A Phase 3, Open-label Study to Evaluate the Safety of TRV130 in Patients With Acute Pain for Which Parenteral Opioid Therapy is Warranted
Phase: PHASE3
Conditions: Acute Pain
Sponsor: Trevena Inc.

 
 
 
Protocol Title:  
 A phase 3, open-label study to evaluate the safety of oliceridine (TRV130) 
in patients with acute pain for which parenteral opioid therapy is warranted 
 
Protocol Number:  CP130-3003 
 
Protocol Version:  5.0 
 
Protocol Date:  
 14 September 2016 
 
NCT:  
 
02656875 

Trevena, Inc. 
 
Protocol CP130-3003 
 
 
Version 5.0 
 
 
14 Sep 2016 
Confidential 
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-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Trevena, Inc. Any 
unauthorized copying or use of this document is prohibited. 
 
Protocol Title: 
A phase 3, open-label study to evaluate the safety of oliceridine 
(TRV130) in patients with acute pain for which parenteral opioid 
therapy is warranted 
Protocol Number: 
CP130-3003 
 
Clinical Phase: 
Phase 3 
Protocol Version and 
Date: 
Version 5.0 
14 Sep 2016 
US Investigational 
New Drug Number: 
113,537 
Sponsor: 
Trevena, Inc. 
1018 West 8th Avenue, Suite A 
King of Prussia, PA 19406 USA 
Phone: 610-354-8840 
 
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SIGNATURE PAGE 
Protocol Title: A phase 3, open-label study to evaluate the safety of oliceridine (TRV130) in 
patients with acute pain for which parenteral opioid therapy is warranted. 
The undersigned have reviewed the format and content of this protocol and have approved the 
clinical study protocol. 
Any modifications of the clinical study protocol must be agreed upon by the sponsor and the 
investigator and must be documented in writing. 
 
Sponsor Approval: 
Signature: 
 
 
Date: 
 
Name (print): 
 
 
 
 
 
 
 
 
 
Title: 
 
 
 
 
 
Investigator Agreement: 
 
I have read the clinical study protocol and agree to conduct the study as outlined herein. 
 
 
Signature: 
 
 
Date: 
 
Name (print): 
 
 
 
 
 
 
 
 
 
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Chief Medical Officer
David Soergel
9/15/2016

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Protocol CP130-3003 
 
 
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SYNOPSIS 
PROTOCOL TITLE 
A phase 3, open-label study to evaluate the safety of oliceridine 
(TRV130) in patients with acute pain for which parenteral opioid 
therapy is warranted 
PROTOCOL NUMBER CP130-3003. 
INVESTIGATOR(S)/S
TUDY CENTER(S) 
This study will be conducted at approximately 60-90 study centers 
located in the United States.  
PHASE OF 
DEVELOPMENT 
Phase 3. 
OBJECTIVES 
Primary objective 
 To evaluate the safety and tolerability of oliceridine in patients 
with moderate to severe acute pain for which parenteral opioid 
therapy is warranted. 
 
Secondary objective 
 To evaluate the analgesic efficacy of oliceridine. 
STUDY DESIGN AND 
PROCEDURES 
This phase 3, open-label, safety study in surgical and medical 
patients will be conducted in inpatient hospitals, outpatient hospital 
departments, ambulatory surgical care centers, and emergency 
departments (EDs). Patients recruited in EDs may continue 
oliceridine treatment if hospitalized and parenteral opioid therapy is 
warranted. 
Representative surgeries include orthopedic (eg, total hip 
replacement, total knee replacement, spine), abdominal (eg, upper 
or lower abdominal, perineal), gynecologic (eg, total abdominal 
hysterectomy), vascular, soft tissue, and surgical procedural pain. 
Representative medical conditions include acute pancreatitis, acute 
exacerbation of existing noncancerous chronic pain, 
musculoskeletal pain, sickle-cell disease, inflammatory orofacial 
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muscle pain, and renal colic. Medical conditions that could 
confound the evaluation of oliceridine are excluded, such as acute 
pain without a specific etiology, undifferentiated acute abdominal 
pain, acute breakthrough pain in palliative “end of life” care, and 
pain associated with advanced cancer (somatic, visceral, or 
neuropathic) or with concurrent use of chemotherapeutic or 
biologic agents for the treatment of cancer. 
Representative ED conditions include visceral pain (eg, renal colic, 
upper abdominal pain, abdominal pelvic pain); nonvisceral pain 
(eg, traumatic and atraumatic acute musculoskeletal pain, chest 
wall pain, burns, orofacial pain/headache, cutaneous and soft tissue 
pain); procedural analgesia (eg, reduction of orthopedic fractures 
and dislocations, abscess incision and drainage); acute painful 
episodes associated with a medical condition (eg, sickle cell painful 
vaso-occlusive episode). Oliceridine will not be used to 
intentionally suppress a patient’s level of consciousness (procedural 
sedation and analgesia as defined by the American College of 
Emergency Physicians [ACEP]). 
The study has four phases: a screening/baseline phase, a treatment 
phase (consisting of a predose period and a dosing period), an 
end-of-treatment phase, and a follow-up phase. 
Screening/baseline phase 
Written informed consent will be obtained before any protocol-
related activities are conducted. All screening procedures will be 
completed within 14 days before the first oliceridine dose. Select 
standard of care assessments (eg, chemistry, hematology, urine or 
serum pregnancy test, urine or serum toxicology screen, 
electrocardiogram (ECG)) obtained before informed consent may 
be used as study data if protocol specifications and timeframes are 
met. 
When screening and baseline procedures are anticipated to occur 
within 48 hours of each other, they may be executed as a single 
procedure, unless the clinical condition of the patient has 
significantly changed since screening. 
Adverse events (AEs) occurring from time of informed consent to 
the follow-up phase will be recorded in source and will also be 
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recorded in eCRF if the patient receives oliceridine. Serious 
Adverse Events (SAEs) occurring from time of informed consent to 
the follow-up phase or 7 days after the last dose of oliceridine 
(whichever occurs later) will be recorded in source and eCRF; 
ongoing SAEs after this time frame will be followed until the 
investigator, medical monitor, and sponsor agree that the SAE is 
satisfactorily resolved. SAEs considered by the investigator to be 
related to oliceridine, regardless of the time of onset after treatment, 
should be reported. 
Prior medications taken or administered within the 14 days before 
the first dose of oliceridine will be recorded in source and will also 
be recorded in eCRF. 
Treatment phase 
The treatment phase begins with the predose period and ends when 
the investigator documents that the last dose of oliceridine was 
administered and that the patient will no longer be treated with 
oliceridine. 
The duration of treatment for each patient will be determined by the 
clinical need for parenteral opioid therapy. In current practice, 
parenteral opioids are used as-needed for up to several days. 
Although preclinical toxicology studies support intravenous (IV) 
administration of oliceridine for up to 14 days, it is unlikely that 
patients will receive oliceridine for that duration in the context of 
this study. 
Predose period 
Before dosing with oliceridine, vital signs (blood pressure, heart 
rate, respiratory rate), oxygen saturation, and somnolence/sedation 
will be measured. Somnolence/sedation will be measured using the 
Moline-Roberts Pharmacologic Sedation Scale (MRPSS). During 
the predose period, an additional, post-surgical ECG will be 
performed only in surgical patients. Prior medications and 
AEs/SAEs will be recorded. 
Pain intensity will be measured using a 0-10 point numeric pain 
rating scale (NPRS). 
Predose period procedures will occur within 30 minutes before the 
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first oliceridine dose. If the dosing period is delayed, predose 
period procedures (except the additional, post-surgical ECG 
performed only in surgical patients) will be repeated. 
Dosing period 
Oliceridine IV infusion may be administered either by 
clinician-administered bolus, patient-controlled analgesia device 
(PCA), or both bolus and PCA, according to the clinical situation. 
During dosing with oliceridine, vital signs, oxygen saturation, and 
somnolence/sedation will be measured at any and all times during 
the dosing period consistent with individual patient need and 
institutional standards of care for a patient receiving a parenteral 
opioid. An ECG will be obtained 60 minutes after the first dose of 
oliceridine, and at every 24 hours of oliceridine treatment. Blood 
will be collected for oliceridine pharmacokinetics and future 
cytochrome P450 2D6 (CYP2D6) genotyping. Concomitant 
medications and AEs/SAEs will be recorded. 
NPRS assessments will also be completed at 30 minutes 
+/-10 minutes after the first dose of oliceridine and at any and all 
times during the dosing period consistent with individual patient 
need and institutional standards of care for a patient receiving a 
parenteral opioid. 
End-of-treatment phase 
When the investigator documents that the last dose of oliceridine 
was administered and that the patient will no longer be treated with 
oliceridine, the treatment phase is complete and the 
end-of-treatment phase begins. A physical examination will be 
performed at this time. 
Within 1 hour after completion of the treatment phase, vital signs, 
oxygen saturation, and somnolence/sedation will be measured, and 
concomitant medications and AEs/SAEs will be recorded. 
Within 3 hours after completion of the treatment phase, blood will 
be collected for clinical laboratory tests. Concomitant medications 
and AEs/SAEs will be recorded. 
Patients will be observed for at least three hours after the last dose 
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of oliceridine; however, medically-required transfer of an ED 
patient to another facility takes precedence over study procedures. 
The Subjective Opioid Withdrawal Scale (SOWS) will be 
administered to detect symptoms of opioid withdrawal. If the 
patient is discharged or transferred before the time when the SOWS 
is to be performed, it will be performed one day after completion of 
the treatment phase and returned to the site by mail or in person. 
Follow-up phase 
A follow-up contact will be made between 2 and 3 days after 
completion of the treatment phase. The contact may be conducted 
in person or by telephone. Concomitant medications and AEs/SAEs 
will be recorded. 
The surgical procedure, medical diagnosis or ED diagnosis for 
which parenteral opioid therapy was warranted will be captured 
using the International Classification of Diseases, 10th Revision 
(ICD-10) terminology. 
PLANNED SAMPLE 
SIZE 
Approximately 1000 patients will be treated with oliceridine. 
KEY PATIENT 
SELECTION 
CRITERIA 
Eligibility Criteria 
Inclusion criteria 
Patients must meet all inclusion criteria: 
1. Age >=18 years at screening. 
2. Moderate to severe acute pain for which parenteral opioid 
therapy is warranted, defined as NPRS pain intensity of >=4 
during the predose period. 
3. Able to understand and comply with the procedures and study 
requirements, and to provide written informed consent before 
any study procedure. 
4. If it is anticipated that the patient will be treated with 
oliceridine in the ED with subsequent discharge or transfer to 
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another facility, that the patient will remain under the care of 
the investigator for at least three hours after the last dose of 
oliceridine.  
Exclusion criteria 
Given that the primary objective of this study is to evaluate the 
safety and tolerability of oliceridine in patients with moderate to 
severe acute pain for which parenteral opioid therapy is warranted, 
inclusion of patients that would unduly increase patient risk or 
confound the evaluation of oliceridine’s safety and tolerability is 
not acceptable. The stated exclusion criteria are not exhaustive and 
prudent clinical judgment must also be applied. 
Patients must not meet any of the following exclusion criteria: 
1. Participated in another oliceridine clinical study. 
2. Clinically significant medical, surgical, postsurgical, psychiatric 
or substance abuse condition or history of such condition that 
would confound the interpretation of safety, tolerability, or 
efficacy data in the study. 
3. Hemodynamic instability or respiratory insufficiency; or 
requires a tracheostomy or mechanically assisted ventilation. 
4. If a surgical or medical patient, American Society of 
Anesthesiologists (ASA) Physical Status Classification System 
score of IV or worse; if an ED patient, Emergency Severity 
Index (ESI) triage score of 1. 
5. If an ED patient, alcohol intoxication, acute substance 
impairment or positive urine or serum toxicology screen. 
6. Advanced cancer in palliative or end-of-life care. 
7. Concurrent use of chemotherapeutic or biologic agents for the 
treatment of cancer. 
8. Another current painful condition (other than acute pain for 
which parenteral opioid therapy is warranted) that would 
confound the interpretation of safety, tolerability, or efficacy 
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data in the study.  
9. Clinically significant, immune-mediated hypersensitivity 
reaction to opioids. 
10. Pregnancy, breastfeeding, or positive urine or serum pregnancy 
test at screening. 
11. Hepatic impairment (total bilirubin >2 × upper limit of normal 
[ULN], aspartate aminotransferase [AST] >=1.5 × ULN AND 
alanine aminotransferase [ALT] >=1.5 × ULN) or renal 
impairment (estimated Glomerular Filtration Rate [eGFR] <= 
29 mL/min/1.73 m2 based on the Modification of Diet in Renal 
Disease [MDRD] equation), known or obtained at screening. 
12. History of human immunodeficiency virus, hepatitis B, or 
hepatitis C. 
13. Clinically significant abnormal clinical laboratory values, 
known or obtained at screening. 
14. Clinically significant abnormal ECG, including a QT interval 
corrected for heart rate (Fridericia; QTcF interval) of 
>450 msec in males and >470 msec in females, known or 
obtained at screening. 
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STUDY DRUG 
Oliceridine will be administered as-needed (PRN) via the IV route. 
Depending on the clinical considerations for which parenteral 
opioid therapy is warranted (eg, anticipated duration of therapy, 
clinical site/setting), a patient could receive oliceridine using 
clinician-administered bolus dosing or PCA dosing. A patient may 
receive both methods of administration. 
As in current practice, patient need, analgesic efficacy, and adverse 
responses will guide oliceridine use. Consistent with current opioid 
prescribing practices for acute pain, oliceridine should not be 
administered on a fixed, around-the-clock dosing schedule. 
The oliceridine dosing regimen should be initiated for each patient 
individually, taking into account the patient's severity of pain, 
patient response and prior analgesic treatment experience. 
Individually titrate oliceridine to a dose that provides adequate 
analgesia and minimizes AEs. Continually reevaluate patients 
receiving oliceridine to assess the maintenance of pain control and 
the relative incidence of AEs. 
Clinician-administered bolus dosing 
For clinician-administered bolus dosing, the oliceridine initial dose 
is 1 mg to 2 mg. If clinically indicated, a 1 mg supplemental dose 
may be administered as early as 15 minutes after the initial dose. 
Subsequent doses are 1 to 3 mg every 1 to 3 hours PRN based on 
individual patient need and previous response to oliceridine. 
In settings where rapid analgesia is targeted (e.g., ED or post-
anesthesia care unit (PACU)), the oliceridine initial dose is 1 mg to 
3 mg. If clinically indicated, 1 mg to 3 mg supplemental doses may 
be administered every 5 minutes PRN. Subsequent doses are 1 to 3 
mg every 1 to 3 hours PRN based on individual patient need and 
previous response to oliceridine. 
PCA Regimen 
For PCA dosing, the oliceridine regimen will consist of a loading 
dose, a demand dose, and a lockout interval without a continuous 
baseline infusion.  
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Oliceridine PCA regimen: 
 Loading dose: 1.5 mg. 
 Demand dose: 0.5 mg. 
 Lockout interval: 6 minutes. 
If clinically indicated, throughout the treatment phase, a 1 mg 
supplemental dose may be administered PRN, taking into account 
the patient's utilization of PCA demand doses, individual patient 
need and previous response to oliceridine. 
DURATION OF 
TREATMENT 
The duration of treatment for each patient will be determined by the 
clinical need for parenteral opioid therapy. In current practice, 
parenteral opioids are used as-needed for up to several days. 
Although preclinical toxicology studies support IV administration 
of oliceridine for up to 14 days, it is unlikely that patients will 
receive oliceridine for that duration in the context of this study. 
PERMITTED AND 
PROHIBITED PRIOR 
AND CONCOMITANT 
MEDICATIONS 
Concomitant non-opioid analgesics are permitted. If a concomitant 
parenteral or oral opioid analgesic is used during the treatment 
phase, oliceridine treatment will cease, and the patient will be 
discontinued early and will undergo the end-of-treatment phase and 
follow-up phase procedures as scheduled. 
Unless specifically prohibited, other medications are permitted, 
including common treatments of opioid-related adverse effects (eg, 
antiemetics, antacids, stool laxatives) and medications used to treat 
underlying medical conditions. 
As with conventional opioids, prior and concomitant use of 
anxiolytics, sedative-hypnotics, or other potential CNS depressants 
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requires elevated vigilance, consistent with the Joint Commission 
Sentinel Event Alert for the safe use of opioids in hospitals (The 
Joint Commission, 2012). Similarly, the perioperative use of 
epidural or intrathecal opioids prior to oliceridine requires cautious 
administration and increased monitoring, consistent with the 
American Society of Anesthesiologists Task Force on Neuraxial 
Opioids and the American Society of Regional Anesthesia and Pain 
Medicine Practice Guidelines for the Prevention, Detection, and 
Management of Respiratory Depression Associated with Neuraxial 
Opioid Administration (American Society of Anesthesiologists 
2016). 
Patients receiving medications known to inhibit the CYP2D6 
enzyme or potent cytochrome P450 3A4 (CYP3A4) inhibitors may 
require less frequent dosing of oliceridine. Given that oliceridine is 
administered PRN, differential dosing instructions are not required 
for these patients. 
MAIN PARAMETERS 
OF SAFETY AND 
TOLERABILITY 
The safety and tolerability of oliceridine will be measured as the 
incidence of self-reported or observed AEs, including those related 
to vital sign measurements, oxygen saturation measurements, 
somnolence/sedation scores, physical examination findings, and 
clinical laboratory assessments. 
MAIN PARAMETERS 
OF EFFICACY 
Analgesic efficacy will be measured using NPRS at the following 
time points: 
 
During the predose period. 
 
30 minutes +/-10 minutes after the first dose of oliceridine. 
 
At any and all times during the dosing period consistent with 
individual patient need and institutional standards of care for a 
patient receiving a parenteral opioid. 
STATISTICAL 
ANALYSES 
Sample size 
No formal sample size calculations were made. Approximately 
1000 patients will be treated with oliceridine. 
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Study populations 
All enrolled patients receiving at least 1 dose of oliceridine 
constitute the safety and tolerability analysis data set.  
Safety and tolerability analyses 
The number and incidence of AEs/SAEs will be summarized 
overall and by severity and causality. The Medical Dictionary for 
Regulatory Activities (MedDRA, Version 19.0) will be used to 
classify all events with respect to system organ class and preferred 
term. The World Health Organization Drug Dictionary (WHODD, 
March 2016) will be used to categorize prior and concomitant 
medications. Summaries will include only treatment-emergent AEs 
and will be summarized for the safety and tolerability analysis data 
set. Clinically significant changes in vital sign measurements, 
oxygen saturation measurements, somnolence/sedation scores, 
physical examination findings, and clinical laboratory assessments 
will be summarized via descriptive summary statistics. 
Summary statistics for observed values and change from baseline 
values for vital sign measurements, oxygen saturation 
measurements, somnolence/sedation scores, physical examination 
findings, and clinical laboratory assessments will be summarized. 
Baseline values are defined as the last measurements taken before 
the first dose of oliceridine. SOWS total scores will be summarized. 
Prior and concomitant medications will be summarized. 
Exposure analyses 
The total number of patients treated and the percentage of the 
overall sample treated by method of administration (bolus, PCA, 
both bolus and PCA) will be presented. Exposure data including 
date, time, and dose for each administration of oliceridine will be 
listed for each patient and will include the total amount of 
oliceridine administered using any method of administration within 
0-1 hours, 1-2 hours, 2-3 hours, and every subsequent 3-hour 
period to 24 hours; 24-48 hours, 48-72 hours, and every subsequent 
24-hour period of the treatment phase. Subsequently, the amount of 
oliceridine administered to all patients over these periods and the 
total amount administered during the treatment phase will be 
summarized (mean, standard deviation, median, minimum, and 
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maximum) by the method of administration (bolus, PCA, both 
bolus and PCA) for the safety and tolerability population. All doses 
of oliceridine, whether administered by IV bolus or PCA, will be 
listed. 
Additionally, data will be presented by subgroups for descriptive 
purposes. 
Efficacy analyses 
The NPRS scores at baseline and 30 minutes after the first dose of 
oliceridine, as well as the change from baseline to 30 minutes, will 
be summarized using descriptive summary statistics. All NPRS 
assessments will be listed at each time point where an assessment 
has occurred. 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
SYNOPSIS ...................................................................................................................................... 3 
TABLE OF CONTENTS .............................................................................................................. 15 
TABLES ....................................................................................................................................... 18 
FIGURES ...................................................................................................................................... 18 
LIST OF ABBREVIATIONS ....................................................................................................... 19 
ADMINISTRATIVE STRUCTURE ............................................................................................ 21 
1 
INTRODUCTION ................................................................................................................ 22 
1.1 Background ....................................................................................................................... 22 
1.2 Rationale ........................................................................................................................... 24 
1.3 Study Endpoints ................................................................................................................ 24 
1.3.1 Safety and Tolerability Endpoints ............................................................................. 24 
1.3.2 Efficacy Endpoints .................................................................................................... 25 
1.4 Risks and Benefits for Patients ......................................................................................... 25 
2 
STUDY OBJECTIVES ......................................................................................................... 26 
2.1 Primary Objective ............................................................................................................. 26 
2.2 Secondary Objective ......................................................................................................... 26 
3 
INVESTIGATIONAL PLAN ............................................................................................... 27 
3.1 Overall Study Design and Plan ......................................................................................... 27 
Figure 1: 
Study Schematic ........................................................................................................ 28 
3.1.1 Screening/baseline phase ........................................................................................... 28 
3.1.2 Treatment phase ........................................................................................................ 28 
3.1.3 Predose period ........................................................................................................... 29 
3.1.4 Dosing period ............................................................................................................ 29 
3.1.5 End of treatment phase .............................................................................................. 29 
3.1.6 Follow up phase ......................................................................................................... 30 
3.2 Study Duration .................................................................................................................. 30 
3.3 Study Population ............................................................................................................... 30 
3.3.1 Inclusion Criteria ....................................................................................................... 30 
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3.3.2 Exclusion Criteria ...................................................................................................... 31 
3.4 Early Discontinuation ....................................................................................................... 32 
3.5 Treatments......................................................................................................................... 33 
3.5.1 Details of Study Treatments ...................................................................................... 33 
Table 1:  
Details of the Investigational Product ....................................................................... 33 
3.5.2 Oliceridine Dosing .................................................................................................... 33 
3.5.3 Drug Inventory and Accountability ........................................................................... 34 
3.5.4 Treatment Compliance .............................................................................................. 35 
3.5.5 Permitted and Prohibited Prior and Concomitant Medications ................................. 35 
3.5.6 Drug-Drug Interactions ............................................................................................. 35 
3.6 Study Procedures .............................................................................................................. 36 
Table 2:  
Schedule of Events .................................................................................................... 37 
3.6.1 Screening and Baseline Procedures ........................................................................... 39 
3.6.2 Safety and Tolerability Procedures ........................................................................... 39 
3.6.3 Pharmacokinetic Procedures ..................................................................................... 41 
3.6.4 Efficacy Procedures ................................................................................................... 42 
3.6.5 Other Procedures ....................................................................................................... 42 
4 
ADVERSE EVENT REPORTING....................................................................................... 43 
4.1 Definitions and Criteria..................................................................................................... 43 
4.1.1 Adverse Events .......................................................................................................... 43 
4.1.2 Serious Adverse Events ............................................................................................. 44 
4.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events .......................................................................... 45 
Figure 2: 
Monitoring of Patients with Elevated Hepatic Transaminases ................................. 46 
4.1.4 Evaluating Adverse Events and Serious Adverse Events ......................................... 47 
4.2 Reporting Procedures and Requirements .......................................................................... 49 
4.2.1 Adverse Events .......................................................................................................... 49 
4.2.2 Serious Adverse Events ............................................................................................. 49 
4.2.3 Prompt Reporting of Serious Adverse Events ........................................................... 50 
4.3 Special Considerations ...................................................................................................... 51 
4.3.1 Pregnancy .................................................................................................................. 51 
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4.3.2 Individual Patient Stopping Criteria .......................................................................... 52 
4.3.3 Site Requirements to Ensure Patient Safety .............................................................. 52 
5 
DATA MANAGEMENT...................................................................................................... 54 
6 
STATISTICAL ANALYSIS ................................................................................................ 55 
6.1 Sample Size ....................................................................................................................... 55 
6.2 Study Populations ............................................................................................................. 55 
6.3 Safety and Tolerability Analyses ...................................................................................... 55 
6.4 Exposure Analyses ............................................................................................................ 55 
6.5 Efficacy Analyses ............................................................................................................. 56 
6.6 Protocol Deviations ........................................................................................................... 56 
7 
STUDY MANAGEMENT ................................................................................................... 57 
7.1 Ethics and Consent ............................................................................................................ 57 
7.1.1 Regulations and Guidelines ....................................................................................... 57 
7.1.2 Institutional Review Board/Independent Ethics Committee ..................................... 57 
7.1.3 Informed Consent ...................................................................................................... 57 
7.2 Discontinuation of the Study by the Sponsor ................................................................... 57 
7.3 Study Documentation........................................................................................................ 57 
7.4 Study Monitoring and Auditing ........................................................................................ 58 
7.5 Retention of Records......................................................................................................... 59 
7.6 Use of Study Findings ....................................................................................................... 59 
7.7 Publications ....................................................................................................................... 59 
8 
REFERENCES ..................................................................................................................... 61 
9 
APPENDICES ...................................................................................................................... 63 
9.1 Moline-Roberts Pharmacologic Sedation Scale................................................................ 63 
9.2 Numeric Pain Rating Scale ............................................................................................... 64 
9.3 ASA Physical Status Classification System ..................................................................... 65 
9.4 Emergency Severity Index Triage Algorithm ................................................................... 66 
9.5 Subjective Opiate Withdrawal Scale (SOWS) .................................................................. 67 
 
 
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TABLES 
Table 1:  
Details of the Investigational Product ....................................................................... 33 
Table 2:  
Schedule of Events .................................................................................................... 37 
 
FIGURES 
Figure 1: 
Study Schematic ........................................................................................................ 28 
Figure 2: 
Monitoring of Patients with Elevated Hepatic Transaminases ................................. 46 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ACEP 
American College of Emergency Physicians 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ASA 
American Society of Anesthesiologists  
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CYP2D6 
cytochrome p450 2d6 
CYP3A4 
cytochrome p450 3a4 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ED 
emergency department 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HCV 
hepatitis C virus 
HR 
heart rate 
ICD-10 
International Classification of Diseases, 10th Revision  
IEC 
independent ethics committee 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IgM 
immunoglobulin M  
IND 
investigational new drug  
IB 
investigator’s brochure  
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration 
MDRD 
modification of diet in renal disease 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
MRPSS 
Moline-Roberts Pharmacologic Sedation Scale 
NPRS 
numeric pain rating scale 
PACU 
post-anesthesia care unit 
PCA 
patient-controlled analgesia device 
PK 
pharmacokinetic 
PRN 
as-needed 
Q6min 
every 6 minutes 
RBC 
red blood cells 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOWS 
Subjective Opiate Withdrawal Scale 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WBC 
white blood cells 
WHODD 
World Health Organization Drug Dictionary 
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ADMINISTRATIVE STRUCTURE 
 
Sponsor 
Responsible 
Physician/Back-up 
Medical Monitor: 
Franck Skobieranda, MD 
VP, Clinical Development  
Trevena, Inc. 
1018 West 8th Avenue, Suite A 
King of Prussia, PA 19406 USA 
Phone: (610) 354-8840 
Email: fskobieranda@trevenainc.com 
 
Medical Monitor: 
Joseph “Josh” Krotec, MD, FACOG 
Medical Director 
Chiltern 
1016 West 9th Avenue 
King of Prussia, PA 19406 USA  
Phone: (484) 832-8770  
Email: Joseph.Krotec@Chiltern.com 
 
 
 
 
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1 INTRODUCTION 
1.1 Background 
Inadequately treated pain has significant short- and long-term consequences, including prolonged 
emergency department stays, psychological disturbances, and dissatisfaction with medical care. 
Opioid analgesics like morphine, fentanyl, and hydromorphone are mainstays of acute pain 
management; however, their use is hampered by well-known adverse events (AEs), such as 
respiratory depression, nausea, vomiting, and sedation (Lubawski, 2008) (Philip, 2002). 
Ultimately, the unmet medical need in acute pain therapy is an increased level of efficacy with 
acceptable tolerability. 
Beta-arrestin knock-out animals treated with morphine were shown to experience improved 
analgesic efficacy, less respiratory depression and less constipation, compared with wild-type 
animals (Bohn, 1999) (Raehal, 2005). This led to the hypothesis that analgesia and AEs are 
mediated by two distinct signaling pathways distal to the μ-opioid receptor and that a selective 
μ-opioid receptor ligand that stimulates G protein signaling without stimulating β-arrestin 
recruitment could be a better analgesic. 
Oliceridine selectively binds to the μ-opioid receptor with high affinity; however, oliceridine is a 
G protein biased ligand at the μ-opioid receptor in that it stimulates G protein signaling without 
stimulating β-arrestin recruitment. In preclinical species, this biased signaling profile has led to 
potent analgesic efficacy, with less respiratory depression, slowing of gastrointestinal motility, 
and sedation, compared with morphine.  
To date, oliceridine has been evaluated in phase 1 and 2 clinical studies. A total of 185 healthy 
subjects have received single intravenous (IV) infusions of oliceridine (0.15 mg to 7 mg), and 
40 healthy subjects have received multiple IV infusions (<=4.5 mg every 6 hours; 4 mg every 
4 hours) in phase 1 studies. At those doses, oliceridine was generally well tolerated. The most 
commonly reported AEs included dizziness, nausea, somnolence, and feeling hot.  
A total of 296 patients have received IV infusions of oliceridine (0.5 mg to 4 mg) in two phase 2 
studies. At those doses, oliceridine was generally well-tolerated. The most commonly reported 
AEs were nausea, dizziness, vomiting, and headache. 
Oliceridine was evaluated for the treatment of moderate to severe acute pain following 
bunionectomy in a multicenter, double-blind, randomized, placebo- and active-controlled, 
2-stage, adaptive-design, phase 2 study (Viscusi, 2016). A total of 339 subjects received 
oliceridine (0.5 mg to 4 mg every 3 or 4 hours), morphine (4 mg every 4 hours), or placebo. The 
oliceridine dosing frequency of every 4 hours was found to be suboptimal in the first stage of the 
study; thus, the frequency was shifted to every 3 hours in the second stage. Oliceridine 2 mg 
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(-1.4, P=0.0024) and oliceridine 3 mg (-2.4, P<0.0001) administered every 3 hours and morphine 
4 mg (-1.3, P=0.0023) administered every 4 hours produced analgesic efficacy, as measured by 
time-weighted average change from baseline in numeric rating scale (NRS) pain intensity scores 
over 48 hours, compared with placebo. In a pre-specified secondary analysis, oliceridine 3 mg 
resulted in significant improvement (P=0.014) in NRS scores over 48 hours compared with 
morphine. Furthermore, oliceridine 2 mg and 3 mg resulted in significant categorical pain relief 
following the first dose, compared with placebo (P<0.0001) and morphine (P=0.0005 and 
P<0.001, respectively). The majority of subjects receiving oliceridine >=1 mg reported 
stopwatch-method meaningful pain relief. The most frequently reported AEs following treatment 
with oliceridine were nausea, dizziness, headache, and vomiting. AEs and their severity were 
generally dose related. 
Oliceridine was evaluated for the treatment of moderate to severe acute pain following 
abdominoplasty in a double-blind, randomized, placebo- and active-controlled, phase 2 study. 
Study treatments were delivered by a patient-controlled analgesia (PCA) regimen, consisting of a 
loading dose, demand dose, and a lockout-interval. For the first half of the study, the oliceridine 
regimen was a 1.5 mg loading dose (as two 0.75 mg doses separated by 10 minutes), 0.1 mg 
demand doses, and a 6-minute lockout interval. The morphine regimen was a 4 mg loading dose 
(as two 2 mg doses separated by 10 minutes), 1 mg demand doses and a 6-minute lockout 
interval. As oliceridine was not previously administered in a PCA regimen, a prespecified 
interim analysis was planned to adjust the oliceridine PCA regimen after review of existing 
efficacy, safety and tolerability, and utilization data. For the second half of the study, the 
oliceridine demand dose was 0.35 mg with a 6-minute lockout interval. Oliceridine demonstrated 
statistically significant pain reduction compared to placebo and similar efficacy to morphine 
(oliceridine 0.1 mg regimen reduced average pain scores [LS mean change in time-weighted 
average over 24 hours] by 2.3 points [P<0.0001 vs. placebo]; oliceridine 0.35 mg by 2.1 points 
[P=0.0003 vs. placebo]; morphine, by 2.1 points [P=0.0001 vs. placebo]). The mean oliceridine 
utilization over the 24-hour treatment period for the 0.1 mg group was 7.6 mg, and for the 0.35 
group, 14.8 mg. Rescue pain medication use was similar for both oliceridine (31% with 
oliceridine 0.1 mg, 21% with oliceridine 0.35 mg) and morphine (25%), and less than half the 
rate for placebo (64%; post hoc P<0.0005 for all three active groups vs. placebo). For the 
purpose of this study, hypoventilation events were defined as apparent and persistently decreased 
respiratory rate, respiratory effort or oxygen saturation. Oliceridine had a significantly lower 
prevalence of hypoventilation events, nausea, and vomiting than the morphine group (post hoc 
P<0.05 for both oliceridine regimens vs. morphine): 
 
 
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Placebo 
Oliceridine 
0.1 mg 
Oliceridine 
0.35 mg 
Morphine 
 
Hypoventilation 
10% 
15% 
31% 
53% 
Vomiting 
8% 
15% 
15% 
42% 
Nausea 
18% 
41% 
46% 
72% 
Oliceridine preclinical and clinical data are summarized in the current investigator’s brochure 
(IB).  
1.2 Rationale 
Consistent with the Food and Drug Administration (FDA) requirements for premarketing safety 
databases, the proposed population in this clinical study is sufficiently diverse to adequately 
represent the target population (patients with moderate to severe acute pain for which parenteral 
opioid therapy is warranted) (Food and Drug Administration, 2005). 
Consistent with the known pharmacological properties of oliceridine and clinical observations 
obtained from completed studies with oliceridine, essentially, only patients with 
contraindications to opioid therapy or other clinical considerations confounding an interpretation 
of safety, tolerability, or efficacy data have been excluded. Eligibility criteria therefore support 
evaluation of oliceridine in patients with a range of conditions warranting parenteral opioid 
therapy, treated across a clinical trial environment characterized by diverse site topologies 
(institutions, investigators) within the United States, for variable durations of treatment. 
Oliceridine will be administered as-needed (PRN) via the IV route. Depending on the clinical 
considerations for which parenteral opioid therapy is warranted (eg, anticipated duration of 
therapy, clinical setting), a patient could receive oliceridine using clinician-administered bolus 
dosing, PCA, or both bolus and PCA. 
1.3 Study Endpoints 
1.3.1 Safety and Tolerability Endpoints 
The safety and tolerability of oliceridine will be measured as the incidence of self-reported or 
observed AEs, including those related to vital sign measurements, oxygen saturation 
measurements, somnolence/sedation scores, physical examination findings, and clinical 
laboratory assessments. Somnolence/sedation will be measured using the Moline-Roberts 
Pharmacologic Sedation Scale (MRPSS; see Section 9.1) (Moline, 2012). The MRPSS is 
designed to provide a consistent method of assessing pharmacologic sedation and assist in the 
decision-making process regarding the administration of opioids, sedatives, and other agents 
which produce sedation. For patients receiving a parenteral opioid in current practice, intensive 
monitoring is the standard of care. This monitoring will be used in the current study to evaluate 
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oliceridine. Protocol-specified patient monitoring is compatible with the Joint Commission 
Sentinel Event Alert for the safe use of opioids in hospitals (The Joint Commission, 2012). 
1.3.2 Efficacy Endpoints 
The analgesic efficacy of oliceridine will be measured using a 0-10 point numeric pain rating 
scale (NPRS, see Section 9.2). NPRS was selected given its frequent use in clinical practice and 
clinical research (McCaffery, 1989). The NPRS may be explained or shown to the patient, who 
responds by indicating a number (Hjermstad, 2011). 
1.4 Risks and Benefits for Patients 
The potential benefit of study participation is that patients may experience a reduction in pain as 
a result of treatment with oliceridine. Patients will also contribute to the clinical data set for 
oliceridine, an investigational product (IP). No other benefits of participation are anticipated. 
The potential risks of study participation include lack of analgesic efficacy, known or unknown 
serious or non-serious AEs, and unknown risks inherent in the evaluation of an IP. Additional 
risks are those associated with medical evaluation, such as those associated with venipuncture. 
Oliceridine preclinical and clinical data are summarized in the current IB. Investigators must 
become familiar with all sections of the IB before the start of the study. 
 
 
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2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to evaluate the safety and tolerability of oliceridine in patients with 
moderate to severe acute pain for which parenteral opioid therapy is warranted. 
2.2 Secondary Objective 
The secondary objective is to evaluate the analgesic efficacy of oliceridine. 
 
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3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan 
This phase 3, open-label, safety study will be conducted in inpatient hospitals, outpatient hospital 
departments, ambulatory surgical care centers, and emergency departments (EDs). Patients 
recruited in EDs may continue oliceridine treatment if hospitalized and parenteral opioid therapy 
is warranted.  
Representative surgeries include orthopedic (eg, total hip replacement, total knee replacement, 
spine), abdominal (eg, upper or lower abdominal, perineal), gynecologic (eg, total abdominal 
hysterectomy), vascular, soft tissue, and surgical procedural pain. 
Representative medical conditions include acute pancreatitis, acute exacerbation of existing 
noncancerous chronic pain, musculoskeletal pain, sickle-cell disease, inflammatory orofacial 
muscle pain, and renal colic. Medical conditions that could confound the evaluation of 
oliceridine are excluded, such as acute pain without a specific etiology, undifferentiated acute 
abdominal pain, acute breakthrough pain in palliative “end of life” care, and pain associated with 
advanced cancer (somatic, visceral, or neuropathic) or with concurrent use of chemotherapeutic 
or biologic agents for the treatment of cancer. 
Representative ED conditions include visceral pain (eg, renal colic, upper abdominal pain, 
abdominal pelvic pain); nonvisceral pain (eg, traumatic and atraumatic acute musculoskeletal 
pain, chest wall pain, burns, orofacial pain/headache, cutaneous and soft tissue pain); procedural 
analgesia (eg, reduction of orthopedic fractures and dislocations, abscess incision and drainage); 
acute painful episodes associated with a medical condition (eg, sickle cell painful vaso-occlusive 
episode). Oliceridine will not be used to intentionally suppress a patient’s level of consciousness 
(procedural sedation and analgesia as defined by the American College of Emergency Physicians 
[ACEP]). 
The study has four phases: a screening/baseline phase, a treatment phase (consisting of a predose 
period and a dosing period), an end-of-treatment phase, and a follow-up phase. 
 
 
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Figure 1: 
Study Schematic 
 
Abbreviations: T0 = time of first dose of oliceridine; h = hours 
* Combined if occurring within 48 hours of each other, unless the clinical condition of the patient has significantly changed since 
screening 
3.1.1 Screening/baseline phase 
Written informed consent will be obtained before any protocol-related activities are conducted. 
All screening procedures will be completed within 14 days before the first oliceridine dose. 
Select standard of care assessments (eg, chemistry, hematology, urine or serum pregnancy test, 
urine or serum toxicology screen, electrocardiogram (ECG)) obtained before informed consent 
may be used as study data if protocol specifications and timeframes are met (see Section 3.6.1). 
When screening and baseline procedures are anticipated to occur within 48 hours of each other, 
they may be executed as a single procedure, unless the clinical condition of the patient has 
significantly changed since screening. 
Adverse events (AEs) occurring from time of informed consent to the follow up phase will be 
recorded in source and will also be recorded in eCRF if the patient receives oliceridine. Serious 
Adverse Events (SAEs) occurring from time of informed consent to the follow-up phase or 
7 days after the last dose of oliceridine (whichever occurs later) will be recorded in source and 
eCRF; ongoing SAEs after this time frame will be followed until the investigator, medical 
monitor, and sponsor agree that the SAE is satisfactorily resolved. SAEs considered by the 
investigator to be related to oliceridine, regardless of the time of onset after treatment, should be 
reported. 
Prior medications taken or administered within the 14 days before the first dose of oliceridine 
will be recorded in source and will also be recorded in eCRF. 
3.1.2 Treatment phase 
The treatment phase begins with the predose period and ends when the investigator documents 
that the last dose of oliceridine was administered and that the patient will no longer be treated 
with oliceridine. 
The duration of treatment for each patient will be determined by the clinical need for parenteral 
opioid therapy. In current practice, parenteral opioids are used as-needed for up to several days. 
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Although preclinical toxicology studies support intravenous (IV) administration of oliceridine for 
up to 14 days, it is unlikely that patients will receive oliceridine for that duration in the context of 
this study. 
3.1.3 Predose period 
Before dosing with oliceridine, vital signs (blood pressure, heart rate, respiratory rate), oxygen 
saturation, and somnolence/sedation will be measured. Somnolence/sedation will be measured 
using the MRPSS. During the predose period, an additional, post-surgical ECG will be 
performed only in surgical patients. Prior medications and AEs/SAEs will be recorded. 
Pain intensity will be measured using a 0-10 point numeric pain rating scale (NPRS). 
Predose period procedures will occur within 30 minutes before the first oliceridine dose. If the 
dosing period is delayed, predose period procedures (except the additional, post-surgical ECG 
performed only in surgical patients) will be repeated. 
3.1.4 Dosing period 
Oliceridine IV infusion may be administered either by clinician-administered bolus, PCA, or 
both bolus and PCA, according to the clinical situation. 
During dosing with oliceridine, vital signs, oxygen saturation, and somnolence/sedation will be 
measured at any and all times during the dosing period consistent with individual patient need 
and institutional standards of care for a patient receiving a parenteral opioid. An ECG will be 
obtained 60 minutes after the first dose of oliceridine, and at every 24 hours of oliceridine 
treatment. Blood will be collected for oliceridine pharmacokinetics and future cytochrome P450 
2D6 (CYP2D6) genotyping. Concomitant medications and AEs/SAEs will be recorded. 
NPRS assessments will also be completed at 30 minutes +/ 10 minutes after the first dose of 
oliceridine and at any and all times during the dosing period consistent with individual patient 
need and institutional standards of care for a patient receiving a parenteral opioid. 
3.1.5 End of treatment phase 
When the investigator documents that the last dose of oliceridine was administered and that the 
patient will no longer be treated with oliceridine, the treatment phase is complete and the end of 
treatment phase begins. A physical examination will be performed at this time. 
Within 1 hour after completion of the treatment phase, vital signs, oxygen saturation, and 
somnolence/sedation will be measured, and concomitant medications and AEs/SAEs will be 
recorded. 
Within 3 hours after completion of the treatment phase, blood will be collected for clinical 
laboratory tests. Concomitant medications and AEs/SAEs will be recorded. 
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Patients will be observed for at least three hours after the last dose of oliceridine; however, 
medically-required transfer of an ED patient to another facility takes precedence over study 
procedures. 
The Subjective Opioid Withdrawal Scale (SOWS) will be administered to detect symptoms of 
opioid withdrawal. If the patient is discharged or transferred before the time when the SOWS is 
to be performed, it will be performed one day after completion of the treatment phase and 
returned to the site by mail or in person. 
3.1.6 Follow up phase 
A follow up contact will be made between 2 and 3 days after completion of the treatment phase. 
The contact may be conducted in person or by telephone. Concomitant medications and 
AEs/SAEs will be recorded. 
The surgical procedure, medical diagnosis or ED diagnosis for which parenteral opioid therapy 
was warranted will be captured using the International Classification of Diseases, 10th Revision 
(ICD-10) terminology. 
3.2 Study Duration 
The duration of treatment for each patient will be determined by the clinical need for parenteral 
opioid therapy. In current practice, parenteral opioids are used as-needed for up to several days. 
Although preclinical toxicology studies support IV administration of oliceridine for up to 14 
days, it is unlikely that patients will receive oliceridine for that duration in the context of this 
study. 
3.3 Study Population 
The study population consists of patients with moderate to severe acute pain for which parenteral 
opioid therapy is warranted. 
3.3.1 Inclusion Criteria 
Patients must meet all the inclusion criteria:  
1. Age >=18 years at screening. 
2. Moderate to severe acute pain for which parenteral opioid therapy is warranted, defined as 
NPRS pain intensity of >=4 during the pre-dose period. 
3. Able to understand and comply with the procedures and study requirements, and to provide 
written informed consent before any study procedure. 
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4. If it is anticipated that the patient will be treated with oliceridine in the ED with subsequent 
discharge or transfer to another facility, that the patient will remain under the care of the 
investigator for at least three hours after the last dose of oliceridine. 
3.3.2 Exclusion Criteria 
Given that the primary objective of this study is to evaluate the safety and tolerability of 
oliceridine in patients with moderate to severe acute pain for which parenteral opioid therapy is 
warranted, imprudent inclusion of unsuitable patients that would unduly increase patient risk or 
confound the evaluation of oliceridine is not acceptable. The stated exclusion criteria are not 
exhaustive and prudent clinical judgment must be applied. 
Patients must not meet any of the following exclusion criteria: 
1. Participated in another oliceridine clinical study. 
2. Clinically significant medical, surgical, postsurgical, psychiatric or substance abuse condition 
or history of such condition that would confound the interpretation of safety, tolerability, or 
efficacy data in the study. 
3. Hemodynamic instability or respiratory insufficiency; or requires a tracheostomy or 
mechanically assisted ventilation. 
4. If a surgical or medical patient, American Society of Anesthesiologists (ASA) Physical 
Status Classification System score of IV or worse (see Section 9.3) (American Society of 
Anesthesiologists, 2014); if an ED patient, Emergency Severity Index (ESI) triage score of 1 
(see Section 9.4) (Gilboy, 2011). 
5. If an ED patient, alcohol intoxication, acute substance impairment or positive urine or serum 
toxicology screen. 
6. Advanced cancer in palliative or end-of-life care. 
7. Concurrent use of chemotherapeutic or biologic agents for the treatment of cancer. 
8. Another current painful condition (other than acute pain for which parenteral opioid therapy 
is warranted) that would confound the interpretation of safety, tolerability, or efficacy data in 
the study.  
9. Clinically significant, immune-mediated hypersensitivity reaction to opioids. 
10. Pregnancy, breastfeeding, or positive urine or serum pregnancy test at screening. 
11. Hepatic impairment (total bilirubin >2 × upper limit of normal [ULN], aspartate 
aminotransferase [AST] >=1.5 × ULN AND alanine aminotransferase [ALT] >=1.5 × ULN) 
or renal impairment (estimated Glomerular Filtration Rate [eGFR] <= 29 mL/min/1.73 m2 
based on the Modification of Diet in Renal Disease [MDRD] equation), known or obtained at 
screening (Levey, 2009). 
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12. History of human immunodeficiency virus, hepatitis B, or hepatitis C. 
13. Clinically significant abnormal clinical laboratory values, known or obtained at screening. 
14. Clinically significant abnormal electrocardiogram (ECG), including a QT interval corrected 
for heart rate (Fridericia; QTcF interval) of >450 msec in males and >470 msec in females, 
known or obtained at screening. 
3.4 Early Discontinuation 
All patients will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. Every reasonable attempt should be made by the 
investigator to keep patients in the study; however, patients must be withdrawn from the study if 
they withdraw consent to participate. 
If a patient is discontinued early, the investigator will make every effort to complete 
end-of-treatment phase and follow-up phase procedures. 
An electronic case report form (eCRF) should be completed for every patient who receives 
oliceridine, whether or not the patient completes the study. The reason for the early 
discontinuation should be indicated on this form. The following standard categories should be 
used to select a primary reason for early discontinuation: 
 Adverse event: clinical or para-clinical events occurred that, in the medical judgment of 
the investigator for the best interest of the patient, are grounds for discontinuation. This 
includes serious and non-serious AEs regardless of relation to the IP. 
 Lack of efficacy 
 Withdrawal of consent: the patient desired to withdraw from further participation in the 
study in the absence of an investigator-determined medical need to withdraw. If the 
patient gave a reason for withdrawing, it should be recorded in the eCRF. 
 Investigator decision 
 Protocol deviation: the investigator or patient was noncompliant with study procedures 
or the patient did not satisfy the entry criteria for the study 
 Lost to follow-up: the patient stopped coming for visits and study personnel were unable 
to contact the patient. 
 Other: the patient was discontinued for a reason other than those listed above, such as 
“dosing limit”, pregnancy or termination of study by the sponsor. The reason(s) should be 
recorded in the eCRF. 
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3.5 Treatments 
3.5.1 Details of Study Treatments 
Information about oliceridine is provided in Table 1Table 1. 
Table 1:  
Details of the Investigational Product 
 
Oliceridine 
IP name 
TRV130 fumarate for injection 
Manufacturer 
Trevena, Inc. 
Vial size 
1, 2, 10 or 30 mL 
Route 
IV 
Formulation 
Injection 
Strength(s) 
1 mg/mL as free base 
Oliceridine (TRV130 fumarate for injection) is formulated as a sterile aqueous solution 
(1 mg/mL, as free base) in a pH 7 solution containing L-histidine and mannitol. 
Oliceridine is provided as a sterile, clear, colorless solution filled in 1, 2, 10, or 30 mL clear glass 
(type I) vials sealed with a coated rubber stopper, aluminum crimp, and flip-off plastic cap. The 
vial size(s) provided to the site will be determined by vial availability and the planned use at the 
site (e.g., 30 mL vials will only be provided to sites using the PCA regimen). 
Refer to the Pharmacy and Oliceridine (TRV130) Medication Use Manual for the drug product 
stability, shipping, and storage conditions, and preparation instructions. 
3.5.2 Oliceridine Dosing 
3.5.2.1 General considerations 
Oliceridine will be administered PRN via the IV route. Depending on the clinical considerations 
for which parenteral opioid therapy is warranted (eg, anticipated duration of therapy, clinical 
site/setting), a patient could receive oliceridine using clinician-administered bolus dosing or PCA 
dosing. A patient may receive both methods of administration. 
As in current practice, patient need, analgesic efficacy, and adverse responses will guide 
oliceridine use. Consistent with current opioid prescribing practices for acute pain, oliceridine 
should not be administered on a fixed, around-the-clock dosing schedule. 
The oliceridine dosing regimen should be initiated for each patient individually, taking into 
account the patient's severity of pain, patient response and prior analgesic treatment experience. 
Individually titrate oliceridine to a dose that provides adequate analgesia and minimizes AEs. 
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Continually reevaluate patients receiving oliceridine to assess the maintenance of pain control 
and the relative incidence of AEs. 
3.5.2.2 Dosing schedule 
3.5.2.2.1 Clinician-administered bolus dosing 
For clinician-administered bolus dosing, the oliceridine initial dose is 1 mg to 2 mg. If clinically 
indicated, a 1 mg supplemental dose may be administered as early as 15 minutes after the initial 
dose. Subsequent doses are 1 to 3 mg every 1 to 3 hours PRN based on individual patient need 
and previous response to oliceridine. 
In settings where rapid analgesia is targeted (e.g., ED or post-anesthesia care unit (PACU)), the 
oliceridine initial dose is 1 mg to 3 mg. If clinically indicated, 1 mg to 3 mg supplemental doses 
may be administered every 5 minutes PRN. Subsequent doses are 1 to 3 mg every 1 to 3 hours 
PRN based on individual patient need and previous response to oliceridine. 
3.5.2.2.2 PCA Regimen 
For PCA dosing, the oliceridine regimen will consist of a loading dose, a demand dose, and a 
lockout interval without a continuous baseline infusion. 
Oliceridine PCA regimen: 
 Loading dose: 1.5 mg. 
 Demand dose: 0.5 mg. 
 Lockout interval: 6 minutes. 
If clinically indicated, throughout the treatment phase, a 1 mg supplemental dose may be 
administered PRN, taking into account the patient's utilization of PCA demand doses, individual 
patient need and previous response to oliceridine.   
3.5.2.3 Dosing Limit  
For the current study, the dosing limit for oliceridine will be 60 mg in the first 12 hours. If a 
patient reaches this dosing limit within the first 12 hours, a PK sample will be obtained, the 
patient will early discontinue oliceridine and will be managed conventionally. 
3.5.3 Drug Inventory and Accountability 
The investigator must keep an accurate accounting of the number of IP units delivered to the site, 
dispensed to patients, returned to the investigator by site staff, returned to the sponsor, or any 
other disposition during and at completion of the study. The IP must be administered by an 
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appropriately qualified person. The IP is to be used in accordance with the protocol by patients 
who are enrolled in this clinical study. Investigators should maintain records that adequately 
document that patients were provided the doses specified by the protocol and reconcile all IP 
received at the site before final disposition. At the end of the study, or as directed, all study 
drugs, including unused, partially used, and empty containers will be accounted for. 
3.5.4 Treatment Compliance 
Treatment consists of parenteral opioid therapy administered by qualified medical personnel. 
There is no opportunity for self-administration outside of the confines of PCA, and the study 
drug is not dispensed to an enrolled patient outside of the confines of the investigative site. 
3.5.5 Permitted and Prohibited Prior and Concomitant Medications 
Prior medications are defined as those taken before the first dose of oliceridine. Concomitant 
medications are defined as those taken after the first dose of oliceridine. 
Concomitant non-opioid analgesics are permitted. If a concomitant parenteral or oral opioid 
analgesic is used during the treatment phase, oliceridine treatment will cease, and the patient will 
be discontinued early and will undergo the end-of-treatment phase and follow-up phase 
procedures as scheduled. 
Unless specifically prohibited, other medications are permitted, including common treatments of 
opioid-related adverse effects (eg, antiemetics, antacids, stool laxatives) and medications used to 
treat underlying medical conditions. 
As with conventional opioids, prior and concomitant use of anxiolytics, sedative-hypnotics, or 
other potential CNS depressants requires elevated vigilance, consistent with the Joint 
Commission Sentinel Event Alert for the safe use of opioids in hospitals (The Joint Commission, 
2012). Similarly, the perioperative use of epidural or intrathecal opioids prior to oliceridine 
requires cautious administration and increased monitoring, consistent with the American Society 
of Anesthesiologists Task Force on Neuraxial Opioids and the American Society of Regional 
Anesthesia and Pain Medicine Practice Guidelines for the Prevention, Detection, and 
Management of Respiratory Depression Associated with Neuraxial Opioid Administration 
(American Society of Anesthesiologists 2016). 
Supplemental oxygen will be recorded as a prior and/or concomitant medication. 
3.5.6 Drug-Drug Interactions 
Both non-clinical and clinical data show that oliceridine is metabolized by both CYP3A4 and 
CYP2D6, with each enzyme contributing approximately 50% to the clearance of oliceridine. 
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The CYP2D6 enzyme is subject to significant genetic polymorphism which may affect the 
clearance of drugs metabolized by CYP2D6. For example, about 7%-10% of the Caucasian 
population may have low functional levels of CYP2D6 in the liver and are classified as “poor 
metabolizers”. The clearance of oliceridine in subjects who are poor metabolizers of CYP2D6 
substrates is reduced by approximately 50% relative to extensive metabolizers. Patients who are 
taking concomitant medications known to inhibit the CYP2D6 enzyme (eg, paroxetine, 
fluoxetine, quinidine, bupropion) will have a similar reduction in oliceridine clearance compared 
to poor metabolizers. Patients who are CYP2D6 poor metabolizers, or who are taking a 
concomitant drug known to inhibit the CYP2D6 enzyme, may require less frequent dosing of 
oliceridine. Given that oliceridine is administered PRN, differential dosing instructions are not 
required for these patients.  
Patients receiving oliceridine concomitantly with a potent CYP3A4 inhibitor (eg, clarithromycin, 
indinavir, itraconazole, ritonavir, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) will also show a reduction in 
clearance of oliceridine of about 50%. These patients may require less frequent dosing of 
oliceridine. Given that oliceridine is administered PRN, differential dosing instructions are not 
required for these patients. 
3.6 Study Procedures 
Study procedures are outlined in the Schedule of Events (Table 2Table 2); selected procedures 
are described thereafter.  
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Table 2:  
Schedule of Events 
Procedures 
Screening 
phase1 
(<= 14 
days 
before 
first dose 
of 
oliceridin
e) 
Baselin
e 
phase1 
(Day 1) 
Treatment phase 
(up to 14 days) 
End-of-treatment phase2 
 
Follow-up phase3 
(Between 2 days and 3 days after 
completion of treatment phase) 
Predose 
(Day 1) 
T0 to last 
dose of 
oliceridine
4 
End-of-
treatment 
documentati
on2 
Within 
1hour after 
completion 
of treatment 
phase2 
Within 
3 hours after 
completion of 
treatment 
phase2 
One day 
after 
completion 
of treatment 
phase 
Informed consent5 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
Eligibility criteria  
X 
X 
 
 
 
 
 
 
 
ASA physical status 
classification6 
X 
X 
 
 
 
 
 
 
 
ESI7 
X 
 
 
 
 
 
 
 
 
Physical examination2 
X 
X 
 
 
X 
 
 
 
 
Clinical laboratories8 
X 
X 
 
 
 
 
X 
 
 
Blood sample for future 
CYP2D6 genotyping 
 
 
 
X 
 
 
 
 
 
Urine or serum 
pregnancy test9 
X 
X 
 
 
 
 
 
 
 
Urine or serum 
toxicology screen10 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
Height11 
X 
 
 
 
 
 
 
 
 
ECG 
X 
X 
X12 
X13 
 
 
 
 
 
PK sampling14 
 
 
 
X 
 
 
 
 
 
PCA patient training15 
X 
X 
X 
X 
 
 
 
 
 
Oliceridine dosing 
 
 
 
X 
 
 
 
 
 
NPRS16 
 
X 
X 
X 
 
X 
 
 
 
Vital signs17 
X 
X 
X 
X 
 
X 
 
 
 
MRPSS18 
 
 
X 
X 
 
X 
 
 
 
SOWS19 
 
 
 
 
 
 
 
X 
 
Oxygen saturation20 
 
 
----------X---------- 
 
 
 
 
 
Prior, concomitant 
medications21 
--------------X-------------- 
------------------------------------------------------------X---------------------------------------------------------- 
AE/SAE reporting22 
-----------------------------------------------------------------------------------X----------------------------------------------------------------------------- 
 
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Abbreviations: AE = adverse event; ASA = American Society of Anesthesiologists; CYP2D6 = cytochrome P450 2D6; ECG = electrocardiogram; ESI = Emergency Severity Index; 
MRPSS = Moline-Roberts Pharmacologic Sedation Scale; NPRS = Numeric Pain Rating Scale; PCA = patient-controlled analgesia device; PK = pharmacokinetic; 
SAE = serious adverse event; SOWS = Subjective Opiate Withdrawal Scale; T0 = time of first oliceridine dose. 
 
1. 
When screening and baseline procedures are anticipated to occur within 48 hours of each other, they may be executed as a single procedure, unless the clinical condition 
of the patient has significantly changed since screening. 
2. 
When the investigator documents that the last dose of oliceridine was administered and that the patient will no longer be treated with oliceridine, the treatment phase is 
complete and the end-of-treatment phase begins. A physical examination will be performed at this time. 
3. 
Follow-up contact may be conducted in person or by telephone. 
4. 
Procedures will be performed at any and all times during the dosing period consistent with individual patient need and institutional standards of care for a patient receiving 
a parenteral opioid. 
5. 
Written informed consent. 
6. 
If a surgical or medical patient. Refer to Section 9.3 for the ASA scale. 
7. 
If an ED patient. Refer to Section 9.4 for the ESI scale. 
8. 
Blood chemistry and hematology will be obtained using local laboratories and local laboratory range values. 
9. 
Female patients of childbearing potential only. 
10. If an ED patient. 
11. Height may be obtained by measurement or patient attestation. 
12. During the predose period, an additional, post-surgical ECG will be performed only in surgical patients. 
13. ECG will be obtained during the Treatment Phase at 60 minutes after the first dose of oliceridine, and at every 24 hours of oliceridine treatment. 
14. PK samples will be collected at two times during the treatment phase: sample 1 at 30 minutes (+/- 10 minutes) after the first dose; sample 2 between 1 and 2 hours after 
the first dose. Unscheduled PK samples may be required. Refer to Sections 3.5.2.3 and 3.6.3. 
15. PCA patient training is required before PCA use. If PCA is planned, training will occur during the screening and baseline phases; if PCA is started during the treatment 
phase, training will occur before PCA use. Training is repeated according to patient need. 
16. NPRS will be measured during the predose period, at 30 minutes +/-10 minutes after the first dose of oliceridine, and at any and all times during the dosing period 
consistent with individual patient need and institutional standards of care for a patient receiving a parenteral opioid (see Section 9.2). 
17. Blood pressure, heart rate, respiratory rate, and temperature. Temperature will be measured at screening and baseline only. 
18. Refer to Section 9.1 for the MPRSS. 
19. Refer to Section 9.5 for the SOWS. If the patient is discharged or transferred before the time when the SOWS is to be performed, it will be performed one day after 
completion of the treatment phase and returned to the site by mail or in person. 
20. Oxygen saturation monitoring will be continuous but will be recorded at any and all times during the dosing period consistent with individual patient need and institutional 
standards of care for a patient receiving a parenteral opioid. The date and time of initiation and discontinuation of continuous oxygen saturation monitoring will be 
recorded in the source documents. 
21. Prior medications are defined as those taken before the first dose of oliceridine. Concomitant medications are defined as those taken after the first dose of oliceridine. Prior 
medications taken or administered within the 14 days before the first dose of oliceridine will be recorded in source and will also be recorded in eCRF. Supplemental 
oxygen will be recorded as a prior and/or concomitant medication. 
22. AEs occurring from time of informed consent to the follow-up phase will be recorded in source and will also be recorded in eCRF if the patient receives oliceridine. SAEs 
occurring from time of informed consent to the follow-up phase or 7 days after the last dose of oliceridine (whichever occurs later) will be recorded in source and eCRF; 
ongoing SAEs after this time frame will be followed until the investigator, medical monitor, and sponsor agree that the SAE is satisfactorily resolved. SAEs considered by 
the investigator to be related to oliceridine, regardless of the time of onset after treatment, should be reported.  
 
 
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3.6.1 Screening and Baseline Procedures 
 When screening and baseline procedures are anticipated to occur within 48 hours of each 
other, they may be executed as a single procedure, unless the clinical condition of the patient 
has significantly changed since screening. 
 For this study, AE reporting begins from time of informed consent. 
 Height without shoes will be measured or obtained by patient attestation and recorded in 
inches. Weight without shoes will be measured and recorded in pounds. 
 Urine or serum pregnancy test will be performed on female patients of childbearing potential 
only. Tests obtained before informed consent may be used as study data if obtained within 24 
hours before the first dose of oliceridine or obtained during the current ED visit. 
 Standard, 12-lead ECG will be captured using local equipment. Tests obtained before 
informed consent may be used as study data if obtained within 14 days before the first dose 
of oliceridine or obtained during the current ED visit. 
 PCA patient training is required before PCA use. If PCA is planned, training will occur 
during the screening and baseline phases; if PCA is started during the treatment phase, 
training will occur before PCA use. Training is repeated according to patient need. 
 American Society of Anesthesiologists (ASA) Physical Status Classification System score (if 
a surgical or medical patient); if an ED patient, Emergency Severity Index (ESI) triage score 
(if an ED patient) (see Sections 9.3 and 9.4). 
 If an ED patient, urine or serum toxicology screen. Test results obtained before informed 
consent may be used as study data if obtained during the current ED visit. 
 Clinical laboratories include blood chemistry and hematology. These will be obtained using 
local laboratories and local laboratory range values. Tests obtained before informed consent 
may be used as study data if obtained within 14 days before the first dose of oliceridine or 
obtained during the current ED visit. 
 Physical examinations will include examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and 
nervous system. 
3.6.2 Safety and Tolerability Procedures 
The safety and tolerability of oliceridine will be assessed through self-reported or observed AEs, 
vital sign measurements, oxygen saturation measurements, somnolence/sedation scores, physical 
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examination findings, clinical laboratory assessments, and the subjective opiate withdrawal scale 
(SOWS). 
3.6.2.1 Adverse Events 
AEs occurring from time of informed consent to the follow-up phase will be recorded in source 
and will also be recorded in eCRF if the patient receives oliceridine. SAEs occurring from time 
of informed consent to the follow-up phase or 7 days after the last dose of oliceridine (whichever 
occurs later) will be recorded in source and eCRF; ongoing SAEs after this time frame will be 
followed until the investigator, medical monitor, and sponsor agree that the SAE is satisfactorily 
resolved. SAEs considered by the investigator to be related to oliceridine, regardless of the time 
of onset after treatment, should be reported. 
AE reporting information is provided in Section 4. 
3.6.2.2 Vital Signs, Height, Weight 
 
Vital signs will include blood pressure (BP), heart rate (HR), respiratory rate (RR), and 
temperature. Temperature will be measured at screening and baseline only. 
3.6.2.3 Oxygen Saturation 
Oxygen saturation monitoring will be continuous but will be recorded at any and all times during 
the dosing period consistent with individual patient need and institutional standards of care for a 
patient receiving a parenteral opioid. The date and time of initiation and discontinuation of 
continuous oxygen saturation monitoring will be recorded in the source documents. 
3.6.2.4 Somnolence/Sedation 
The MRPSS will be used to measure somnolence/sedation (Moline, 2012). This scale was 
developed to measure pharmacologic sedation in non-ICU patients, rather than many sedation 
scales that measure goal-directed sedation. Six levels describe the range of sedation from “non to 
minimal” to “general anesthesia”. Additionally, normal sleep is integrated into these levels, as 
opposed to being positioned as a separate category, easing quantitative analysis (Moline, 2012) 
(Pasero, 1994). 
3.6.2.5 Physical Examination 
The physical examination will include general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and nervous system. 
Clinically significant changes from screening/baseline in the physical examination for a surgical 
or medical patient will not be recorded as AEs unless they are of greater severity and/or intensity 
than would be expected. 
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3.6.2.6 Clinical Laboratories 
Clinical laboratories include blood chemistry and hematology obtained using local laboratories 
and local laboratory range values. 
Chemistry includes: Albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate dehydrogenase, and uric 
acid. 
Hematology includes: hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet 
count (or estimate), and white blood cell (WBC) count including differential. 
Urine or serum toxicology includes any standard of care analytes at the institution where the 
study is being conducted. 
3.6.2.7 Subjective Opiate Withdrawal Scale 
Patients will be monitored for symptoms and signs of opioid withdrawal. Acute opioid 
withdrawal reflects µ opioid receptor upregulation: pain, autonomic hyperactivity, bowel 
hypermotility, temperature instability, and psychological symptoms. Subjective symptoms may 
include physical symptoms (e.g., myalgias, nausea, diarrhea, chills) and psychological symptoms 
(e.g., cravings, insomnia, fatigue). Objective signs may include: tachycardia, hypertension, 
tearing, runny nose, yawning; vomiting; sweating, piloerection; agitation and restlessness. 
The SOWS will be administered to detect symptoms of opioid withdrawal (Handelsman, 1987). 
Patients will score each of 16 symptoms on an intensity scale ranging from 0 (“not at all”) to 4 
(“extremely”). 
3.6.3 Pharmacokinetic Procedures 
PK samples will be collected at two times during the treatment phase: 
 Sample 1 at 30 minutes (+/- 10 minutes) after the first dose; 
 Sample 2 between 1 and 2 hours after the first dose. 
For all samples, the actual sampling time will be recorded. Drug plasma concentration data 
collected in this study and detailed dosing times for each patient will be incorporated into a 
previously developed PK model in order to predict each individual’s oliceridine exposure. 
In addition to the scheduled PK sampling, an unscheduled PK sample will be obtained under the 
following circumstances: 
 If a patient reaches the dosing limit of 60 mg in the first 12 hours (see Section 3.5.2.3) 
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 If a patient experiences a serious AE or a severe AE during the treatment phase. As the 
determination of a serious AE or a severe AE is sometimes retrospective, unscheduled 
PK samples obtained when an event that is suspected to be serious or severe are also 
permitted. 
3.6.4 Efficacy Procedures 
Analgesic efficacy will be measured using NPRS (see Section 9.2) at the following time points: 
 During the predose period. 
 30 minutes +/-10 minutes after the first dose of oliceridine. 
 At any and all times during the dosing period consistent with individual patient need and 
institutional standards of care for a patient receiving a parenteral opioid. 
3.6.5 Other Procedures 
A blood sample will be collected for future 2D6 genotyping. The sample will be collected after 
the first dose of oliceridine and before the conclusion of the end of treatment phase. It is 
recommended that this sample be collected at the time of the first PK sample. 
 
 
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4 ADVERSE EVENT REPORTING 
The investigator and study staff are responsible for detecting and recording AEs and SAEs, 
during scheduled safety and tolerability evaluations and whenever such information is brought to 
their attention. This section of the protocol provides definitions and detailed procedures to be 
followed. 
During each visit, the investigator will question a patient about AEs using an open-ended 
question approach, making sure not to influence that patient’s answers, eg, "Have you noticed 
any change in your health?” or “How do you feel?.” 
4.1 Definitions and Criteria 
4.1.1 Adverse Events 
An AE is any untoward medical occurrence in a study patient that is temporally associated with 
the use of a medicinal product, regardless of its potential relationship to the medicinal product. 
An AE, therefore, can be any unfavorable or unintended sign, including a clinically significant 
abnormal laboratory finding, symptom, or disease temporally associated with the use of the IP, 
whether or not it is considered to be IP related. This includes any newly occurring event or 
previous condition that has increased in severity or frequency from time of informed consent. 
Examples of an AE include: 
 Exacerbation of a pre-existing condition, including either an increase in frequency and/or 
intensity of the condition. 
 A new condition detected or diagnosed. 
 Signs or symptoms of a drug interaction. 
 Signs or symptoms of a suspected overdose of either IP or a concurrent medication (overdose 
per se should not be reported as an AE/SAE). 
 A new laboratory abnormality that results in patient withdrawal from the study or medical 
treatment or further follow-up. 
NOTE: abnormal laboratory values obtained during screening that preclude a patient from 
entering the study are not considered AEs, but they will be recorded. 
AEs may include pre- or post-treatment events that occur as a result of protocol-mandated 
procedures (ie, invasive procedures, modification of patient’s previous therapeutic regimen). 
Symptoms or signs anticipated for a surgical or medical patient will not be recorded as AEs 
unless they are of greater severity and/or intensity than would be expected. Investigators will use 
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their clinical judgment in determining whether the symptoms or signs are of greater severity 
and/or intensity than would be expected. 
A medical intervention to address an AE is an “action taken” and not an AE in itself.  
4.1.2 Serious Adverse Events 
A SAE or reaction is any untoward medical occurrence that at any dose: 
(a) Results in death. 
(b) Is life-threatening. 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
(c) Requires hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an SAE, nor is prolongation of hospitalization for non-medically 
driven circumstances (eg, transportation issues).  
(d) Results in persistent or significant disability or incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
(e) Is a congenital anomaly/birth defect. 
(f) Is an important medical event. 
NOTE: Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening, or result in death or hospitalization, but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other outcomes 
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listed in the above definition. These should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Note that the terms “serious” and “severe” ARE NOT synonymous. The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or 
severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as a severe headache). This is NOT the same as “serious,” which is based 
on patient/event outcome or action criteria described above and are usually associated with 
events that pose a threat to a patient’s life or functioning. A severe AE does not necessarily 
need to be considered serious. For example, persistent nausea of several hours duration may 
be considered severe nausea but not an SAE. On the other hand, a stroke resulting in only a 
minor degree of disability may be considered mild but would be defined as an SAE based on 
the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
4.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events 
Abnormal laboratory findings (eg, clinical chemistry, hematology, and urinalysis) or other 
abnormal assessments (eg, vital signs) that are judged by the investigator as clinically significant 
will be recorded as AEs or SAEs, if they meet the definition of an AE or SAE. Clinically 
significant abnormal laboratory findings or other abnormal assessments that are detected during 
the study or are present at baseline and significantly worsen from time of informed consent will 
be reported as AEs or SAEs. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
Liver chemistry thresholds have been designed to assure patient safety. When patients meet the 
hepatic transaminase threshold criteria (AST or ALT >=3 × ULN), the patient should undergo 
close observation, including monitoring for symptoms (clinical symptoms of hepatitis or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, 
or rash) and hepatic function (AST, ALT, alkaline phosphatase, and fractionated bilirubin) at 
least every 48 hours, until symptoms and/or hepatic function abnormalities resolve, stabilize, or 
return to baseline values. This event must be reported to Trevena within 24 hours of learning of 
its occurrence. 
Figure 2Figure 2 represents the decision tree for whether or not IP will be discontinued. 
Specialist or hepatology consultation should be considered in cases of protocol-mandated IP 
discontinuation. 
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Figure 2: 
Monitoring of Patients with Elevated Hepatic Transaminases 
Liver Function Abnormalities
AST or ALT ≥ 3 x ULN
AST or ALT < 5 x ULN
AST or ALT ≥ 5 x ULN
Discontinue 
Investigational 
Product and begin 
Close Observation
At least Q48H, monitor 
symptoms and hepatic 
function 
(AST, ALT, Alk Phos, total 
& fractionated bilirubin)
Obtain specialist or 
hepatology Consult. 
Close Observation 
At least Q48H, monitor 
symptoms and hepatic 
function 
(AST, ALT, Alk Phos, total & 
fractionated bilirubin)
Investigational Product 
may be continued at the 
discretion of the 
Investigator
In all situations, collect additional laboratory tests as 
indicated in Protocol
Total Bilirubin
< 2 x ULN
Total Bilirubin
≥ 2 x ULN
If not possible
 
 
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In addition, every attempt must be made to obtain the following for any patient who meets the 
hepatic transaminase threshold criteria: 
 Viral hepatitis serology including: 
o Hepatitis A immunoglobulin M (IgM) antibody. 
o Hepatitis B surface antigen and hepatitis B core antibody (IgM).  
o HCV RNA.  
o Cytomegalovirus IgM antibody. 
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
o Hepatitis E IgM antibody (if patient resides outside the USA or Canada, or has 
traveled outside USA or Canada in past 3 months). 
 Serum creatine phosphokinase and LDH. 
 Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, 
fever, or rash, as relevant, on the AE report form. 
 Record the use of concomitant medications, including acetaminophen, herbal remedies, 
other over the counter medications, putative hepatotoxins, or alcohol on the concomitant 
medications report form. 
 The following are required for patients with AST or ALT >=3 × ULN and 
bilirubin >=2 × ULN but are optional for other abnormal liver chemistries: 
o Anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney 
microsomal antibodies. 
o Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
4.1.4 Evaluating Adverse Events and Serious Adverse Events 
All AEs will be assessed on two descriptive parameters: intensity and relationship to the IP: 
 Intensity refers to the severity of an event and references impact on a patient’s 
functioning. 
 Relationship refers to the likelihood that the event being assessed was caused by the IP. 
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4.1.4.1 Severity Rating 
Each AE will be classified according to the following criteria: 
Mild 
 Awareness of sign or symptom, but easily tolerated. 
Moderate 
 Discomfort enough to cause interference with usual activity. 
Severe 
 Incapacitating with inability to work or perform usual activity. 
An AE that is assessed as severe should not be confused with a SAE. An event is defined as 
“serious” when it meets one of the predefined outcomes as described in Section 4.1.2. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted. If the intensity category changes over a number of 
days, those changes should be recorded separately (with distinct onset dates). 
4.1.4.2 Relationship to Investigational Product 
For AEs and SAEs, the relationship to study treatment is to be assessed according to the 
following definitions: 
Not Related 
There is no reasonable association between the study treatment and the 
suspected event. 
 
Unlikely Related 
It is doubtful that there is an association between the study treatment and 
the suspected event. The event could have been produced by the patient’s 
clinical state or other modes of therapy administered to the patient. 
 
Possibly Related 
The suspected AE may or may not follow a reasonable temporal sequence 
from study treatment administration. The event could have been produced 
or mimicked by the patient’s clinical state or by other modes of therapy 
concomitantly administered to the patient. 
 
Probably Related 
The suspected AE follows a reasonable temporal sequence from study 
treatment administration, abates upon discontinuation of the treatment, and 
cannot be reasonably explained by the known characteristics of the 
patient’s clinical state. 
When assessing the relationship to the IP, the following criteria will be considered: 
 Positive rechallenge. 
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 Positive dechallenge (resolution upon stopping the suspect IP, in absence of other 
intervention or treatment). 
 Known class effect. 
 Biological plausibility. 
 Lack of alternative explanation—concomitant drug or disease. 
4.2 Reporting Procedures and Requirements 
4.2.1 Adverse Events 
AEs occurring from time of informed consent to the follow-up phase will be recorded in source 
and will also be recorded in eCRF if the patient receives oliceridine. All AEs must be recorded 
irrespective of whether they are considered medication-related. All AEs that are potentially 
related to IP will be followed until resolution or database lock, whichever occurs first. This 
includes any newly occurring event or previous condition that has increased in severity or 
frequency from time of informed consent. 
Any AEs already documented at a previous assessment and designated as ongoing should be 
reviewed at subsequent visits as necessary. If these have resolved, this should be documented. 
Changes in intensity or frequency of AEs should be recorded as separate events (ie, a new record 
started). 
The investigator should report all AEs on the AE page(s) of the eCRF and source documents, 
regardless of seriousness, severity, and causality. Whenever possible, an AE will be reported 
using a diagnostic term, (eg, “common cold” or “upper respiratory infection” rather than “runny 
nose, cough, mild fever”) and should be described with the attributes described in Section 4.1. 
4.2.2 Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria (see Section 4.1). If 
the AE is considered serious, the investigator should report this event to the sponsor. 
Additionally, a site using a local institutional review board (IRB) / Independent Ethics 
Committee (IEC) will report the event to that body according to its standard operating 
procedures. For sites using a central IRB/IEC, Trevena, or designee, will report to the central 
IRB/IEC. 
SAEs occurring from time of informed consent to the follow-up phase or 7 days after the last 
dose of oliceridine (whichever occurs later) will be recorded in source and eCRF; ongoing SAEs 
after this time frame will be followed until the investigator, medical monitor, and sponsor agree 
that the SAE is satisfactorily resolved. SAEs considered by the investigator to be related to 
oliceridine, regardless of the time of onset after treatment, should be reported. 
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All information about SAEs will be collected and reported via the SAE form and sent by e-mail 
message (contact information will be contained in the investigator site file). The investigator 
should send the initial report within 24-hours of becoming aware of the SAE. At minimum, the 
initial report should include the following information: 
 Event 
 Serious criteria 
 Study code 
 Patient number, initials, and date of birth 
 IP 
 Reporter name and contact information. 
In the case of a “minimum report” (one that solely comprises the information bulleted above), a 
more detailed follow-up report should be sent as soon as more information becomes available but 
no later than 7 calendar days after the date of the initial report. Each SAE should be followed up 
until resolution or stabilization and, for reported deaths, the investigator should supply the 
sponsor and the IRB/IEC with all the additional information requested (eg, autopsy reports and 
terminal medical reports). 
The original SAE form should be kept at the study site. The sponsor or its representative will be 
responsible for determining and, in turn, reporting SAEs to regulatory authorities according to 
the applicable regulatory requirements. 
Trevena, or designee, will be responsible for completing the safety report and for notifying the 
relevant authorities of any SAE as outlined in the International Conference on Harmonisation 
(ICH) guidelines and per local regulatory requirements. The investigator will also ensure that the 
appropriate IRB/IEC is notified of the SAE. 
4.2.3 Prompt Reporting of Serious Adverse Events 
Any SAE, occurring in a patient receiving treatment, or if the investigator becomes aware of any 
SAE post-treatment during the follow-up period, must be reported by the investigator to the 
sponsor within 24 hours even if the SAE does not appear to be medication related. This should 
be done by sending an e-mailed copy of the SAE form, plus any other related information to 
SAETRV130@vigilareintl.com. Additionally, it may be necessary for the medical monitor or 
sponsor to directly communicate with the investigator if additional information is required. 
During both business and non-business hours, the telephone numbers listed should be used if 
discussion with the medical monitor is required:  
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Primary Medical Monitor 
Joseph “Josh” Krotec, MD, FACOG 
Medical Director 
Chiltern 
1016 West 9th Avenue 
King of Prussia, PA 19406 USA 
Phone: (484) 832‐8770 
Email:  Jospeh.Krotec@Chiltern.com 
       
Back-up Medical Monitor 
Franck Skobieranda, MD 
Phone: (610) 888-7269 
Email: fskobieranda@trevenainc.com  
All additional follow-up evaluations must be reported to the sponsor. Such data should be 
e-mailed to the address above within 10 calendar days. SAEs occurring from time of informed 
consent to the follow-up phase or 7 days after the last dose of oliceridine (whichever occurs 
later) will be recorded in source and eCRF; ongoing SAEs after this time frame will be followed 
until the investigator, medical monitor, and sponsor agree that the SAE is satisfactorily resolved. 
SAEs considered by the investigator to be related to oliceridine, regardless of the time of onset 
after treatment, should be reported. 
Trevena, or designee, will be responsible for completing the safety report for notifying the 
relevant authorities of any SAEs as outlined in the ICH guidelines, and per local regulatory 
requirements, and for notifying the central IRB/IEC. The investigator will also ensure that the 
appropriate local IRB/IEC is notified of the SAE. 
4.3 Special Considerations 
4.3.1 Pregnancy 
All women of childbearing potential who participate in the study will be counseled on the need 
to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation. Women should be instructed to contact the investigator or study staff immediately 
if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of IP on female patients of 
childbearing potential. A woman who is found to be pregnant at screening or baseline will be 
excluded from the study and considered to be a screening failure. 
If a female study patient becomes pregnant during the study, the investigator must report the 
pregnancy within 72 hours after learning of the pregnancy. The investigator should contact the 
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designated individual(s) who receive SAE notification and record information related to the 
pregnancy on the designated pregnancy form provided by Trevena or its designee. 
Early discontinuation visit assessments are required as soon as possible after learning of the 
pregnancy. The investigator is also responsible for following the pregnancy until delivery or 
termination if possible. These findings must be reported on the pregnancy form and forwarded to 
the designated individual(s). The event meets the SAE criterion only if it results in a spontaneous 
abortion or a congenital anomaly. 
4.3.2 Individual Patient Stopping Criteria 
Oliceridine is a µ-opioid receptor agonist; therefore, effects on BP and respiration should be 
anticipated. 
As with conventional opioids, oliceridine will be administered PRN; for a patient, analgesia must 
be balanced with intolerability. In a situation of significant intolerability, temporary or 
permanent discontinuation may be warranted: 
 Asymptomatic decreased BP, increased HR, or decreased or increased RR may require 
only temporary discontinuation without additional intervention. 
 Symptomatic hypotension, tachycardia, advancing somnolence/sedation, or respiratory 
signs (bradypnea, tachypnea, decreased respiratory effort, and/or decreased oxygen 
saturation) require temporary discontinuation and may require additional intervention. 
 Symptomatic hypotension, tachycardia, advancing somnolence/sedation, or respiratory 
signs (bradypnea, tachypnea, decreased respiratory effort, and/or decreased oxygen 
saturation) requiring urgent intervention also requires permanent discontinuation. 
 Possibly or probably related increase in QTcF to >= 500 milliseconds, or increase in 
QTcF of > 60 milliseconds versus most recent pre-exposure QTcF requires: permanent 
discontinuation; urgent clinical laboratory assessment and correction of electrolyte 
abnormalities (eg, hypocalcemia, hypokalemia, hypomagnesemia); and hourly ECG until 
QTcF < 500 milliseconds. 
Additionally, if a patient receives 60 mg of oliceridine within the first 12 hours, the patient will 
early discontinue oliceridine and will be managed conventionally. The assigned reason for early 
discontinuation will be “other” and with the comment “dosing limit” (see Section 3.5.2.3). 
4.3.3 Site Requirements to Ensure Patient Safety 
4.3.3.1 Management of Overdose 
Given that oliceridine will be administered by qualified medical personnel, and that there is no 
opportunity for self-administration outside of the confines of PCA, the risk of overdose is 
considered to be low. 
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No specific antidote of oliceridine is known; however, signs or symptoms of possible overdose 
should be treated supportively. While naloxone reversal of oliceridine’s effects has not been 
established in humans, some pharmacological effects (analgesia) of oliceridine have been shown 
to be reversed by naloxone in animals. Should an AE occur that necessitates reversal of 
oliceridine’s effects, naloxone may be administered at its prescribed dose. Since the duration of 
oliceridine’s pharmacodynamic effects in patients has not yet been established, multiple 
administrations of naloxone may be necessary. Naloxone and supplemental oxygen should be 
readily available during dosing. 
4.3.3.2 Medication and Equipment Requirements 
The following medication and equipment must be available on-site and readily accessible in the 
event of an emergency: 
 Crash cart with appropriate devices (eg, cardiac monitor/defibrillator, suction devices, 
bag valve mask); advanced cardiac life support medications (eg, epinephrine, atropine); 
common crash cart medications (eg, dextrose, diazepam); oxygen; intubation medications 
(eg, succinylcholine), intubation equipment, and central and peripheral venous access 
equipment. 
 Specific medication: naloxone. 
 
 
 
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5 DATA MANAGEMENT 
eCRFs will be employed for this study. Case report forms are considered confidential documents 
and should be handled and stored accordingly. To ensure data accuracy, eCRF data for individual 
patient visits should be completed as soon as possible after the visit. All requested information 
must be entered in the electronic data capture (EDC) system. 
The eCRFs may be signed by the investigator or a sub-investigator. These signatures serve to 
attest that the information contained in the eCRF is accurate and true. 
Completed eCRFs for this study will be forwarded to the sponsor, or its representative, where 
editing and construction of a quality-assured database will occur. Data will be checked for 
quality and electronically verified after entry into the database. Queries will be issued for any 
inconsistencies, omissions, and discrepancies and will be resolved by the appropriate parties. The 
statistical analysis of these data will be performed by the sponsor or its representative. All AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (Version 19.0). 
Concomitant medications will be coded using the latest version of the World Health 
Organization Drug Dictionary (WHODD) (World Health Organization, March 2016). Data 
management details will be outlined in a separate data management plan. 
 
 
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6 STATISTICAL ANALYSIS 
A Statistical Analysis Plan (SAP) will be finalized and signed before locking the database or 
conducting study analyses. Any changes in the SAP from the analyses described below will be 
described in the SAP and the clinical study report. 
6.1 Sample Size 
No formal sample size calculations were made. Approximately 1000 patients will be treated with 
oliceridine. 
6.2 Study Populations 
All enrolled patients receiving at least 1 dose of oliceridine constitute the safety and tolerability 
analysis data set.  
6.3 Safety and Tolerability Analyses 
The number and incidence of AEs/SAEs will be summarized overall and by severity and 
causality. MedDRA Version 19.0 will be used to classify all events with respect to system organ 
class and preferred term. WHODD (March 2016) will be used to categorize prior and 
concomitant medications. Summaries will include only treatment-emergent AEs (TEAEs) and 
will be summarized for the safety and tolerability analysis data set. Clinically significant changes 
in vital sign measurements, oxygen saturation measurements, somnolence/sedation scores, 
physical examination findings, and clinical laboratory assessments will be summarized via 
descriptive summary statistics. 
Summary statistics for observed values and change from baseline values for vital sign 
measurements, oxygen saturation measurements, somnolence/sedation scores, physical 
examination findings, and clinical laboratory assessments will be summarized. Baseline values 
are defined as the last measurements taken before the first dose of oliceridine. SOWS total scores 
will be summarized. 
Prior and concomitant medications will be summarized. 
6.4 Exposure Analyses 
The total number of patients treated and the percentage of the overall sample treated by method 
of administration (bolus, PCA, both bolus and PCA) will be presented. Exposure data including 
date, time, and dose for each administration of oliceridine will be listed for each patient and will 
include the total amount of oliceridine administered using any method of administration within 
0-1 hours, 1-2 hours, 2-3 hours, and every subsequent 3-hour period to 24 hours; 24-48 hours, 
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and 48-72 hours, and every subsequent 24-hour period of the treatment phase. Subsequently, the 
amount of oliceridine administered to all patients over these periods and the total amount 
administered during the treatment phase will be summarized (mean, standard deviation, median, 
minimum, and maximum) by the method of administration (bolus, PCA, both bolus and PCA) 
for the safety and tolerability population. All doses of oliceridine, whether administered by IV 
bolus or PCA, will be listed. 
Additionally, data will be presented by subgroups for descriptive purposes. 
6.5 Efficacy Analyses 
The NPRS scores at baseline and 30 minutes after the first dose of oliceridine, as well as the 
change from baseline to 30 minutes, will be summarized using descriptive summary statistics. 
All NPRS assessments will be listed at each time point where an assessment has occurred.  
6.6 Protocol Deviations 
Protocol deviations will be listed by patient and summarized in a table. 
 
 
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7 STUDY MANAGEMENT 
7.1 Ethics and Consent 
7.1.1 Regulations and Guidelines 
The study will be performed in accordance with this protocol, United States investigational new 
drug (IND) regulations (21 CFR 312), ICH guidelines for Good Clinical Practice (GCP), the 
regulations on electronic records and electronic signature (21 CFR 11), and the most recent 
guidelines of the Declaration of Helsinki. These guidelines are on file at Rho, Inc. 
7.1.2 Institutional Review Board/Independent Ethics Committee  
Conduct of the study must be approved by an appropriately constituted IRB/IEC. Approval is 
required for the study protocol, protocol amendments, informed consent form (ICF) documents, 
patient information sheets, and advertising materials. No IP will be shipped to a site until written 
IRB authorization has been received by the sponsor or its representative. 
7.1.3 Informed Consent 
Written informed consent will be obtained before any protocol-related activities are conducted. 
Select standard of care assessments (eg, chemistry, hematology, urine or serum pregnancy test, 
urine or serum toxicology screen, ECG) obtained before informed consent may be used as study 
data if protocol specifications and timeframes are met. As part of this procedure, the investigator 
or a designated representative must explain orally and in writing the nature, duration, and 
purpose of the study, and the action of the IP in such a manner that the patient and (if applicable) 
appointed guardian are aware of the potential risks, inconveniences, or adverse effects that may 
occur. Patients should be informed that they may withdraw from the study at any time. They will 
receive all the information that is required by federal regulations and ICH guidelines. The 
principal investigator or a designated representative will provide the sponsor or its representative 
with a copy of the IRB-approved ICF before the start of the study. 
7.2 Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at any site or multiple sites for any reason 
at any time. Should the study be terminated and/or the site closed for whatever reason, all 
documentation and IP pertaining to the study must be returned to the sponsor or its 
representative. 
7.3 Study Documentation 
By signing a copy of the FDA 1572 form, the principal investigator acknowledges that he/she 
has read and understood the information in the IB and assures the sponsor that he/she will 
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comply with the protocol and the provisions stated in the FDA 1572 form. No changes in this 
protocol can be made without the sponsor’s written approval. 
By signing the Investigator’s Agreement, the investigator agrees to maintain accurate eCRFs and 
source documentation as part of the case histories for all patients who provide written informed 
consent. 
7.4 Study Monitoring and Auditing 
Clinical research personnel will conduct site visits to monitor the study and ensure compliance 
with the protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals and maintain 
periodic communication. The investigator agrees to allow the CRA(s) and other authorized 
Trevena personnel access. The CRA(s) will maintain current personal knowledge of the study 
through observation, review of study records and source documentation, and discussion of the 
conduct of the study with the investigator and staff. While on site or through remote means, the 
CRA(s) will review the following: 
 Regulatory documents  
 Directly comparing entries in the EDC system with the source documents 
 Consenting procedures 
 AE procedures 
 Storage and accountability of IP and study materials  
Examples of acceptable source documentation include, but are not limited to, hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. During the study, select eCRF data may be used 
as original data collection tools as long as a description of this documentation process is 
maintained in the investigator’s study files. 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in EDC guidelines. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement, the investigator agrees to meet with the CRA(s) during 
study site visits; to ensure that study staff is available to the CRA(s) as needed; to provide the 
CRA(s) access to all study documentation and to the clinical supplies dispensing and storage 
area; and to assist the monitors in their activities, if requested. Further, the investigator agrees to 
allow Trevena or designee auditors or inspectors from regulatory agencies to review records and 
to assist the inspectors in their duties, if requested. 
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Medical advisors and CRAs or assistants may request to witness patient evaluations occurring as 
part of this protocol. The investigator and appropriate personnel will be periodically requested to 
attend meetings/workshops organized by the sponsor to assure acceptable protocol execution. 
The study may be subject to audit by the sponsor or by regulatory authorities. If such an audit 
occurs, the investigator must agree to allow access to required patient records. By signing this 
protocol, the investigator grants permission to personnel from the sponsor, its representatives, 
and appropriate regulatory authorities, for on-site monitoring of all appropriate study 
documentation, as well as on-site review of the procedures employed in eCRF generation, where 
clinically appropriate. 
7.5 Retention of Records 
The investigator must arrange for retention of study records at the site for 2 years after the IP’s 
new drug application is approved, or the IND is withdrawn, as required by FDA regulations. The 
investigator should take measures to prevent accidental or premature destruction of these 
documents. 
7.6 Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of the study results for the 
purpose of national and international registration. If necessary, the authorities will be notified of 
the investigator’s name, address, qualifications, and extent of involvement. A clinical study 
report will be prepared by the sponsor or its representative. 
7.7 Publications 
As a multicenter trial, the sponsor intends to publish clinical data from all centers participating in 
the investigation. Additional publications may represent segments of the study; for example, 
publications based on site topology (inpatient hospital, outpatient hospital department, 
ambulatory surgical care center, ED), nature of pain (visceral or non-visceral), or method of 
administration (bolus, PCA, both bolus and PCA) may be developed. 
In conformity with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals 
published by the International Committee of Medical Journal Editors (Kassirer, 1991), 
investigators whose contribution consists solely in the collection of data will not be named 
individually as authors. 
The information generated by this study is the property of Trevena. Publication or other public 
presentation of oliceridine data resulting from this study requires prior review and written 
approval of Trevena. Abstracts, manuscripts, and presentation materials should be provided to 
Trevena for review at least 30 days prior to the relevant submission deadline. 
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It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until the sponsor has reviewed and commented on 
such a presentation or manuscript for publication. 
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8 REFERENCES 
 
American Society of Anesthesiologists. Practice Guidelines for the Prevention, Detection, and 
Management of Respiratory Depression Associated with Neuraxial Opioid Administration: An 
Updated Report by the American Society of Anesthesiologists Task Force on Neuraxial Opioids 
and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology 2016; 
124(3):535-52. 
American Society of Anesthesiologists. ASA Physical Status Classification System. Retrieved 
November 11, 2015, from http://www.asahq.org/resources/clinical-information/asa-physical-
status-classification-system. 
Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine 
analgesia in mice lacking beta-arrestin 2. Science 1999;286(5449):2495-8. 
Food and Drug Administration (2005) Guidance for Industry: Premarketing Risk Assessment. 
Gilboy N, Tanabe T, Travers D, Rosenau AM. (2011) Emergency Severity Index (ESI): A Triage 
Tool for Emergency Department Care, Version 4. Implementation Handbook 2012 Edition. 
AHRQ Publication No. 12-0014. Rockville, MD: Agency for Healthcare Research and Quality.  
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating 
scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987;13(3):293-308. 
Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, Fainsinger R, Aass N, 
Kaasa S; European Palliative Care Research.Collaborative (EPCRC). Studies comparing 
Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of 
pain intensity in adults: a systematic literature review. J Pain Symptom Manage 
2011;41(6):1073-93. 
International Council for Harmonisation. MedDRA® the Medical Dictionary for Regulatory 
Activities. Version 19.0. 
The Joint Commission. Sentinel Event Alert: Safe Use of Opioids in Hospitals.49 (08 Aug 
2012):1-5. October 1, 2015 from 
http://www.jointcommission.org/assets/1/18/SEA_49_opioids_8_2_12_final.pdf 
Kassirer JP, Angell M. On authorship and acknowledgments. N Engl J Med 1991;325(21):1510-
2. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology 
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Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 
2009;150(9):604-12. 
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Pharmacologic Sedation Scale. Clin Nurse Spec 2012;26(3):140-8. 
Pasero, C. (1994) Acute Pain Service: Policy and Procedure Manual. Los Angeles, CA: 
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2005;7(3):E587-91. 
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World Health Organization. (March 2016) WHO-Drug Dictionary.
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9 APPENDICES 
9.1 Moline-Roberts Pharmacologic Sedation Scale1 
 
Moline - Roberts 
Pharmacologic Sedation Scale© 
9/08 
The purpose of this scale is to aid the decision-making process regarding administration of 
opioids and sedatives. At all times, the individual’s physiologic status and unique response to 
opioids/sedatives must be included in the decision process. 
Do not use this scale for any patient with neurological impairment which prevents normal 
response to a stimulus or ability to follow commands. 
 
Presentation 
Auditory 
Stimulus 
Tactile 
Stimulus 
Response 
Sedation 
Awake, aware, alert  
Airway and ventilation  
adequate 
None 
None 
Spontaneous,  
sustained  
interaction 
1 
None to Minimal 
Restful, drowsy, dozing, 
 lightly sleeping 
Airway and ventilation  
adequate 
Soft voice or  
ambient noise 
None or light  
touch, rubbing or  
tapping 
Sustains  
interaction 
2 
Anxiolysis 
Sleeping  
Airway and ventilation 
adequate 
Soft to normal  
voice 
Light touch,  
rubbing or  
tapping 
Limited or brief  
interaction 
3 
Moderate 
Sedation 
Sleeping  
Airway and ventilation 
adequate 
Normal to loud  
voice 
Light touch, 
 rubbing or  
tapping 
Follows simple  
commands 
4 
Moderate 
Sedation 
Sleeping  
Airway and ventilation 
may be impaired 
Loud voice 
Intense to noxious 
Purposeful 
 response or  
non-purposeful  
movement 
5 
Deep  
Sedation 
Sleeping  
Airway and ventilation 
likely impaired 
Loud voice 
Noxious 
No response, unarousable 
6 
General 
Anesthesia 
 
Copyright 2008 Poudre Valley Health System 
                                                 
1 Moline, 2012 
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9.2 Numeric Pain Rating Scale2 
 
 
On a scale of 0-10, please rate your pain by marking an ‘X” in the appropriate box that 
best describes your worst pain NOW. 
 
0     1     2     3     4     5     6     7     8     9     10 
No pain 
Worst pain 
 
imaginable 
 
 
 
 
                                                 
2 McCaffery M, 1989 
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9.3 ASA Physical Status Classification System3 
ASA PHYSICAL STATUS CLASSIFICATION SYSTEM 
Last approved by the ASA House of Delegates on October 15, 2014  
 
Current definitions (NO CHANGE) and Examples (NEW)  
ASA PS Classification 
Definition 
Examples, including, but not limited to: 
ASA I 
A normal healthy patient 
Healthy, non-smoking, no or minimal alcohol 
use 
ASA II 
A patient with mild systemic 
disease 
Mild diseases only without substantive 
functional limitations. Examples include (but 
not limited to): current smoker, social alcohol 
drinker, pregnancy, obesity (30 < BMI < 40), 
well-controlled DM/HTN, mild lung disease 
ASA III 
A patient with severe systemic 
disease 
Substantive functional limitations; One or 
more moderate to severe diseases. 
Examples include (but not limited to): poorly 
controlled DM or HTN, COPD, morbid 
obesity (BMI ≥40), active hepatitis, alcohol 
dependence or abuse, implanted 
pacemaker, moderate reduction of ejection 
fraction, ESRD undergoing regularly 
scheduled dialysis, premature infant PCA 
<60 weeks, history (>3 months) of MI, CVA, 
TIA, or CAD/stents. 
ASA IV 
A patient with severe systemic 
disease that is a constant threat 
to life 
Examples include (but not limited to): recent 
(< 3 months) MI, CVA, TIA, or CAD/stents, 
ongoing cardiac ischemia or severe valve 
dysfunction, severe reduction of ejection 
fraction, sepsis, DIC, ARD or ESRD not 
undergoing regularly scheduled dialysis 
ASA V 
A moribund patient who is not 
expected to survive without the 
operation 
Examples include (but not limited to): 
ruptured abdominal/thoracic aneurysm, 
massive trauma, intracranial bleed with mass 
effect, ischemic bowel in the face of 
significant cardiac pathology or multiple 
organ/system dysfunction 
ASA VI 
A declared brain-dead patient 
whose organs are being 
removed for donor purposes 
 
* The addition of “E” denotes Emergency surgery: (An emergency is defined as existing when delay in 
treatment of the patient would lead to a significant increase in the threat to life or body part)  
 
 
 
                                                 
3 American Society of Anesthesiologists, 2014 
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9.4 Emergency Severity Index Triage Algorithm4 
 
 
 
 
                                                 
4 Gilboy, 2011 
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9.5 Subjective Opiate Withdrawal Scale (SOWS) 
 
 
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