement, and Pain Assessment in Clinical Trials (IMMPACT), which aims to develop consensus 
recommendations for design and execution of clinical trials of pain management [14], as well as in a 
systematic review of predictive experimental pain studies.[15] However, both acknowledge that the SIA 
score is rarely used in pain research and that additional research is needed on its utility. While this 
approach is not part of current consensus recommendations for pain trials, consensus bodies have 
expressed interest in its utility. Importantly, it allows us to jointly assess two important, interlinked 
parameters in the setting of acute post-surgical pain – both opioid use and pain control. While we could 
focus on MMEs as the primary endpoint based on the pilot data described above, we believe that MME 
alone, without knowing the pain control, is difficult to interpret clinically, and thus suboptimal. 
 
References 
1. 
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Dai, F., et al., Integration of pain score and morphine consumption in analgesic clinical studies. 
J Pain, 2013. 14(8): p. 767-77 e8. 
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Ahdieh, H., et al., Efficacy of oxymorphone extended release in postsurgical pain: a randomized 
clinical trial in knee arthroplasty. J Clin Pharmacol, 2004. 44(7): p. 767-76. 
4. 
Gambling, D., et al., A comparison of Depodur, a novel, single-dose extended-release epidural 
morphine, with standard epidural morphine for pain relief after lower abdominal surgery. Anesth Analg, 
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Katz, J., et al., High dose alfentanil pre-empts pain after abdominal hysterectomy. Pain, 1996. 
68(1): p. 109-18. 

Page 70 of 72 
 
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Reinhart, D.J., et al., Postoperative analgesia after peripheral nerve block for podiatric surgery: 
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1996. 83(4): p. 760-5. 
10. 
Reinhart, D.J., et al., Postoperative analgesia after peripheral nerve block for podiatric surgery: 
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Pain Med, 2000. 25(5): p. 506-13. 
11. 
Romundstad, L., et al., Methylprednisolone reduces pain, emesis, and fatigue after breast 
augmentation surgery: a single-dose, randomized, parallel-group study with methylprednisolone 125 
mg, parecoxib 40 mg, and placebo. Anesth Analg, 2006. 102(2): p. 418-25. 
12. 
Therasse, E., et al., Percutaneous biliary drainage: clinical trial of analgesia with interpleural 
block. Radiology, 1997. 205(3): p. 663-8. 
13. 
Wininger, S.J., et al., A randomized, double-blind, placebo-controlled, multicenter, repeat-dose 
study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal 
laparoscopic surgery. Clin Ther, 2010. 32(14): p. 2348-69. 
14. 
Cooper, S.A., et al., Research design considerations for single-dose analgesic clinical trials in 
acute pain: IMMPACT recommendations. Pain, 2016. 157(2): p. 288-301. 
15. 
Werner, M.U., et al., Prediction of postoperative pain: a systematic review of predictive 
experimental pain studies. Anesthesiology, 2010. 112(6): p. 1494-502. 

Page 71 of 72 
 
 
 
14.2 APPENDIX B. TABLE OF MINIMUM REQUIRED VARIANTS 
 
 
Gene 
Allele 
Variant 
dbSNP 
CYP2C19 
*2 
681G>A 
rs4244285 
*3 
636G>A 
rs4986893 
*4 
1A>G 
rs28399504 
*6 
395G>A 
rs72552267 
*8 
358T>C 
rs41291556 
*17 (also *4 haplotype 
[*4B]) 
-806C>T 
rs12248560 
CYP2D6 
*2 
2850C>T 
rs16947 
*2 
4180G>C 
rs1135840 
*3 
2549delA 
rs35742686 
*4 
1846G>A 
rs3892097 
*5 
CYP2D6 deleted 
*6 
1707delT 
rs5030655 
*8 
1758G>T 
rs5030865(A) 
*9 
2615_2617delAAG 
rs5030656 
*10 (also *36 gene 
conversion) 
100C>T 
rs1065852 
*17 
1023C>T 
rs28371706 
*29 (also *70) 
3183G>A 
rs59421388 
*41 
2988G>A 
rs28371725 
1XN 
copy number 
2XN 
copy number 
4XN 
copy number 
9XN 
copy number 
17XN 
copy number 
29XN 
copy number 

Page 72 of 72 
 
 
41XN 
copy number 
 
 
14.3 
APPENDIX C. CYP2D6 INHIBITORS AS DEFINED BY THE FDA GUIDENCE ON DRUG 
INTERACTIONS 
 
 
As of 3/6/20: 
Strong Inhibitors 
bupropion, fluoxetine, paroxetine, 
quinidine, terbinafine 
Moderate Inhibitors 
abiraterone, cinacalcet, duloxetine, 
lorcaserin, mirabegron