LCI-NOS-PAIN-001: A Prospective, Pharmacogenomic-Driven Pilot Study of Pain Management in Oncology Outpatients
Phase: PHASE2
Conditions: Malignant Tumor of Ill-defined Site
Sponsor: Wake Forest University Health Sciences

Protocol Number: LCI-NOS-PAIN-001 
Version 3: July 6, 2016  
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Protocol #:  LCI-NOS-PAIN-001 
TITLE: A PROSPECTIVE, PHARMACOGENOMIC-DRIVEN PILOT STUDY OF PAIN 
MANAGEMENT IN ONCOLOGY OUTPATIENTS  
LAY TITLE: PAIN MANAGEMENT IN ONCOLOGY OUTPATIENTS 
Coordinating Center: 
Levine Cancer Institute 
Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator:  
Jai N. Patel, PharmD 
Levine Cancer Institute 
LCI Cancer Pharmacology Lab 
Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-4113 
Email: Jai.Patel@carolinashealthcare.org  
 
Sub-Investigators: 
Connie Edelen, MD 
Levine Cancer Institute 
Palliative Care Clinic 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-5133 
Email: Connie.Edelen@carolinashealthcare.org 
 
Issam Hamadeh, Pharm D 
Levine Cancer Institute 
LCI Cancer Pharmacology Lab 
Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-4112 
Email: issam.hamadeh@carolinashealthcare.org  
 
 

Protocol Number: LCI-NOS-PAIN-001 
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Rebecca L. Edwards, MSN, RN, AGPCNP-BC, OCN 
Levine Cancer Institute 
Palliative Care Clinic 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-5133 
Email: Rebecca.Edwards@carolinashealthcare.org  
Statistician: 
James Symanowski, PhD 
Levine Cancer Institute 
Department of Biostatistics 
1100 Blythe Boulevard 
Charlotte, NC 28203 
Telephone: (980) 442-2371 
Email: James.Symanowski@carolinashealthcare.org  
 
Investigator-Initiated Research Coordinator: 
Melanie Bamberg, MHA, CCRP 
Levine Cancer Institute 
Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-2366 
Email: Melanie.Bamberg@carolinashealthcare.org 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Sponsor-Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 
 

Protocol Number: LCI-NOS-PAIN-001 
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LIST OF ABBREVIATIONS 
 
ADL 
Activities of Daily Living 
ASCO 
American Society of Clinical Oncology 
BSA 
Body Surface Area 
COMT 
Catechol-O-methyltransferase 
CPIC 
Clinical Pharmacogenetics Implementation Consortium 
CTMS 
Clinical Trials Management System 
eCRF 
Electronic Case Report Form 
EM 
Extensive Metabolizer 
ESAS 
Edmonton Symptom Assessment Scale 
FDA 
Food and Drug Administration 
IM 
Intermediate Metabolizer 
IRB 
Institutional Review Board 
MEDD 
Morphine Equivalent Daily Dose 
NCCN 
National Comprehensive Cancer Network 
OPRM1 
Opioid Receptor-like 1 
PGx 
Pharmacogenomic 
PM 
Poor Metabolizer 
RICE 
Rest, Ice, Compression, Elevation 
UM 
Ultra-rapid Metabolizer 
 
 
 

Protocol Number: LCI-NOS-PAIN-001 
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SCHEMA 
 

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PROTOCOL SUMMARY 
A. Study Title 
A PROSPECTIVE, PHARMACOGENOMIC-DRIVEN PILOT STUDY OF 
PAIN MANAGEMENT IN ONCOLOGY OUTPATIENTS 
B. Indication 
Malignant pain 
C. Clinical Phase Pilot/Single-arm Phase II 
 
D. Summary of 
Rationale 
 
 
About half of all cancer patients seen in oncology clinics have pain at initial 
assessment; pain relief within a one-month period is seen in approximately one 
third of these patients and pain worsening in about one fifth.  Risk factors for 
under-treatment of cancer pain include age older than 65 years, minority status, 
and inadequate pain assessment practices.  There is a need for better methods of 
opioid drug/dose selection and identification of risk factors for worsening pain.  
Pharmacogenomic approaches offer insight into the genetic variables that 
impact the pharmacokinetic and pharmacodynamic behavior of opioids.  
Translating pharmacogenomic results into actionable prescribing decisions will 
ultimately enable a personalized approach to pain management, increasing the 
chance of significant pain improvement. 
E. Objectives 
Primary objective:  
 
To determine the percentage of subjects achieving significant pain improvement 
over a one month period (≥ 2 point decrease from baseline pain score on an 11-
point scale [0-10]) in patients receiving pharmacogenomic testing. 
Secondary objectives: 
To determine the success rate of achieving significant pain improvement at 
Assessment #2 as measured from pain score at Assessment #1 in subjects who 
received a PGx-guided drug/dose modification at Assessment #1.  
 
To determine the success rate of achieving significant pain improvement at the 
Final Assessment as measured from pain score at Assessment #1 in subjects 
who received a PGx-guided drug/dose modification at Assessment #1.   
 
To determine the success rate of achieving significant pain improvement at 
Assessment #1 as measured from baseline pain score in all evaluable subjects. 
 
To determine the success rate of achieving significant pain improvement at 
Assessment #2 as measured from baseline pain score in evaluable subjects who 
complete Assessment #2, per protocol. 
 

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To evaluate the proportion of gene mutations determined in the 
pharmacogenomic panel, “Pain Profile”. 
 
To detect the frequency of “actionable genotypes” and “potentially actionable 
genotypes”.  
 
To correlate morphine equivalent daily doses (MEDD) with pharmacogenomic 
results and pain response. 
 
To describe the rate of observing potential drug-gene interactions not related to 
pain medications. 
 
To determine subjects’ “personalized pain goal” at baseline and measure the 
success rate of achieving his/her “personalized pain goal” at the Final 
Assessment. 
Safety objectives: 
 
To identify rates of opioid-related adverse events including, but not limited to, 
constipation, fatigue, nausea, vomiting, somnolence, dizziness, cognitive 
disturbance, dry mouth, shortness of breath, pruritus, and urticaria.  
To correlate rates of opioid-related adverse events with pain worsening and 
pharmacogenomic results. 
 
Exploratory objective:  
 
To evaluate selected secondary objectives on the subgroup of subjects enrolled 
after the expanded gene panel. 
To 
develop 
a 
model 
that 
may 
predict 
opioid 
response 
using 
pharmacogenomicresults and other factors associated with pain worsening. 
To determine whether caffeine consumption and CYP1A2 genotype correlate 
with pain response. 
To measure subjects’ perceptions of being bothered by pain treatment over the 
course of the study, using a 5-point subjective rating scale. 
 
F. Summary of 
Study Design 
Cancer outpatients with uncontrolled malignant pain will be offered a 
pharmacogenomic panel through participation in the proposed study.  
All subjects will be assessed and prescribed a pain regimen as part of standard 
practice at the initial visit.  Subjects who meet the eligibility criteria will be 

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offered to participate in the clinical trial.  Consented subjects will provide a 
buccal swab for pharmacogenomic testing and will be discharged on their initial 
opioid pain regimen. 
After the initial visit, subjects will be asked to rate their daily pain on a scale of 
0-10 using a standardized, single question.  A nurse or coordinator will follow up 
with the subject by telephone on day 7 +/- 1; this will be “Assessment #1”.  
Subjects will be asked to report information about their pain scores, pain 
medication use, and caffeine intake, in addition to any bothersome symptoms. A 
Subject who continues to have “uncontrolled” pain, is experiencing bothersome 
symptoms, and/or requests for a drug/dose modification will have his/her 
drug/dose modified using the pharmacogenomic test results as a tool.  If the 
subject has had significant pain improvement, stable mild pain and/or is satisfied 
with their level of pain at the assessment (regardless of pain score), he/she will 
be recommended to continue the current drug/dose and return to clinic on day 30 
+/- 5 for the final follow up.  Subjects will be told to call the clinic if their pain 
becomes intolerable or they experience bothersome symptoms after the first 
Assessment for further drug/dose modification, if needed prior to day 30 +/- 5. 
The nurse or coordinator will follow up with subjects receiving a drug/dose 
modification after another 7 days +/- 1; this will be considered “Assessment #2”.  
Subjects who have now had significant pain improvement, stable mild pain, 
and/or are satisfied with their level of pain at the assessment (regardless of pain 
score) will continue on the same regimen.  If the subjects’ pain is still 
“uncontrolled”, they are experiencing bothersome symptoms, and/or they request 
for a drug/dose modification, the clinical team will modify the drug/dose 
accordingly.  Subjects will then be told to call the clinic if they continue to 
experience intolerable pain and/or bothersome symptoms; otherwise, all subjects 
will be seen in clinic on day 30 +/- 5 (the last day of study completion); this will 
be the “Final Assessment.”  
If a subject experiences intolerable pain prior to any scheduled assessment, the 
subject will call the clinic immediately for appropriate drug/dose modification.  
The subject will administer the opioid regimen for at least 48 hours to allow drug 
effect to take place, prior to contacting the clinic for intolerable pain.  If a subject 
is in contact with the LCI Palliative Clinic prior to “Assessment #1” or 
“Assessment #2”, and reports uncontrolled pain or bothersome symptoms 
requiring a drug/dose modification or adjustment, the interaction will be 
considered “Assessment #1” or “Assessment #2”, respectively. Subjects will be 
instructed to administer the pain medication(s) for at least 48 hours prior to 
calling the clinic to allow adequate time for drug effect to take place. 
G. Sample  
71 evaluable subjects   
H. Dosage 
Variable, depending on subject and genetic factors   

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I. Statistical 
analysis  
The primary objective is to evaluate the percentage of subjects achieving at 
least a 2-point improvement in their self-reported pain at one month compared 
to their baseline pain score.  It has been reported that, based on this same scale, 
approximately 30% of cancer patients receiving standard of care pain 
management experienced at least a 2-point improvement in pain score between 
visits.  Assuming a one-sided alpha = 0.10 significance level, a sample size of 
71 will provide at least 90% power to reject the null hypothesis, assuming the 
true pain improvement rate is 0.45.  The study will enroll subjects until the 
evaluable population consists of 71 subjects.  
 
 
 

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TABLE OF CONTENTS 
1. 
OBJECTIVES ................................................................................................................ 1 
2. 
BACKGROUND AND RATIONALE ......................................................................... 2 
3. 
SUBJECT SELECTION ............................................................................................... 7 
4. 
INVESTIGATIONAL PLAN ....................................................................................... 9 
5. 
STUDY PROCEDURES ............................................................................................. 17 
6. 
STUDY CALENDAR………………………………………………………...……….22 
7. 
STUDY TREATMENT-RELATED ADVERSE EVENTS ..................................... 23 
8. 
DATA AND SAFETY MONITORING PLAN ......................................................... 25 
9. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING ................. 26 
10. 
STATISTICAL CONSIDERATIONS……………………………………………….30 
11. 
STUDY COMPLETION AND TERMINATION ..................................................... 37 
12. 
RETENTION OF RECORDS .................................................................................... 37 
13. 
ETHICAL AND LEGAL ISSUES…………………………………………………...38 
14. 
REFERENCES………………………………………………………………………..40 
15. 
APPENDICES………………………………………………………………………...42 

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1. OBJECTIVES 
 
1.1. 
Primary Objective 
To determine the percentage of subjects achieving significant pain improvement over a 
one month period (defined as a ≥ 2 point decrease from baseline pain score on an 11-
point scale [0-10]) in oncology outpatients receiving pharmacogenomic testing. 
 
1.2. 
Secondary Objectives 
a. To determine the success rate of achieving significant pain improvement at 
“Assessment #2” (i.e. after initial pharmacogenomic-driven therapy selection) as 
measured from pain score at Assessment #1 in subjects who received a PGx-
guided drug/dose modification at Assessment #1. 
 
b. To determine the success rate of achieving significant pain improvement at the 
Final Assessment as measured from pain score at Assessment #1 in subjects who 
received a PGx-guided drug/dose modification at Assessment #1. 
 
c. To determine the success rate of achieving significant pain improvement at 
Assessment #1 as measured from baseline pain score in all evaluable subjects. 
 
d. To determine the success rate of achieving significant pain improvement at 
Assessment #2 as measured from baseline pain score in evaluable subjects who 
complete Assessment #2, per protocol. 
 
e. To evaluate the proportion of gene mutations determined in the pharmacogenomic 
panel, “Pain Profile”. 
 
f. To evaluate the frequency of “actionable genotypes” (i.e. presence of 
mutation(s)/genotype(s) that were used to guide a drug/dose modification) and 
“potentially actionable genotypes” (i.e. presence of mutation(s)/genotype(s) 
associated with drug the patient currently is on or presence of 
mutation(s)/genotype(s) associated with drug the patient is changed to, but the 
mutation(s)/genotype(s) were not used to guide drug/dose modification) at 
Assessments #1, #2 (if applicable), and at any unscheduled assessments. 
  
g. To correlate morphine equivalent daily doses (MEDD) with pharmacogenomic 
results and pain response. 
 
h. To describe the rate of observing potential drug-gene interactions not related to 
pain medications. (i.e. how often did the Investigator identify a drug-gene 

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interaction for non-pain related medications, regardless of whether or not a 
modification was made). 
 
i. To determine subjects’ “personalized pain goal” (the maximal intensity of pain 
from 0 to 10 that would still be considered comfortable for the subject) at baseline 
and measure the success rate of achieving his/her “personalized pain goal” at the 
Final Assessment. 
 
 
 
1.3. 
Safety Objectives 
a. To identify rates of opioid-related adverse events including, but not limited to, 
constipation, fatigue, nausea, vomiting, somnolence, dizziness, cognitive 
disturbance, dry mouth, shortness of breath, pruritus, and urticaria.  
b. To correlate rates of opioid-related adverse events with pain worsening and 
pharmacogenomic results. 
1.4. 
Exploratory Objectives 
a. To evaluate selected secondary objectives on the subgroup of subjects enrolled after 
the expanded gene panel. 
b. To develop a model that may predict opioid response using CYP2D6, CYP3A4, 
COMT, and OPRM1 status and other factors associated with pain control (i.e. 
baseline demographics, baseline pain, bother by adverse events, caffeine intake, 
other genetic variants etc.). A second model will be estimated using the subgroup 
of subjects enrolled after the expanded gene panel to assess the impact of the 
expanded gene panel in addition to the genes and other factors used in the first 
model. 
c. To determine whether caffeine consumption and CYP1A2 genotype correlate with 
pain response. 
d. To measure subjects’ perceptions of being bothered by pain treatment over the 
course of the study, using a 5-point subjective rating scale. 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Pain in Oncology Patients 
Pain is one of the most persistent and burdensome symptoms in patients with cancer, 
affecting 49% to 57% of patients with curable cancer and 56% to 75% of patients with 
advanced disease.  Even when treated, pain is often severe enough to impair patients’ 
ability to function [1].  A meta-analysis of 52 pain studies showed that pain prevalence 
exceeds 50% for all cancer types.  Of these patients, one-third graded their pain as 
moderate or severe [2].  Estimates of sub-therapeutic treatment of pain in cancer 
patients range from 25-43% worldwide [3], with approximately one-third of cancer 

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patients in the United States achieving significant pain improvement at one month [4].  
Risk factors for under-treatment of cancer pain include age older than 65 years, 
minority status, misconceptions about analgesics and their adverse effects, as well as 
clinician knowledge deficits and inadequate pain assessment practices.  Studies have 
also demonstrated a relationship between pain control and survival.  In a study of 339 
head and neck cancer patients, the 5-year survival rate was 81.8% for patients with 
low post-treatment pain and 65.1% for those with high pain [5].  In addition to its 
influence on survival and quality of life, the economic costs of chronic pain are 
enormous [6].  In fact, a study found that the annual cost of [cancer and non-cancer] 
pain (total financial cost, including health care cost and loss of productivity, ranged 
from $560-635 billion) was greater than the annual costs in 2010 dollars of heart 
disease ($309 billion), cancer ($243 billion), and diabetes ($188 billion) [7]. 
 
Published in 2014, the largest prospective evaluation of pain in ambulatory cancer 
patients in the United States sought to understand how cancer-related pain changes and 
what factors influence it [6].  Investigators analyzed a total of 2,761 patients who had 
pain scores reported at both the initial assessment and follow up (one month).  Of the 
entire sample, 53% had no pain, 23.5% had mild pain, 10.3% had moderate pain, and 
13.2% had severe pain.  Of the patients presenting with any pain, 32.2% had reduced 
pain, 19.6% had worse pain, and 48.2% had stable pain at follow-up assessment.  Of 
the entire sample, 54.9% of patients had adequate pain management at both visits, 
11.4% had adequate pain management at initial visit but were undertreated at follow-
up visit, 10.2% of patients were undertreated at initial visit but had adequate pain 
management at follow-up visit, and 11.7% of patients were undertreated at both visits.  
Of the patients presenting with any pain, 42.5% were at least moderately bothered by 
adverse effects related to treatment of pain (higher for those taking stronger opioids).  
In a multivariable logistic analysis, pain owing to cancer, neuropathic pain, moderate-
to-severe constipation, comorbidity-related discomfort, lung cancer, taking fewer 
medicines, unemployment, and treatment in community institutions were associated 
with increased odds of worsening pain[6]. 
A Special Series of 14 articles published in May 2014 in the Journal of Clinical 
Oncology on “Pain in Patients with Cancer” acknowledged that untreated or 
undertreated pain is common in cancer patients, with little evidence of recent 
improvements.  This special issue was assembled with the hope of enhancing 
clinicians’ understanding of cancer pain and treatment, and provides practical methods 
to managing malignant pain such as the use of a multidisciplinary approach involving 
non-pharmacologic interventions (education, psychosocial support, physical therapy, 
etc.).  However, the influence of pharmacogenomic variables on pain management was 
not discussed, likely due to the paucity of prospective clinical data that exists. 

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2.2. 
Pharmacogenomics and opioids 
CYP2D6 is the primary metabolic enzyme responsible for the activation of weak 
opioids (codeine, tramadol, oxycodone and hydrocodone) into stronger opioids 
(morphine, o-desmethyltramadol, oxymorphone and hydromorphone, respectively); 
however, it is important to note that oxycodone and hydrocodone parent metabolites 
still carry significant opioid activity compared to parent codeine and tramadol.  More 
than 100 CYP2D6 alleles have been identified, with *3, *4, and *5 accounting for 
approximately 95% of the poor metabolizer (PM) phenotype.  The most common 
intermediate metabolizer (IM) phenotypes are *10 and *17.  Additionally, multiple 
copies of a functional allele may result in the ultra-rapid metabolizer (UM) phenotype 
(most often occurring with *1 or *2 duplications).  Patients harboring the *1 and/or *2 
alleles are termed extensive metabolizers (EM; normal genotype).  Allele frequencies 
vary by ethnicity; Caucasians have a higher frequency of the *4 allele (18-23%), the 
African American population have a higher frequency of the *17 allele (15-34%), and 
the Japanese population have a higher frequency of the *10 allele (39-41%) [8]. 
 
Codeine and tramadol rely almost exclusively on CYP2D6 for activation to their 
active metabolites, morphine, and O-desmethyltramadol, respectively.  The clinical 
analgesic effect of codeine is mainly attributed to its conversion to morphine, which 
has a 200 times higher affinity and 50 times higher intrinsic activity at the mu-opioid 
receptor than codeine itself [9].  Case reports of codeine fatalities in CYP2D6 UMs 
[10-15] resulted in a black box warning being issued in 2013, stating that codeine use 
in certain children with the UM phenotype may result in life-threatening adverse 
events or death.  As a result, institutions such as St. Jude Children’s Hospital require 
preemptive CYP2D6 genotyping prior to codeine administration.  Similarly, a case 
report of tramadol-induced respiratory depression was reported in a UM patient who 
also had renal impairment [16].  Alternatively, it has been demonstrated that the 
analgesic activity of tramadol in PM patients is significantly reduced [16-19].  In a 
prospective study of nearly 300 patients recovering from abdominal surgery, the 
percentage of non-responders was significantly higher in the PM group (46.7%) 
compared with the EM group (21.6%; p=0.005)[19]. 
Oxycodone and hydrocodone are metabolized by CYP2D6 to more potent metabolites, 
oxymorphone, and hydromorphone, respectively, and by CYP3A4 to inactive 
metabolites, noroxycodone, and norhydrocodone [20].  In one study, CYP2D6 PMs 
required significantly larger cumulative oxycodone doses for equianalgesic effect 
compared to EMs (25 mg vs. 16 mg; P=0.005) [21].  Similarly, a study showed that 
PMs achieved 8-fold lower hydromorphone concentrations versus UMs, which 
significantly correlated with pain relief [20].  Another study demonstrated that 
CYP2D6 UMs experienced 40% higher pain tolerance thresholds compared to EMs, 

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while PMs had a 20-30-fold lower pain tolerance compared to EM/IMs [22].  
Although no studies have investigated the association between CYP3A4 
polymorphisms and oxycodone or hydrocodone response, drug-interaction studies 
have demonstrated that CYP3A4 inhibition increases exposure and pharmacodynamic 
effects of oxycodone [23].  Studies have confirmed that the CYP3A4*22 allele 
(frequency in Caucasian population is 5-7%) results in significantly lower enzyme 
activity, impairing the metabolism of common CYP3A4-metabolized drugs [24]. 
While the change in opioid levels due to the use of competing CYP450 drugs is an 
iatrogenic effect, a similar mechanism is at the root of natural polymorphisms that give 
rise to the varying metabolic capacity of opioids that utilize this pathway. Drug-gene 
and drug-drug interactions may overlap, resulting in additive effects on drug 
disposition and ultimately therapeutic response and/or toxicity.  
 
The efficacy of opioid analgesia can be enhanced by the co-administration of 
catecholamines, which are involved in the modulation of pain.  Catechol-O-
methyltransferase (COMT) is responsible for the inactivation of catecholamines 
(dopamine, adrenaline and norepinephrine).  As a result, genetic variability in COMT 
can contribute to pain sensitivity.  It has been shown that a common variant allele 
(1947G>A) (allele frequency 48%) results in a three- to four-fold reduction in COMT 
enzyme activity [25].  A study of 207 Caucasian cancer patients demonstrated that 
patients with the GG genotype required significantly more morphine (155 mg/24 hrs) 
compared to AG (117 mg/24 hrs) and AA genotypes (95 mg/ 24 hrs)[26].  Another 
study in 197 Caucasian cancer patients found that certain haplotypes within the COMT 
gene influence the cumulative morphine dose needed [27]. 
 
Lastly, the mu-opioid receptor, the primary site of action of opioids, is encoded by the 
gene opioid receptor-like 1 (OPRM1).  The OPRM1 118A>G polymorphism (allele 
frequency 8-17%) results in less effective opioid analgesia, as demonstrated with 
cancer patients with the GG genotype requiring higher morphine doses for pain relief 
compared to AA patients [28].  A study showed that patients undergoing total knee 
arthroplasty with the GG genotype consumed approximately 60% more morphine than 
patients who were heterozygous or homozygous wild-type [29].   
 
Organizations, such as the Clinical Pharmacogenetics Implementation Consortium 
(CPIC)[30], provide pharmacogenomic-based guidelines on dosing recommendations 
for codeine, while the Dutch Pharmacogenetics Working Group[31] provides 
guidelines for codeine, oxycodone, and tramadol (amongst other classes of drugs 
metabolized by the CYP2D6 pathway, such as antidepressants). 
 
 

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2.3. 
Study Rationale 
There is an evident unmet clinical need for optimal methods of personalizing pain 
management.  Current standard of care for pain management is highly empirical, drug 
and dose selection is often based on subjective measurements, and continuous dose 
modifications are required in at least half of all patients. 
 
The existing literature regarding opioid pharmacogenomics has been correlative in 
nature.  The paucity of interventional trials conducted in clinical practice has resulted 
in the lack of routine clinical use of these tests, particularly in cancer patients.  To our 
knowledge, this pilot trial will be the first prospective, interventional study to 
investigate the clinical application of a multigene pharmacogenomic panel, or “Pain 
Profile” provided by XGene Diagnostics to guide opioid drug and dose modifications.  
After study activation, this “Pain Profile” was expanded by XGene Diagnostics to 
include additional genes not in the original panel, here referenced as “expanded gene 
panel.” Given the number of pain medications and dosages available coupled with the 
large variability in equianalgesic dosing, our proposed method provides an advantage 
over existing methodologies by using an informed approach to pharmacotherapy 
selection based on patient-specific genetic factors that influence drug disposition and 
action, potentially allowing for enhanced pain control.  In the same manner a clinician 
modifies therapy based on pain score, drug interactions, lab values, tolerability, and 
other clinical factors, pharmacogenomic information is an additional tool that can be 
used to further personalize drug and dose selection.  By incorporating subjects’ 
genotype into medication management, in addition to the use of a validated pain 
assessment tool (Edmonton Symptom Assessment Scale [ESAS]) which is already 
integrated into our electronic medical record, our approach reduces the subjectivity 
inherent in the nature of the pain phenotype.  Given the lack of prospective studies, our 
interventional trial is imperative to allow better interpretation of the clinical 
actionability of these pharmacogenomic variants and how they influence opioid 
response. 
 
Additionally, given that caffeine consumption has been demonstrated to influence pain 
response [32], we hypothesize that pharmacogenomic variations in the drug 
metabolizing enzyme of caffeine, CYP1A2, in addition to caffeine consumption, may 
influence pain response through modulation of caffeine levels.  We will explore this 
association as an exploratory endpoint. 
 
The results of this study will allow clinicians in our palliative medicine clinic to better 
understand the clinical utility of applying pharmacogenomic information to 
personalize pain medication management.  Given that approximately 50-60 cancer 
patients are referred to the palliative medicine clinic per month (the majority of whose 

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chief complaint is malignant pain), we will be able to rapidly assess the feasibility of 
our approach in a pilot setting (expected study duration is approximately 24 months).  
If this proof of concept is met, we plan to conduct a randomized study to validate our 
approach versus standard of care.  The results of these studies will help to confirm or 
nullify the clinical utility and applicability of using pharmacogenomic testing to guide 
pain management in ambulatory cancer patients, an important and lingering question 
amongst oncology professionals.  If successful in meeting the primary endpoints, these 
studies may help define a paradigm in which pharmacogenomic testing is routinely 
used in clinical practice to optimize pain management in cancer patients. 
 
 
3. SUBJECT SELECTION 
 
3.1. 
Accrual 
Accrual is expected to be 71 evaluable subjects, those enrolled subjects who complete 
the pain question as part of the Edmonton Symptom Assessment Scale at both the 
initial visit and on the final visit, over an enrollment period of approximately 24 
months.  Subjects will be recruited from the LCI Palliative Care Clinic. 
 
3.2. 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
 Presence of uncontrolled malignant pain (score of ≥ 2 on an 11point scale [0-
10]) as diagnosed and assessed by the Investigator, using the Edmonton 
Symptom Assessment Scale (ESAS) (Appendix B) 
 Documentation of any stage of cancer of any tumor location (solid or 
hematological) 
 At least 18 years of age 
 Either nociceptive or neuropathic painAnticipated to begin treatment with at 
least one opioid analgesic for treatment of malignant pain, or continue 
treatment with an opioid analgesic if opioid-tolerantAble to understand and be 
willing to sign the study consent form  
 
3.3. 
Exclusion Criteria 
Subjects must not meet any of the following criteria: 
 
 Inpatient service at baseline visit 
 Significant dysphagia and inability to swallow oral medications as determined 
by the Investigator 

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 Active or recent (within one year) drug and/or alcohol abuse as determined by 
the Investigator 
 Significant baseline cognitive impairment, as determined by the Investigator 
 Known (anaphylactic) hypersensitivity to any opioid 
 Severe oral mucositis that would impair proper buccal testing as determined by 
the Investigator 
 Receiving concurrent rehabilitation medicine care, nociception modulation 
(e.g. electrical stimulation), use of modalities with physiologic effects that 
indirectly influence nociception (e.g. light, laser therapy), or any other non-
pharmacologic approaches to malignant pain management other than exercise 
and rest, ice, compression, and elevation (RICE) 
 Presence of major psychiatric disorders as determined by the Investigator 
 Receiving active treatment or prophylaxis for epilepsy 
 Unable or unwilling to sign the study consent form  
 
3.4. 
Subject Withdrawal 
 
Subjects must be withdrawn from the study (treatment and procedures) for the 
following reasons: 
 
 Subject withdraws consent from study treatment and study procedures.  A 
subject will be removed from the trial at his/her own request.  At any time 
during and without giving reasons, a subject may decline to participate further.  
The subject will not suffer any disadvantages as a result.  
 If, in the Investigator’s opinion, continuation of the trial would be harmful to 
the subject’s well-being. 
 Study samples for pharmacogenomic testing are lost or non-evaluable. 
 Severe opioid-related toxicity requiring inpatient hospitalization 
 Death 
 
Subjects may be withdrawn from the study for the following reasons: 
 
 The subject is non-compliant with the study treatment, procedures, or both, 
where non-compliance is defined as lack of drug administration for any reason 
other than tolerability  
 Subject is lost to follow-up and/or is unable to be contacted for Assessment #1 
and/or #2 during the time window indicated in the protocol. 
 Development of a concurrent illness or situation which would, in the judgment 
of the Investigator, significantly affect assessments of clinical status and trial 
endpoints. 

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 Use, or suspicion of use, of illicit drugs or substances (self-reported) that may, 
in the opinion of the Investigator, have a reasonable chance of contributing to 
non-compliance, opioid abuse, drug toxicity, and/or otherwise skewing the trial 
result 
 Any other (non-disease related) reason, at the Investigator’s discretion 
 Pharmacogenomic test results are not returned prior to the subject needing a 
drug/dose modification. 
 Subject is unable to return to clinic within 5 days before or after day 30 (day 30 
+/- 5). 
 
Any subject removed from the trial will remain under medical supervision per 
standard of care procedures until discharge or transfer is medically acceptable. 
 
In all cases, the reason for withdrawal must be recorded in the CTMS and in the 
research record.  
 
3.5. 
Screen Failures 
A subject who, for any reason (e.g. failure to satisfy the selection criteria or withdraws 
consent), terminates their participation in the study before providing a buccal swab 
sample is regarded as a “screen failure”. 
 
All screen failures will be recorded in the Clinical Trial Management System (CTMS). 
 
3.6. 
Replacements 
Subjects who withdraw consent after providing a buccal swab sample will not be 
replaced.  Screen failures may be replaced. 
 
4. INVESTIGATIONAL PLAN 
 
4.1. 
Milestone Date Definitions 
Eligibility date: the date when the last procedure occurred that confirmed subject 
eligibility. 
Enrollment date: the date of buccal swab collection. 
Treatment Discontinuation date: the date the subject is taken off their prescribed 
pain medications, whether it be doctor-alone or PGX-guided.  This is prior to the Off 
Study date.  If the subject continues their prescribed pain medication after completing 
study procedures, the Treatment Discontinuation date will be the same as the Off 
Study date. 

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Off Study date: the day after the Final Assessment Day 30 +/- 5 or sooner if subject is 
withdrawn from the study. 
 
4.2. 
Overall Study Design and Plan 
This is a prospective, single arm, Phase II interventional study involving the use of 
pharmacogenomics to guide pain management in oncology outpatients with pain.  All 
subjects will be assessed and diagnosed using the Edmonton Symptom Assessment 
Scale (ESAS) at baseline and prescribed an opioid pain regimen per standard practice.  
Following consent and eligibility confirmation, all subjects will submit a specimen 
(buccal swab) for pharmacogenomic testing, the results of which will be used to help 
determine their appropriate pain medication/dose modification in the event their initial 
regimen does not result in pain improvement.  All drug/dose modifications will be 
within standard guideline recommendations, such as those set forth by the National 
Comprehensive Cancer Network Assessments and follow-up will be done according to 
the Study Calendar. 
 
4.3. 
Enrollment 
The Investigators will identify potential subjects suitable for the study and will notify 
the Sponsor-Investigator and/or Protocol Coordinator of the potential enrollment.  
Written informed consent will be obtained prior to enrollment.  The following 
documents will be obtained/completed: 
 Consent form signed by the subject 
 Authorization for the Release of Medical Records form signed by the subject 
 Lab Requisition Form (XGene Diagnostics)  
Following informed consent and eligibility check per standard operating procedures, 
subjects will be registered and assigned a Study ID number.  The Study ID will be a 
four digit number sequentially assigned to the subject, where 1001 will be the Study 
ID number assigned to the first subject. 
 
4.4. 
Baseline  
Cancer outpatients referred to the palliative care clinic with uncontrolled malignant 
pain (pain score ≥ 2 on an 11 point scale [0-10]) will be assessed and prescribed an 
opioid pain regimen as part of standard practice.  Subjects will be assessed using 
ESAS and treated by their Clinician (MD or NP) Investigator according to standard of 
care treatment pathways developed by the LCI Palliative Medicine Section at baseline.  
The treatment pathways have been developed using NCCN and ASCO Guidelines, in 
addition to a review of the best available literature. 

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Subjects who consent and are considered eligible will provide a buccal sample for 
pharmacogenomic testing.  The buccal specimen for sample analysis, completed 
laboratory requisition form, and copy of the subject’s medication list will be mailed to 
XGene Diagnostics.  Subjects will also be given a tool to aid in recording pain drug 
compliance, caffeine intake, and any other pain medications taken as well as a 
Bothersome Symptom Log to complete at home.  The Bothersome Symptom Log and 
recording tool will be provided to the subject upon discharge from the Baseline visit 
(multiple copies will be provided in case the subject loses one or more forms).  Only 
subjects who do not experience significant pain improvement and who receive a 
new pain regimen at Assessment #1 will be asked to report information about 
their pain scores, pain medication use, and caffeine intake at Assessment #2 (all 
subjects will be asked to report this information at Assessment #1).  If the subject 
has experienced pain improvement, has stable mild pain, or requests no drug/dose 
modification (regardless of pain score) at Assessment #1, he/she will not require an 
Assessment #2.  All subjects will be asked to complete the Bothersome Symptom log 
as needed throughout the study period.  Baseline bothersome symptoms and adverse 
events will be recorded at the Baseline visit.  
 
The Investigator will document the subject’s personalized pain goal at Baseline, 
defined as the maximal intensity of pain which the subject deems “comfortable.” 
The cutoff points for categories of pain severity will be determined using Serlin 
criteria [36].  Subjects’ pain ratings of 1-3 will be coded as mild, 4-5 as moderate, and 
6-10 as severe pain at both initial and follow-up assessments.  Performance status will 
be assessed using Eastern Cooperative Oncology Group (ECOG) standards. 
Other study procedures as indicated on the Study Calendar will also be completed at 
Baseline. 
4.5. 
Treatment 
Drug administration is variable, depending on drug regimen.  Opioids of consideration 
may include codeine, tramadol, oxycodone, hydrocodone, morphine, oxycontin, MS 
contin, hydromorphone, fentanyl, or methadone.  All drugs are FDA approved, and 
will be prescribed in the outpatient setting.  Dosages and titrations are within 
guidelines set forth by the National Comprehensive Cancer Network 
(http://www.nccn.org/professionals/clinician_gls/f_guidelines.asp). 
Upon receiving the initial prescription for their opioid pain regimen and completing 
the buccal swab (Baseline visit), subjects will be informed to fill their prescription at a 
pharmacy that same day.  A delay in filling the prescription will not be considered a 

Protocol Number: LCI-NOS-PAIN-001 
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protocol violation.  Subjects will be asked to rate their pain daily on a scale of 0-10 
using the same standard pain question from ESAS (Appendix B) and report their pain 
medication use at the next assessment. 
Subjects will also be asked to report other pain medications or treatments for pain and 
caffeine intake at Assessments 1 and 2.  Caffeine consumption will be measured as the 
total consumption of all sources of caffeine daily.  Subjects will be asked to indicate 
their primary source(s) of caffeine.  In the event that a subject consumes >1 source of 
caffeine, the exploratory analysis will assume 1 cup of coffee = 1 soda = 1 energy 
drink = 1 caffeine pill, etc. 
Subjects will complete a Bothersome Symptom Log in the event they experience any 
bothersome symptoms throughout the study period.  Subjects will call the clinic if they 
continue to have intolerable pain or experience bothersome symptoms prior to day 7 
+/- 1. This intervention will be considered Assessment #1.  Subjects will be instructed 
at the Baseline visit to take their pain medication(s) as prescribed for at least 48 hours 
prior to calling the clinic to allow adequate time for drug effect to take place.  The 
subject will be contacted by a research designee via telephone on day 7 +/- 1 for 
follow-up using the phone call script, if the subject has not already contacted the 
clinic.  The interaction with the subject, whether on day 7 +/- 1 or prior, is defined as 
“Assessment #1” per the Study Calendar in Section 6. 
 
4.5.1. Assessment #1:  
 
The clinic nurse or research designee will transcribe the information the subject 
provides. The relevant information (medication, dose, number of pills taken, pain 
score, and caffeine intake) will be included on the supplementary Study Data 
Sheet for Assessments 1 [and 2].  The Assessment #1 call will take place on day 7 
+/-1, unless the subject is in contact with the LCI Palliative Clinic prior to day 7 
+/-1 reporting uncontrolled pain or bothersome symptoms requiring a drug/dose 
modification or adjustment. If the subject experienced any bothersome symptoms 
and/or adverse events, they will also be recorded at this time.  All information 
obtained during the Assessments will be provided to the multidisciplinary team, 
including the PharmD and subject’s Investigator. 
 
Situations in which there is reason to doubt the validity of the data shared by the 
subject at their assessment, will prompt a discussion between the Sponsor-
Investigator and Protocol Coordinator to consider whether the subject should be 
withdrawn from the study.  These situations do not mandate immediate removal 
of the subject from the study as certain endpoints may still be evaluable. 
 
 

Protocol Number: LCI-NOS-PAIN-001 
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If the subject accidentally or unknowingly calls another physician for therapy 
modification and a drug/dose change is made, the Sponsor-Investigator and 
Protocol Coordinator will determine whether the subject should be withdrawn 
from the study; however, this situation does not mandate immediate removal of 
the subject from the study as certain endpoints may still be evaluable. 
 
The change in pain severity from baseline to Assessment #1 will be calculated for 
all evaluable subjects by computing the difference between pain score at baseline 
and pain score at Assessment #1.  Pain worsening will be defined as ≥ 2 point 
increase in pain score from baseline on an 11 point scale (0-10), pain 
improvement as ≥ 2 point decline in pain score from baseline, and stable pain will 
be ≤ 1 point increase or decrease from baseline.  Uncontrolled pain will be 
defined as either pain worsening or stable moderate-to-severe pain (4-10) and will 
constitute a drug/dose modification. 
 
If the subject has experienced significant pain improvement, mild pain, and/or 
feels like their pain is adequately treated at Assessment #1:  
 
Subject will continue their prescribed opioid regimen at the same drug and dose 
and will return to clinic on day 30 +/- 5 for the Final Assessment.  If the subject 
experiences initial pain improvement, but has subsequent pain worsening or 
experiences bothersome symptoms prior to day 30 +/- 5, they will be requested to 
call the clinic immediately for drug/dose modification, using pharmacogenomic 
results, if applicable. 
 
If the subject has pain worsening, stable moderate-to-severe pain, request for 
further drug/dose modification, and/or has bothersome symptoms (or specifically 
requests for therapy modification at clinician’s discretion) at Assessment #1: 
 
Pharmacogenomic test results, in addition to a review of drug interactions and 
clinical factors, will be used to guide drug and dose modification.  A treatment 
algorithm has been developed as a starting point to initiate a multidisciplinary 
discussion of treatment options based on pharmacogenomic test results.  This 
pharmacogenomic-driven treatment algorithm was developed based on opioid 
metabolism and currently available literature regarding pharmacogenomics and 
response.  There will be no requirement to abide by this set of proposed 
guidelines as each case will be different based on pain score, clinical factors, drug 
interactions, and other subject specific variables.  A multidisciplinary team 
including physicians, nurse practitioners and pharmacists (one of which has 

Protocol Number: LCI-NOS-PAIN-001 
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particular training and expertise in pharmacogenomics) will evaluate each case to 
decide on the most appropriate course of treatment. 
 
If at any point the subject requests for or against a medication/dose change, the 
Investigator will respect this request regardless of the subject’s pain score and/or 
pharmacogenomic test results, and in his/her best clinical judgment may prescribe 
or not prescribe a medication or dose adjustment.  This will not be considered a 
protocol violation and a discussion will be made between the Sponsor-
Investigator and Protocol Coordinator as to whether this subject should be 
potentially withdrawn.  In the event a medication change is made, the subject 
must return to the clinic to pick up the new prescription. If the subject requires a 
change in the number or frequency of pills to take, the directions may be provided 
over the phone and will be appropriately documented.   
 
Subjects will call the clinic if they continue to have intolerable pain prior to the 7th 
day after initiating the new opioid regimen.  Subjects will be instructed to 
administer the new opioid regimen for at least 48 hours prior to calling the clinic 
to allow adequate time for drug effect to take place.  Otherwise, the subject will 
be contacted 7 days +/- 1 after Assessment #1 by a research designee using the 
phone call script.  This interaction with the subject is defined as “Assessment #2”. 
 
Study procedures as indicated on the Study Calendar will be completed at 
Assessment #1. 
 
4.5.2. Assessment #2: 
 
Subjects will only have Assessment #2 if a modification to their pain regimen 
occurred at Assessment #1. 
 
The change in pain severity from Assessment #1 to Assessment #2 will be 
calculated for subjects receiving a PGx-guided drug/dose modification at 
Assessment #1 by computing the difference between pain score at Assessment #1 
and pain score at Assessment #2.  Additionally, the change in pain severity from 
baseline to Assessment #2 will be calculated for evaluable subjects who complete 
Assessment #2, per protocol, by computing the difference between pain score at 
baseline and pain score at Assessment #2.  Pain worsening will be defined as ≥ 2 
point increase in pain score on an 11 point scale (0-10), pain improvement as ≥ 2 
point decline in pain score, and stable pain will be ≤ 1 point increase or decrease 
in pain score.  Uncontrolled pain will be defined as either pain worsening or 

Protocol Number: LCI-NOS-PAIN-001 
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stable moderate-to-severe pain (4-10) and will constitute a drug/dose 
modification. 
 
The Assessment #2 call will take place for applicable subjects 7 days +/-1 after 
Assessment #1, unless the subject is in contact with the LCI Palliative Clinic prior 
to 7 days +/-1 reporting uncontrolled pain or bothersome symptoms requiring a 
drug/dose modification or adjustment. The clinic nurse or research designee will 
transcribe the information shared by the subject (medication, dose, number of 
pills taken, pain score, and caffeine intake) and relay this information to the 
multidisciplinary team as well as add the results to the subject’s research chart.  If 
the subject experienced any bothersome symptoms and/or adverse events, this 
will also be recorded.  Subjects who experience pain worsening, stable moderate-
to-severe pain, bothersome symptoms, or request a drug/dose modification may 
have their drug/dose modified per Investigator discretion.  A new prescription will 
be provided, if needed.  Subjects will be informed to call the clinic if they 
continue to experience intolerable pain and/or bothersome symptoms on the new 
regimen for a subsequent drug/dose modification; otherwise the subject will 
return to clinic on day 30 +/- 5 for the Final Assessment. 
 
There is no limit on the number of medication and/or dose modifications that can 
be made throughout the study period, and subsequent modifications after 
Assessment #2 will be per Investigator discretion. 
 
Subjects who have had significant pain improvement, mild pain, no bothersome 
symptoms and/or feel like their pain is adequately treated at Assessment #2 will 
continue on the same drug and dose and will return to clinic on day 30 +/- 5 for 
the Final Assessment.  Mutation(s)/genotype(s) considered “Actionable” at 
Assessment #1 or Assessment #2 will not be considered “Potentially Actionable” 
at Assessment #2 or thereafter for the purposes of the study. 
 
Study procedures as indicated on the Study Calendar will be completed at 
Assessment #2. 
 
4.5.3. Unscheduled Visit(s) 
 
Subsequent to Assessment #1 or #2, if the patient experiences pain worsening 
prior to the Final Assessment, phone contact will be made with the clinic to allow 
the Investigator to make a drug/dose modification, as needed. The Investigator 
will use pharmacogenomic test results to make a drug/dose modification, when 
appropriate.  The subject may need to come in to the office to receive the new or 

Protocol Number: LCI-NOS-PAIN-001 
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modified prescription.  The date of the unscheduled visit, pain score during the 
assessment, subsequent medication/dose change, and evaluation of actionable and 
potentially actionable genotypes will be documented. 
 
4.5.4. Final Assessment 
 
All subjects will have a Final Assessment on day 30 +/- 5 regardless of whether a 
drug modification was previously made or not.  Subjects will be seen on day 30 
+/- 5 and will be re-assessed using ESAS. If a subject is unable to return to clinic 
within the window, the pain question from ESAS may be collected via phone as 
per Assessment 1 or 2 procedure. Remaining Final Assessment procedures will be 
completed when the subject returns to clinic. 
 
The change in pain severity from Baseline to Final Assessment will be calculated 
for all subjects by computing the difference between initial baseline pain score 
and pain score at final assessment.  Pain worsening will be defined as ≥ 2 point 
increase in pain score from baseline on an 11 point scale (0-10), pain 
improvement as ≥ 2 point decline in pain score from baseline, and stable pain will 
be ≤ 1 point increase or decrease from baseline.  Uncontrolled pain will be 
defined as either pain worsening or stable moderate-to-severe pain (4-10) and will 
constitute a drug/dose modification. 
 
In addition, the change in pain severity from Assessment #1 to Assessment #2 (in 
those completing Assessment #2) and from Assessment #1 to Final Assessment 
will be calculated for subjects receiving a PGx-guided drug/dose modification at 
Assessment #1 by computing the difference between pain score at Assessment 1 
and pain score at second or final assessment, respectively.  Pain worsening will be 
defined as ≥ 2 point increase in pain score from Assessment #1 on an 11 point 
scale (0-10), pain improvement as ≥ 2 point decline in pain score from 
Assessment #1, and stable pain will be ≤ 1 point increase or decrease from 
Assessment #1.  Uncontrolled pain will be defined as either pain worsening or 
stable moderate-to-severe pain (4-10) and will constitute a drug/dose 
modification. 
 
The Investigator will determine the success of achieving the subject’s 
personalized pain goal at this time. 
 
The morphine equivalent daily dose (MEDD) will be calculated and recorded at 
the Final Assessment by converting the subject’s total daily opioid consumption 
at the Final Assessment to morphine equivalent doses using the following 

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website: http://www.globalrph.com/narcoticonv.htm widely used across many 
health systems for drug/dose conversions and fully referenced.  If the subject 
consumes a different amount of opioid each day, the average daily consumption 
over the previous week will be calculated and recorded. 
 
Subjects will be asked to describe their perceptions of being bothered by pain 
treatment overall throughout the course of the one-month period, which will be 
defined as “bothersome symptoms” and measure on the following 5-point rating 
scale: “1 - Not at all”, “2 - A little bit”, “3 – Moderately”, “4 - Quite a bit”, “5 - 
Extremely”. If a subject is unable to return to clinic within the window, the 
subject’s “bothersome symptoms” question may be collected via phone. 
 
Bothersome symptoms and/or adverse events experienced by the subject will be 
assessed.  Other study procedures as indicated on the Study Calendar will also be 
completed at the Final Assessment. 
 
4.6. 
Off Study 
Subjects will be considered Off Study on the day after their Final Assessment Day 30 
+/- 5 or sooner if any criteria requiring subject withdrawal apply.  The Off Study date 
will be recorded in the CTMS. 
 
Adverse events ongoing at the Final Assessment will be managed according to 
standard of care procedures since subjects may continue on pain regimen and/or 
undergo changes in their pain regimen after completing all study procedures. 
 
5. STUDY PROCEDURES 
The following study procedures are outlined on the Study Calendar. 
5.1. 
Informed Consent 
Written informed consent will be obtained from each subject prior to undergoing any 
protocol-specific evaluations or procedures and prior to initiating treatment.  
Additionally, all subjects will provide authorization for the release of their medical 
records for research purposes. 
 
5.2. 
Demographics and Medical/Treatment History 
Demographics and medical/treatment history will be collected at the Baseline visit.  
Significant medical history findings, as determined by the Clinician Investigator, 
which occurred prior to the subject signing the study consent, will be documented in 

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the medical record.  Relevant medical and treatment history include, but are not 
limited to, active medication list, alcohol/tobacco/drug use, prior drug or alcohol 
rehabilitation, surgical history, past medical history and family history. 
 
5.3. 
Office Visit 
Physical exam and evaluation by body system, height (baseline only), weight, and 
body surface area (BSA) will be documented in the electronic medical record during 
the Baseline and Final Assessment visits.  Vital signs will also be recorded in the 
electronic medical record at the Baseline and Final Assessment visits.  ECOG 
performance status will be assessed at the Baseline and Final visit.  The Edmonton 
Symptom Assessment Scale (ESAS) evaluation will be completed at the Baseline visit 
and at the Final Assessment visit.  Subjects will also be assessed for 
delirium/confusion and active constipation at the Baseline visit and at the Final 
Assessment Visit.  Their personalized pain goal will be determined and recorded at the 
Baseline visit.  Office visits will occur according to the Study Calendar in Section 6. 
 
5.4. 
Concomitant Medications 
Concomitant medications (active and past medication history within previous two 
weeks of consent, including prescription, herbal and over the counter medications) will 
be collected per standard clinic procedure for medical and treatment purposes.  Any 
known opioid history will also be noted. 
 
 
Given that several of the opioids are metabolized by CYP2D6 (but not all) and 
partially by CYP3A4, potential drug–interactions exist.  Precautions should be taken, 
at the Investigator’s discretion, if subjects must receive concomitant medications 
which are strong CYP2D6 inhibitors and CYP3A4 inhibitors/inducers (examples listed 
below).  Close monitoring of interacting drugs and/or appropriate drug/dose 
modifications are indicated per Investigator discretion. 
Examples of strong CYP2D6 inhibitors (use with caution): 
 Bupropion 
 Fluoxetine 
 Paroxetine 
 Quinidine 
 Methadone 
Examples of moderate CYP2D6 inhibitors (use with caution): 
 Duloxetine 

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 Cinacalcet 
 Terbinafine 
 Sertraline 
Examples of strong CYP3A4 inhibitors (use with caution): 
 HIV protease inhibitors 
 Clarithromycin 
 Grapefruit juice 
 Itraconazole 
 Ketoconazole 
 Nefazodone 
 Posaconazole 
 Voriconazole 
Examples of strong CYP3A4 inducers (use with caution): 
 Carbamazepine 
 Phenytoin 
 Rifampin 
 St. John’s Wort 
5.5. 
Buccal Collection, Shipping, and Analysis 
Collection: 
Enrolled subjects will provide a buccal swab for pharmacogenomic testing using a 
specimen kit from XGene Diagnostics at the Baseline visit (after confirmation of study 
eligibility) using the supplementary Buccal Swab Collection Instructions. 
 
Shipping:  
The shipping materials are pre-paid and supplied by XGene Diagnostics on an as 
needed basis.  Once samples have been obtained and packaged, they will be shipped 
ambient overnight to XGene Diagnostics.  The laboratory does not operate on 
Saturdays or holidays. 
 
Ship to:  
X-Gene Diagnostics 
5330 Spectrum Drive, Suite K Frederick, MD 21703 
 
Analysis: 
Specimen analysis will be conducted per standard procedures atXGene Diagnostics 
(Appendix A).  Test results will be available on a HIPAA compliant web database, 

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DataPharm (www.xgenedx.com/datapharm), approximately 24 hours after receipt of 
the specimen at XGene Diagnostics and will be accessible by all Investigators. 
 
Results will be recorded for all subjects, regardless of whether or not the results are 
used to guide therapy.  The pharmacogenomic panel (“Pain Profile”) tests may include 
but is not limited to the following genes: CYP3A5, CYP2B6, CYP2D6, CYP3A4, 
OPRM1, COMT, CYP2C9, VKORC1, CYP2C19 and CYP1A2.  Genes previously 
reported to be related to opioid use are CYP2D6, CYP3A4, CYP2B6, CYP3A5, 
OPRM1 and COMT.  The genetic test results for these six genes will be used to guide 
opioid therapy, if applicable.  Pharmacogenomic results may also be used to modify 
other commonly used drugs not relating to pain management, pending subject consent.  
Regardless, the number of times a potential drug-gene interaction not relating to pain 
medications are identified will be recorded as a secondary objective.  The results for 
the entire panel of genes may or may not be released to the subject, depending on the 
subject’s request. 
 
 
5.6. 
Toxicity Assessment 
All adverse events (AEs) and serious adverse events related to the subject’s prescribed 
opioid pain regimen will be monitored and documented (regardless of grade) and 
reported to the sponsor on an ongoing basis beginning at the Baseline visit and until 
the subject is off study.  The AEs will be documented in the research record and 
recorded on the eCRF. 
 
Adverse events will be graded according to CTCAE version 4.0 and categorized as 
“unrelated”, “unlikely related”, “possibly related”, “probably related”, or “definitely 
related” to the subject’s pain medication by the Investigator.  All AEs will be 
recorded per standard procedures.  However, only AEs deemed “possibly 
related”, “probably related”, and “definitely related” by the Investigator will be 
included in the study data set.  Investigators will refer to the medication package 
inserts for the expected side effects.  As with any drug, there is always the potential for 
unexpected AEs, including hypersensitivity reactions. 
 
5.7. 
Bothersome Symptoms Log Completion 
Subjects will track and record their side effects on their Bothersome Symptom Log 
beginning at Baseline and report these during Assessment #1, Assessment #2 (if 
applicable), and at the Final Assessment.  Subjects will be asked to include the start 
date, symptoms description, stop/resolve date, frequency of the symptom, severity of 
the symptom, what relieves the symptom and what makes the symptom worse.  

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Instructions on how to complete the Log will be provided to the subject.  Bothersome 
symptom information provided by the subjects will be used by the Investigator to 
assign a toxicity grade and attribution.  In the event that the bothersome symptom is 
related to the subject’s prescribed opioid pain regimen, the bothersome symptom will 
also be recorded as an adverse event and/or serious adverse event. 
 
At the Final Assessment, subjects will rate their overall bothersome symptoms on a 
subjective scale of 1 to 5 as indicated in Section 4.5.4.  The score at the Final 
Assessment will be recorded in the eCRF. 
 
A subject’s failure to complete the Bothersome Symptom Log is not considered a protocol 
deviation.  However, the subject may be withdrawn from the study if failure to complete the Log 
is categorized as non-compliance per the Investigator. 
 
 
5.8. 
Subject Reported Assessment Information 
At Assessments 1 and 2, enrolled subjects will be asked to share their medication use, 
daily pain scores, caffeine intake and additional pain medications taken with the 
research designee. Subjects will be asked to rate his/her pain symptoms “at their 
worst” in the previous 24 hours on a scale ranging from 0 (“not present”) to 10 (“as 
bad as you can imagine”).  Subjects will be instructed to rate their pain daily at 9PM 
(or prior to going to sleep).  In the event that a subject does not report their daily pain 
scores upon the Assessment, the subject will be asked to rate their pain at the time of 
assessment to determine whether their pain has improved, worsened, or has remained 
the same. 
 
All subjects will be asked to report this information from Baseline visit through the 
Assessment #1 time point or up to 7 days +/- 1, whichever occurs first. Only subjects 
who have uncontrolled pain/bothersome symptoms at Assessment #1, per the 
Investigator, protocol and/or subject assessment, and who receive a new pain regimen 
will be asked to report this information through the Assessment #2 time point or up to 
7 days +/- 1 from Assessment #1, whichever occurs first.  Subjects may reference their 
own notes or the tool provided at Baseline for this information. After Assessment #2, 
subjects will not be asked to report this information.  
 
5.9. 
Morphine Equivalent Daily Dose Calculation  
The morphine equivalent daily dose (MEDD) will be calculated at the Final 
Assessment and recorded in the eCRF. 
 
 

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6. STUDY CALENDAR 
 
 
Baseline 
(Day 0) 
Assessment #1 
(Day 7, +/- 1 
day)a 
Assessment #2  
(7 days +/- 1 
after 
Assessment 
#1)a,b   
Unscheduled 
Visitsc 
Final 
Assessment    
(Day 30, +/- 5 
days)  
O F F        S T U D Y 
Informed Consent 
X 
 
 
 
 
Medical &Treatment 
History 
X 
 
 
 
 
Office Visit 
X 
 
 
 
X 
ECOG Performance Status 
X 
 
 
 
X 
Concomitant Medications 
X 
 
 
 
 
Buccal Collection 
X 
 
 
 
 
Toxicity Assessment  
X 
X 
X 
X 
X 
MEDD 
 
 
 
 
X 
Bothersome Symptoms 
Log 
X 
X 
X 
X 
X 
 
ESAS 
X 
Xd  
Xd  
Xd 
Xe 
 
a Completed via telephone using the phone call script.  Assessment #1 and #2 may occur prior to day 
7 +/-1 and day 14 +/-1, respectively, if the subject continues to experience pain/bothersome 
symptoms and is in contact with the clinic prior to this time. 
b Only subjects who have uncontrolled pain/bothersome symptoms at Assessment #1 AND who 
receive a new pain regimen will complete Assessment #2. 
c A visit or call with a subject outside of protocol defined Assessment window in which the subject 
reports uncontrolled pain or bothersome symptoms, whereby a drug/dose modification is necessary. 
Presence of “actionable” or “potentially actionable” mutation(s)/genotype(s) may or may not guide 
modification. An office visit may be required if the subject needs a new prescription.  Otherwise, the 
visit will be completed over the phone.  
d Only the pain question from ESAS will be asked at Assessment #1, Assessment #2 and/or an 
Unscheduled Visit. 
e Pain question from ESAS may be completed via telephone. 
 
 

Protocol Number: LCI-NOS-PAIN-001 
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7. STUDY TREATMENT-RELATED ADVERSE EVENTS 
 
7.1. Serious Adverse Events (SAE) Related to Pain Regimen 
Serious adverse events related to strong opioids at high doses include respiratory 
depression, myoclonus, and severe cognitive dysfunction (frequency <1% with proper 
titration)[34].  Pain is the physiological antagonist to the central depressant effects of 
opioids.  Clinically important respiratory depression is rare in cancer patients because 
the dose of the opioid is balanced by the underlying pain.  Subjects who become very 
sedated by the medication may, however, develop respiratory depression.  This may 
occur during the initial titration or because of metabolic dysfunction.  Respiratory 
depression can be reversed immediately by the intravenous administration of 0.2-0.4 mg 
of naloxone, an opioid antagonist.  In subjects who are taking drugs with a long plasma 
half-life, such as methadone, it may be necessary to administer naloxone every 2-3 
hours. 
 
All SAEs (including event name, grade, start/stop dates and attribution) will be 
documented in the subject research record and in the eCRF.  The Investigator is 
responsible for verifying and providing source documentation for all SAEs and 
assigning the attribution for each event for all subjects enrolled on the study. 
 
Note: Subjects may experience SAEs related to their cancer or cancer treatments.  These 
SAEs (e.g. laboratory abnormalities, hospitalizations, secondary malignancies, etc.) 
should be recorded in the subject research record and managed according to standard of 
care procedures but should not be identified as SAEs for the purposes of this study, 
reported to the sponsor, or included in the dataset.  Deaths while on study or within 30 
days of the off study date (regardless of expectedness or relatedness) are the only 
exception to this criteria.  Subject deaths occurring on study or within 30 days of the off 
treatment date will be considered SAEs for this study and will be reported to the sponsor 
and included in the dataset. 
 
7.2. Most Common Adverse Events (AE) Related to Pain Regimen 
The following toxicities commonly occur in subjects taking opioids: 
 Constipation and/or bowel obstruction 
 Nausea 
 Vomiting 
 Drowsiness 
 Confusion  
 Histamine release resulting in pruritus, bronchoconstriction, etc. 
 

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Investigators will refer to the medication package inserts for the expected side effects.  
As with any drug, there is always the potential for unexpected AEs, including 
hypersensitivity reactions. 
 
Adverse events will be managed according to Investigator discretion and standard of 
care procedures.  LCI treatment guidelines may be utilized as a resource to treat adverse 
events such as constipation and nausea/vomiting.   
 
7.3. Adverse Event (AE) Grading  
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 will be utilized for AE grading.  All Levine Cancer Institute staff will have access 
to a copy of the CTCAE version 4.0. 
 
Grade refers to the severity (intensity) of the AE: 
 
CTCAE Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
 
CTCAE Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; 
limiting to age-appropriate instrumental activities of daily living (ADL; instrumental 
ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.). 
 
CTCAE Grade 3: severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to self-
care ADL (self-care ADL refers to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden). 
 
CTCAE Grade 4: life-threatening consequences; urgent intervention is indicated. 
 
CTCAE Grade 5: death due to an AE. 
 
7.4. Adverse Event Attribution Assignment 
Attribution is based on the question of whether there was a “reasonable causal 
relationship” to the subject’s prescribed opioid pain medication while on study as 
determined by the Investigator.  AEs are considered to be “unrelated” or “related” to the 
pain medication according to the definitions in Section 9.3. 
 

Protocol Number: LCI-NOS-PAIN-001 
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8. DATA AND SAFETY MONITORING PLAN 
 
8.1. 
Safety Monitoring 
This protocol will be monitored according to the processes in effect for all Levine 
Cancer Institute investigator- initiated studies and the protocol-specific monitoring plan, 
and will abide by standard operating procedures set forth by both the Carolinas 
Healthcare System Office of Clinical and Translational Research and the Levine Cancer 
Institute Clinical Trials Office.  It is the responsibility of the Sponsor-Investigator to 
monitor the safety data for this study.  The Sponsor-Investigator, Statistician, Protocol 
Coordinator, and other team members as needed will meet regularly to monitor subject 
consents, enrollment and retention, safety data for all subjects [including adverse events 
(AE’s) for all grades and attributions, serious adverse events (SAE’s)], prescribed opioid 
regimen administration, and validity/integrity of the data.  Documentation of these 
meetings will be kept with study records.  SAEs will be reported to the IRB per their 
requirements.  Major protocol deviations that result in a threat to subject safety or the 
integrity of the study will be reported to the IRB per their requirements.  The Sponsor-
Investigator will submit data to the LCI Data and Safety Monitoring Committee 
according to the overarching LCI Data and Safety Monitoring Plan. 
 
As part of the trial, subjects will be assessed at least 3 times within a one month period 
after the initial visit.  At these times, the multidisciplinary team involving a physician, 
nurse practitioner, pharmacist, and/or research designee will evaluate the subject for 
symptoms of opioid toxicity (these assessments will be completed by the research 
designee over the phone, who will then update the clinical team).  If the subject 
experiences any opioid-related severe toxicity, he/she will be admitted to the hospital for 
in-patient services and will be withdrawn from the study.  Given the short duration of 
the study and the extended approved usage of opioids, safety issues apart from standard 
side effect management involving primarily constipation and nausea are not expected. 
 
8.2. 
Data Quality Assurance 
 This study will be organized, performed, and reported in compliance with the study 
protocol, standard operating procedures (SOPs) of the Levine Cancer Institute and 
Carolinas Medical Center Office of Clinical and Translational Research, and other 
applicable regulations and guidelines (e.g. GCP). 
 
Subject data will be monitored by Levine Cancer Institute Research Monitors routinely 
for data quality.  This monitoring will be done by comparing source documentation to 
the eCRFs.  Any variation between the two data sets will be discussed with the Protocol 
Coordinator, Sponsor-Investigator, and/or appropriate research personnel. 

Protocol Number: LCI-NOS-PAIN-001 
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26 
 
 
The study database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures.  Data 
queries requiring clarification will be generated and addressed by the appropriate study 
team member, Protocol Coordinator and/or Sponsor- Investigator.  Only authorized 
personnel will make corrections to the study database and all corrections will be 
documented in an electronic audit trail. 
 
8.3. 
Communication Between Investigational Sites 
Investigational sites will be required to report applicable AEs, SAEs, deviations or any 
other problem that could affect the validity/integrity of the study data to the Sponsor-
Investigator.  All investigational sites will report AEs using the eCRFs, and SAEs using 
the SAE reporting function in the CTMS to the Sponsor.  AEs will be reported within 10 
business days of the investigator learning of the event.  SAEs will be reported within 24 
hours of the investigator learning of the event.  Drug administration or any other 
problem should be communicated to the Protocol Coordinator and/or Sponsor-
Investigator in writing as soon as possible but within 2 business days of learning of the 
event.  
 
9. SAFETY DATA COLLECTION, RECORDING AND REPORTING 
 
All subjects who receive at least one dose of the prescribed opioid regimen will be valid for 
the safety analysis.  All observations pertinent to the safety of the prescribed opioid regimen 
will be recorded and included in the final report. 
 
Safety variables include AEs and SAEs (whether related to the pain regimen or not) which 
will be assessed according to the Study Calendar.  AEs will be evaluated continuously 
throughout the study.  Safety, tolerability, relationship to the prescribed opioid regimen, and 
intensity will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
 
9.1. 
Unanticipated Problem (UAP) Definition 
An unanticipated problem is any event, experience, issue, instance, problem, or outcome 
meeting all 3 of the following criteria: 
 
 Unexpected in terms of nature, severity or frequency given the research 
procedures that are described in the protocol –related documents AND the 
characteristics of the subject population being studied. 

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 Possibly, probably, or definitely related to participation in the research.  This 
means that there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research 
study. 
 The event, experience, issue, instance, problem or outcome suggests that the 
research places the subject or others at greater risk of harm that was previously 
known or recognized. 
 
9.2. 
Adverse Event Definition 
 
An adverse event (AE) is any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related.  An AE can therefore be any 
unfavorable and unintended symptom, or disease temporally associated with the use of 
a study drug, whether or not considered related to the study drug.  Pre-existing 
conditions that increase in frequency or severity or change in nature during, or as a 
consequence of use of a drug in human clinical trials are also considered AEs. 
 
Any continuing medical condition with an onset date before the first date of prescribed 
opioid regimen administration should be considered pre-existing and should be 
documented at Baseline. 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result 
of an AE (e.g., surgical insertion of central line) need not be considered AEs and 
should not be recorded as an AE. 
 
An AE does not include: 
• Relapse or progression of the underlying malignant disease; 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion).  The condition that leads to the procedure is the adverse event; 
• Overdose of either pain medication or concomitant medication without any signs 
or symptoms unless the subject is hospitalized for observation; and 
• Toxicities which can be attributed to the subject’s cancer, cancer therapies, 
comorbidities, or concomitant medications other than the prescribed opioid 
regimen prescribed as part of participation on this study. 
 
An AE for the study is defined as a toxicity which is deemed possibly, probably, 
or definitely related to the subject’s prescribed opioid regimen by the 
Investigator.  However, only AEs attributed to the subject’s prescribed opioid 
regimen  will be recorded in the eCRF and included in the study dataset.  
 

Protocol Number: LCI-NOS-PAIN-001 
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28 
 
9.3. 
Adverse Event Attribution 
 
The relationship to the prescribed opioid regimen should be assessed using the following 
definitions: 
 
Not Related: Evidence exists that the AE has an etiology other than the prescribed opioid 
regimen (e.g., pre-existing condition, underlying disease, intercurrent illness, cancer 
therapies, or concomitant medications).  This includes events that are considered 
unrelated or unlikely related to the prescribed opioid regimen. 
 
Related: A temporal relationship exists between the event onset and administration of the 
prescribed opioid regimen.  It cannot be readily explained by the subject’s clinical state, 
intercurrent illness, cancer therapies, or concomitant therapies (other than the pain 
medication).  In the case of cessation or reduction of the dose of pain medication, the 
event abates or resolves and reappears upon rechallenge.  It should be emphasized that 
ineffective pain medication should not be considered causally related in the context of 
AE reporting.  This includes events that are considered possibly, probably, or definitely 
related to the prescribed opioid regimen. 
 
Final attribution of AEs should be stated and recorded as follows (choose only one): 
 
Definite – The AE is clearly related to the prescribed opioid regimen. 
Probable – The AE is likely related to the prescribed opioid regimen. 
Possible – The AE may be related to the prescribed opioid regimen. 
Unlikely – The AE is doubtfully related to the prescribed opioid regimen. 
Unrelated – The AE is clearly NOT related to the prescribed opioid regimen. 
 
Adverse events (including event name, grade, start/stop date and attribution) will be 
documented in the research record and recorded on the eCRF for this protocol. 
 
The Investigator is responsible for verifying and providing source documentation for 
adverse events and assigning the attribution for each event for all subjects enrolled on the 
study. 
 
9.4. “Unexpected” Definition 
An AE is considered unexpected if the specificity or severity of it is not consistent with 
the applicable product information (e.g. package insert/summary of product 
characteristics). 
 
 

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9.5. “Serious” and “Life-Threatening” Definitions 
An AE or SAE is to be considered serious if the Investigator or Sponsor-Investigator 
deem it as such and the event results in any of the following outcomes: 
 
 Death; 
 Life-threatening situation (subject is at immediate risk of death); 
 Inpatient hospitalization or prolongation of an existing hospitalization (excluding 
those for treatment of cancer, palliative or hospice care, or placement of an 
indwelling catheter, unless associated with other serious events); 
 Persistent or significant disability/incapacity; 
 Other: Important medical events that may not result in death, be immediately life-
threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic 
bronchospasm; 
o Blood dyscrasias or convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse. 
 
An AE or SAE is to be considered life-threatening if the Investigator or Sponsor-
Investigator deems it as such and the event poses an immediate threat of death. 
 
9.6. Serious Adverse Event (SAE) Definition 
Adverse events may also be considered serious adverse events.  SAEs for this study are 
defined as medical events that are related to the prescribed opioid regimen 
(suspected adverse reactions), serious (meeting the definitions in Section 9.5), and 
unexpected.  Any important medical event, if deemed appropriate by the Sponsor-
Investigator, can and should be reported as an SAE to the Sponsor, IRB, and other 
applicable entities per their requirements.  
 
SAEs will be captured from the time of subject enrollment until the Final Assessment.  
SAEs will be followed according to standard of care procedures until clinical recovery is 
complete or until there has been acceptable resolution of the event.  This may at times 
cause the follow-up period of SAEs to be greater than 30 days.  The above referenced 30 
day time period applies even if the subject is taken off study during this time period.  
Similarly, the Sponsor-Investigator is responsible for following the subject during the 
required follow-up period even if the subject lives elsewhere or has been released from 
his/her care and is being treated under another service at LCI. 

Protocol Number: LCI-NOS-PAIN-001 
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30 
 
 
Planned hospitalizations and the development of new cancers should not be indicated as 
SAEs for this study and should not be reported to the sponsor, IRB, or other applicable 
entities. 
 
Deaths: 
  While there is no additional protocol mandated follow-up after the subject is considered 
Off Study, deaths occurring greater than 30 days of the protocol-defined Off Study date 
thought to be possibly, probably, or definitely related to the prescribed opioid regimen 
must be reported to the sponsor, IRB, and other applicable entities within 24 hours of 
knowledge of the event. 
 
All SAEs (including event name, grade, start/stop date, and attribution) will be 
documented in the medical record and/or research chart and recorded in the study dataset. 
 
The Investigator is responsible for verifying and providing source documentation for all 
SAEs and assigning the attribution for each event for all subjects enrolled on the study. 
 
SAEs are not expected for this study.  An example of a rare potential SAE for this 
study is an anaphylactic reaction possibly, probably, or definitely related to pain 
medication. 
 
9.7. Safety Reporting to the IRB 
All safety events occurring during the conduct of a protocol and meeting the definition of 
an UAP or SAE will be reported to the IRB within 10 working days of the Sponsor-
Investigator learning of the event. 
 
Protocol deviations involving the informed consent process or subject safety will be 
reported promptly to the Sponsor-Investigator and IRB but no later than 10 working days 
of the Investigator learning of the event. 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. Sample Size 
The study will enroll to target 71 evaluable subjects for the final analysis.  The primary 
objective is to evaluate the percentage of subjects achieving at least a 2-point 
improvement in their self-reported pain at one month compared to their baseline pain 
score.  The self-reported pain score is based on the standardized pain question ranging 
from 0 (pain not present) to 10 (pain as bad as you can imagine) that is included in the 

Protocol Number: LCI-NOS-PAIN-001 
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31 
 
Edmonton Symptom Assessment Scale (ESAS).  It has been reported that, based on this 
same scale, approximately 30% of cancer patients receiving standard of care pain 
management experienced at least a 2-point improvement in pain score between visits [5].  
A single-stage design will be used to test the hypothesis that the pain improvement rate is 
less than or equal to 0.30.  If at least 27 of the 71 subjects experience at least a 2-point 
improvement in pain on day 30 +/- 5, the null hypothesis will be rejected (based on an 
exact binomial test) and the pharmacogenomic-guided therapy for pain management may 
be considered for further evaluation.  Assuming a one-sided alpha = 0.10 significance 
level, this sample size will provide at approximately 90% power to reject the null 
hypothesis, assuming the true pain improvement rate is 0.45.  
 
10.2. Endpoint Definitions 
 
10.2.1. Primary Endpoint 
 
The primary endpoint for this study is a binary variable that will be 
determined for each subject indicating whether or not they experienced at 
least a 2-point improvement in pain on day 30 +/- 5. 
 
10.2.2. Secondary Endpoints 
 
A secondary endpoint will be calculated for each subject as an ordered 
categorical variable indicating at least a 2-point improvement in pain score, 
stable pain (no more than a 1-point change in score), or at least a 2-point 
worsening in pain score between baseline and the final assessment. 
 
A secondary endpoint for this study is a binary variable that will be 
determined for each subject in the subset of subjects receiving a PGx-guided 
drug/dose modification at Assessment #1 indicating whether or not they 
experienced at least a 2-point improvement in pain as calculated between 
reported pain scores at “Assessment #1” and “Assessment #2”.  Additionally, 
a secondary endpoint will be calculated for subjects receiving a PGx-guided 
drug/dose modification at Assessment #1 as an ordered categorical variable 
indicating at least a 2-point improvement in pain score, stable pain (no more 
than a 1-point change in pain score), or at least a 2-point worsening in pain 
score within this interval. 
 
A secondary endpoint for this study is a binary variable that will be 
determined for each subject in the subset of subjects receiving a PGx-guided 
drug/dose modification at Assessment #1 indicating whether or not they 

Protocol Number: LCI-NOS-PAIN-001 
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32 
 
experienced at least a 2-point improvement in pain as calculated between 
reported pain scores at “Assessment #1” and Final Assessment.  Additionally, 
a secondary endpoint will be calculated for subjects receiving a PGx-guided 
drug/dose modification at Assessment #1 as an ordered categorical variable 
indicating at least a 2-point improvement in pain score, stable pain (no more 
than a 1-point change in pain score), or at least a 2-point worsening in pain 
score within this interval. 
 
A secondary endpoint for this study is a binary variable that will be 
determined for each subject indicating whether or not they experienced at 
least a 2-point improvement in pain as calculated between reported pain 
scores at baseline and Assessment #1.  Additionally, a secondary endpoint 
will be calculated as an ordered categorical variable indicating at least a 2-
point improvement in pain score, stable pain (no more than a 1-point change 
in pain score), or at least a 2-point worsening in pain score within this interval. 
 
A secondary endpoint for this study is a binary variable that will be 
determined for each subject completing Assessment #2, per protocol, 
indicating whether or not they experienced at least a 2-point improvement in 
pain as calculated between reported pain scores at baseline and Assessment 
#2.  Additionally, a secondary endpoint will be calculated as an ordered 
categorical variable indicating at least a 2-point improvement in pain score, 
stable pain (no more than a 1-point change in pain score), or at least a 2-point 
worsening in pain score within this interval. 
 
Other secondary endpoints will include binary and count variables indicating 
the presence and frequency of “actionable genotypes” (i.e. 
mutation(s)/genotype(s) that were present and used to guide drug/dose 
modifications) and “potentially actionable genotypes” (i.e. presence of 
mutation(s)/genotype(s) associated with drug the subject currently is on or 
presence of mutation(s)/genotype(s) associated with drug the subject is 
changed to, but the mutation(s)/genotype(s) were not used to guide a 
drug/dose modification) for each subject, during Assessment 1, Assessment 2, 
or any unscheduled visit. 
 
Binary variables will be calculated for each subject and for each gene 
provided in the pharmacogenomic test results indicating whether or not the 
genotype is a mutation. 
 

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Outcomes from the pharmacogenomic panel, “Pain Profile”, and derived 
morphine equivalent daily doses will also be reported as a secondary endpoint.  
The MEDD conversion website: http://www.globalrph.com/narcoticonv.htm 
will be used to convert the average milligrams of opioid consumed daily just 
prior to the Final Assessment to morphine equivalent daily doses. 
 
A secondary endpoint will be reported as a binary variable indicating whether 
or not the subject achieves their personalized pain goal (the maximal intensity 
of pain from 0 to 10 that would still be considered comfortable for the subject) 
recorded at baseline at the Final Assessment. 
 
10.2.3. Safety Endpoints 
 
Safety endpoints will include opioid-related adverse events (based on CTCAE 
Version 4.0) and serious adverse events. 
 
 
            10.2.4 Exploratory Endpoints 
 
Average daily caffeine product consumption will be calculated and recorded 
for each subject as a continuous variable and exploratory endpoint using the 
information recorded at Assessment #1 and Assessment #2 for those subjects 
who have an Assessment #2.  This measure will be considered both separately 
and in conjunction with CYP1A2 genotype as correlates with pain response. 
 
A scale of bothersome symptoms related to treatment of pain or other 
symptoms is reported as a 5-point rating scale (“Not at all”, “A little bit”, 
“Moderately”, “Quite a bit”, “Extremely”).  Outcomes for the subjects 
enrolled will be recorded as an ordered categorical variable and exploratory 
endpoint at the Final Assessment. 
 
10.3. Analysis Populations 
The primary efficacy analysis will be conducted on the population of enrolled 
subjects who complete the pain question as part of the Edmonton Symptom 
Assessment Scale at both the initial visit and on the final visit (i.e., the evaluable 
population).  Safety analyses will be conducted on all enrolled subjects.  Secondary 
analyses concerning changes in pain scores from Assessment 1 to Assessment 2 will 
be conducted on the subgroup of subjects receiving a PGx-guided drug/dose 
modification at Assessment #1.  Secondary analysis concerning changes in pain score 
from baseline to Assessment #1 will be conducted in all evaluable subjects 
completing Assessment #1.  Secondary analysis concerning changes in pain score 

Protocol Number: LCI-NOS-PAIN-001 
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34 
 
from baseline to Assessment #2 will be conducted in all evaluable subjects 
completing Assessment #2, per protocol. Secondary analysis concerning the 
frequency of actionable and ‘potentially actionable’ genotypes as well as the 
prevalence of gene mutations will be conducted on the population of subjects 
receiving pharmacogenomic test results. Aforementioned secondary analyses 
concerning frequency of genotypes and the prevalence of genes mutations will be 
evaluated for the original gene panel on the entire cohort of subjects receiving 
pharmacogenomics results and secondly evaluated for the expanded genes on the 
cohort of subjects receiving pharmacogenomics results for the expanded gene panel. 
Other secondary analyses will be conducted on the population of enrolled subjects 
who are not withdrawn from the study secondary to a protocol violation or the 
Investigator’s discretion.  The date of the buccal swab collection will be the 
enrollment date.  Subjects with a baseline pain score of 9 or 10 will be excluded from 
the analyses of the pain worsening binary variable and the ordered categorical 
variable described above (because these subjects cannot show a 2-point worsening). 
 
10.4. Analysis Methods 
 
10.4.1. Subject Disposition 
 
An accounting of all enrolled subjects will be provided at the end of the study. 
This will include a breakdown of subjects who consented, who provided a 
buccal swab, who completed each assessment, who died on study, who were 
lost to follow-up during the on study period and/or withdrew consent. 
 
10.4.2. Baseline Subject and Disease Characteristics 
 
A summary of subject demographics (age, race, gender) and disease-related 
characteristics (as described in Section 5.3) will be completed and subject 
medical history will be assessed. 
 
10.4.3. Efficacy Analyses 
 
10.4.3.1. Primary Analysis 
 
The frequency and proportion of subjects experiencing at least a 2- 
point improvement in pain score at Day 30 +/- 5 will be calculated, 
along with a 95% Clopper Pearson confidence interval. A one-sided 
exact binomial test of proportions, with α = 0.10, will be carried out, 
testing the null hypothesis that the pain improvement rate is less than 

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35 
 
or equal to 0.30.   
 
10.4.3.2. Secondary Analyses 
 
Similar analyses of the pain improvement rate as described in 
Section 10.4.3.1 will be conducted on the subset of subjects who 
receive a drug/dose modification at Assessment #1 between two 
differing intervals: difference in pain scores from Assessment #1 to 
Assessment #2 and difference in pain scores from Assessment #1 to 
Final Assessment. 
 
The frequency and distribution of “actionable genotypes” and 
“potentially actionable genotypes” from the pharmacogenomic 
panel, “Pain Profile”, will be summarized and described. 
 
The frequency and distribution of gene mutations for each gene 
provided in the pharmacogenomic panel, “Pain Profile”, will be 
summarized and described. 
 
Logistic regression models will be used to model the probability of 
pain improvement as a function of morphine equivalent daily doses.  
A cumulative logistic regression model will be used to model the 3-
level ordered categorical variable describing pain improvement 
(described in Section 10.2.2) as a function of morphine equivalent 
daily doses.  Additionally, linear regression models will be used to 
determine if morphine equivalent daily doses (the response variable) 
are associated with the pharmacogenomic parameters. 
 
The frequency and proportion of subjects achieving their 
“personalized pain goals” (described in Section 10.2.2) at the Final 
Assessment will be summarized and described. 
  
10.4.4. Safety Analyses 
 
Incident rates for adverse events and SAEs will be summarized.  Logistic 
regression models will be used to model the probability of pain worsening as a 
function of selected adverse events and pharmacogenomics results. 
 
 
 

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10.4.5. Exploratory Analyses 
 
Logistic regression models will be used to model the probability of pain 
improvement as a function of CYP2D6, CYP3A4, COMT, and OPRM1 gene 
status.  Additional logistic regression models will be estimated using the 
subgroup of subjects enrolled after the expanded gene panel to assess the 
impact of the expanded genes in addition to the genes and other factors used 
in the aforementioned models.  Univariate models will be used to identify 
genes that are individually predictive and multivariate models including 
backward elimination and forward selection will be used to identify genes that 
are independently predictive of response.  Additionally, other baseline subject, 
disease, pain, and bother by adverse event characteristics will be correlated 
with outcomes. 
 
Logistic regression models will be used to model the probability of pain 
improvement both univariately as a function of average daily caffeine product 
consumption or CYP1A2 genotype and bivariately as a function of both 
average daily caffeine product consumption and CYP1A2 genotype. 
 
Subjects’ perceptions of being bothered by pain treatment over the course of 
the study is recorded using a 5-point rating subjective scale (‘Not at all’, ‘A 
little bit’, ‘Moderately’, ‘Quite a bit’, ‘Extremely’).  It has been reported that, 
based on this same scale, approximately 58% of patients reported some degree 
of bother by adverse events related to treatment of pain or other symptoms 
and approximately 30% of patients reported at least moderate bother by 
adverse events related to treatment of pain or other symptoms.  The 
proportions and 95% Clopper-Pearson confidence intervals of patients 
reporting any degree of bother and at least moderate degree of bother will be 
calculated.  A one-sided exact binomial test of proportions, with α = 0.10, will 
be carried out, testing the null hypothesis that the proportion of subjects 
reporting some degree of bother by adverse events related to treatment of pain 
or other symptoms is less than or equal to 0.60.  A one-sided exact binomial 
test of proportions, with α = 0.10, will be carried out, testing the null 
hypothesis that the proportion of subjects reporting at least moderate bother 
by adverse events related to treatment of pain or other symptoms is 0.30. 
 
10.5. Interim Analyses 
No interim analyses are planned for this study. 
 
 

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37 
 
11. STUDY COMPLETION AND TERMINATION 
 
11.1. Completion 
The study will be considered complete when one or more of the following conditions are 
met: 
 All subjects have completed all study visits. 
 All subjects have discontinued participation in the study. 
 The IRB, LCI DSMC, or Sponsor-Investigator discontinues the study for any 
reason. 
 The Sponsor-Investigator defines an administrative or clinical cut-off date. 
 
11.2. Termination 
The study will be terminated when one of the following conditions occurs: 
If the risk-benefit ratio becomes unacceptable owing to, for example: 
 Results of any interim analysis. 
 Results of any parallel clinical studies. 
 If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame. 
 
The Sponsor-Investigator has the right to close the study at any investigational site at any 
time. 
For any of the above closures, the following applies: 
 Closures should occur only after consultation between involved parties. 
 All affected investigational sites must be informed as applicable according to 
regulation. 
 In case of a partial study closure, ongoing subjects, including those in follow-up, 
must be taken care of in an ethical manner. 
 
Details for individual subject withdrawal can be found in Section 3.4. 
 
12. RETENTION OF RECORDS 
Essential documentation, including all IRB correspondence, will be retained for at least 2 
years after the study is completed.  Documentation will be readily available upon request. 
 
 
 

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38 
 
13. ETHICAL AND LEGAL ISSUES 
 
13.1. Ethical and Legal Conduct of the Study 
The procedures outlined in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor-Investigator abide 
by Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in 
the Declaration of Helsinki.  The study will also be carried out in keeping with applicable 
local law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g. DSMC, IRB) will be obtained for 
all participating investigational sites before the start of the study, according to GCP, local 
laws, regulations, and organizations.  
 
Strict adherence to all specifications laid out in this protocol is required for all aspects of 
study conduct; the Investigators may not modify or alter the procedures described in this 
protocol.  Any deviations from the protocol must be explained and documented by the 
Investigator. 
 
Modifications to the study protocol may be made by the Sponsor-Investigator in the form 
of a protocol amendment and will not be implemented until after documented approval 
from the IRB. 
 
The Sponsor-Investigator is responsible for the conduct of the study at all the 
investigational sites in accordance with Title 21 of the Code of Federal Regulations 
and/or the Declaration of Helsinki.  The Sponsor-Investigator is responsible for 
overseeing the treatment of all study subjects.  The Sponsor-Investigator must assure that 
all study site personnel, including Sub-Investigators and other study staff members, 
adhere to the study protocol and applicable regulations and guidelines regarding the study 
both during and after study completion.  
 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
 
13.2. Confidentiality 
All records identifying the subjects will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publically available.  
 
13.3. National Protocol Registration 
The Sponsor-Investigator will ensure that the information regarding the study be 
publically available on the internet at www.clinicaltrials.gov.  
 
 

Protocol Number: LCI-NOS-PAIN-001 
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39 
 
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Ciszkowski, C., et al., Codeine, ultrarapid-metabolism genotype, and postoperative 
death. N Engl J Med, 2009. 361(8): p. 827-8. 
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Madadi, P., et al., Genetic transmission of cytochrome P450 2D6 (CYP2D6) ultrarapid 
metabolism: implications for breastfeeding women taking codeine. Curr Drug Saf, 2011. 6(1): p. 
36-9. 
12. 
Gasche, Y., et al., Codeine intoxication associated with ultrarapid CYP2D6 metabolism. 
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Koren, G., et al., Pharmacogenetics of morphine poisoning in a breastfed neonate of a 
codeine-prescribed mother. Lancet, 2006. 368(9536): p. 704. 
14. 
Madadi, P., et al., Communicating pharmacogenetic research results to breastfeeding 
mothers taking codeine: a pilot study of perceptions and benefits. Clin Pharmacol Ther, 2010. 
88(6): p. 792-5. 
15. 
Madadi, P. and G. Koren, Pharmacogenetic insights into codeine analgesia: implications 
to pediatric codeine use. Pharmacogenomics, 2008. 9(9): p. 1267-84. 
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Stamer, U.M., et al., Respiratory depression with tramadol in a patient with renal 
impairment and CYP2D6 gene duplication. Anesth Analg, 2008. 107(3): p. 926-9. 
17. 
Stamer, U.M., et al., Concentrations of tramadol and O-desmethyltramadol enantiomers 
in different CYP2D6 genotypes. Clin Pharmacol Ther, 2007. 82(1): p. 41-7. 
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Musshoff, F., et al., Enantiomeric determination of tramadol and O-desmethyltramadol 
by liquid chromatography- mass spectrometry and application to postoperative patients 
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Stamer, U.M., et al., Impact of CYP2D6 genotype on postoperative tramadol analgesia. 
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20. 
Stauble, M.E., et al., Hydrocodone in postoperative personalized pain management: pro-
drug or drug? Clin Chim Acta, 2014. 429: p. 26-9. 
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Stamer, U.M., et al., CYP2D6 genotype dependent oxycodone metabolism in 
postoperative patients. PLoS ONE, 2013. 8(3): p. e60239. 
22. 
Samer, C.F., et al., Genetic polymorphisms and drug interactions modulating CYP2D6 
and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J 
Pharmacol, 2010. 160(4): p. 919-30. 
23. 
Kummer, O., et al., Effect of the inhibition of CYP3A4 or CYP2D6 on the 
pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin Pharmacol, 2011. 67(1): p. 
63-71. 
24. 
Elens, L., et al., CYP3A4*22: promising newly identified CYP3A4 variant allele for 
personalizing pharmacotherapy. Pharmacogenomics, 2013. 14(1): p. 47-62. 
25. 
Lotta, T., et al., Kinetics of human soluble and membrane-bound catechol O-
methyltransferase: a revised mechanism and description of the thermolabile variant of the 
enzyme. Biochemistry, 1995. 34(13): p. 4202-10. 
26. 
Rakvag, T.T., et al., The Val158Met polymorphism of the human catechol-O-
methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. 
Pain, 2005. 116(1-2): p. 73-8. 
27. 
Rakvag, T.T., et al., Genetic variation in the catechol-O-methyltransferase (COMT) gene 
and morphine requirements in cancer patients with pain. Mol Pain, 2008. 4: p. 64. 
28. 
Klepstad, P., et al., The 118 A > G polymorphism in the human mu-opioid receptor gene 
may increase morphine requirements in patients with pain caused by malignant disease. Acta 
Anaesthesiol Scand, 2004. 48(10): p. 1232-9. 
29. 
Chou, W.Y., et al., Association of mu-opioid receptor gene polymorphism (A118G) with 
variations in morphine consumption for analgesia after total knee arthroplasty. Acta 
Anaesthesiol Scand, 2006. 50(7): p. 787-92. 
30. 
Crews, K.R., et al., Clinical Pharmacogenetics Implementation Consortium Guidelines 
for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. Clin Pharmacol Ther, 
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Samer, C.F., et al., Applications of CYP450 testing in the clinical setting. Mol Diagn 
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32. 
Derry, C.J., S. Derry, and R.A. Moore, Caffeine as an analgesic adjuvant for acute pain 
in adults. Cochrane Database Syst Rev, 2012. 3: p. CD009281. 
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Quill, Timothy E. "Introduction." Primer of Palliative Care. 6th ed. Glenview, IL: 
American Academy of Hospice and Palliative Medicine, 2014. 15. Print.  
34. 
Quigley, C., Opioid switching to improve pain relief and drug tolerability. Cochrane 
Database Syst Rev, 2004(3): p. CD004847. 
 
 
 
 
 
 
 
 
 

Protocol Number: LCI-NOS-PAIN-001 
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41 
 
APPENDICES 
 
A. Genotyping information 
 
Pharmacogenomic testing will be conducted at XGene Diagnostics.    Specimens will be 
analyzed for gene mutations by real-time polymerase chain reaction (PCR) (TaqMan 
SNP Genotyping, Thermo Fisher) developed by X-Gene, Inc.    All assays were validated 
pursuant to the 1988 Clinical Laboratory Improvement Amendment (CLIA) standards by 
XGene Diagnostics.  Performance characteristics were validated by the X-Gene 
Laboratory with analytical specificity and sensitivity of >99% for detection of all variants 
listed. The FDA has neither cleared nor approved these assays, nor is FDA pre-market 
review required.  XGene Diagnostics is certified under the Federal 1988 CLIA legislation 
to perform high complexity clinical laboratory testing and is inspected and accredited by 
the College of American Pathologists.  All pharmacogenetic test results will be available 
24 hours after the sample has been received at the laboratory of XGene Diagnostics.  
Results will be uploaded to a HIPAA compliant web database called DataPharm.  
Interpretation and commentary are provided to the clinician for educational and 
consultation purposes only.  Diagnosis and treatment decisions are the sole responsibility 
of the clinician. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number: LCI-NOS-PAIN-001 
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42 
 
B. Edmonton Symptom Assessment System (integrated into electronic medical record) 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Comment 
Pain 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
Depression 
 
 
 
 
 
 
 
 
 
 
 
 
Anxiety 
 
 
 
 
 
 
 
 
 
 
 
 
Drowsy 
 
 
 
 
 
 
 
 
 
 
 
 
Appetite 
 
 
 
 
 
 
 
 
 
 
 
 
Well 
Being 
 
 
 
 
 
 
 
 
 
 
 
 
SOB 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
symptom