Clinical trial NCT03323385
Conditions: Pain, Postoperative
Keywords: Colorectal surgery Pain Analgesia N1539 Phase 3b
Sponsor: Baudax Bio
Start date: 2017-10-24; Completion date: 2018-09-26
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of preoperative dosing of N1539 30 mg in subjects undergoing colorectal surgery, including clinical laboratory tests, wound healing evaluation, incidence of anastomotic leaks, and incidence of Adverse Events (AEs) and Serious AEs (SAEs).

Detailed description:

Arms: arm 1: N1539 (meloxicam injection for IV use) 30 mg every 24 hours arm 2: IV Placebo every 24 hours
Interventions: intervention 1: N1539 intervention 2: Placebo
Intervention descriptions: intervention 1: Once Daily intervention 2: Once Daily

Protocol documents:
Prot_000.pdf: 
 
 
 
REC-17-024 
 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Evaluation of the 
Safety and Efficacy of Preoperative N1539 In Colorectal Surgery 
 
NCT03323385 
 
Study Protocol – Amendment 002 
 
16 November 2017 


Recro Pharma, Inc. 
Protocol REC-17-024 Amendment 002 
CONFIDENTIAL 
1 
30 August 2017 
CLINICAL STUDY PROTOCOL 
Compound Name: 
Protocol Number: 
Protocol Title: 
Date of Original Protocol: 
Date of Amendment 001: 
Date of Amendment 002: 
Study Designated Physician 
Study Contact: 
N1539 (Injectable NanoCrystal® Colloidal Dispersion 
(NCD) Meloxicam) 
REC-17-024 Amendment 002 
A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter, Evaluation of the Safety and Efficacy of 
Preoperative N1539 In Colorectal Surgery 
01 June 2017 
30 August 2017 
16 November 2017 
Stewart McCallum, MD 
490 Lapp Rd 
Malvern, PA 19355 
Mobile:  
Fax: 484-395-2471 
Email: smccallum@recropharma.com 
Alexis Gomez 
Sr. Director Clinical Project Management 
490 Lapp Rd 
Malvern, PA 19355 
Telephone: 484-395-2422 
Email: agomez@recropharma.com 
Unauthorized copying or use of this information is prohibited. 


Recro Pharma, Inc. 
Protocol REC-17-024 Amendment 002 
CONFIDENTIAL 
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INVESTIGATOR’S AGREEMENT 
 
By signing below, I confirm that I have read this protocol and agree 
• to assume responsibility for the proper conduct of the study at this site 
• to conduct the study according to the procedures described in this protocol and any future 
amendments 
• not to implement any deviation from, or changes to, the protocol without agreement of 
the sponsor and written approval from the Institutional Review Board or Independent 
Ethics Committee, except where necessary to eliminate an immediate hazard to subject(s) 
• that I am aware of and will comply with all applicable regulations and guidelines 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
Principal Investigator’s Title (Print) 
 
 
 
 
 
 
 
 
Site Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol REC-17-024 Amendment 002 
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SYNOPSIS (PAGE 1 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Objective:  The primary objective of this study is to evaluate the safety and tolerability of 
preoperative dosing of N1539 30 mg in subjects undergoing colorectal surgery, including clinical 
laboratory tests, wound healing evaluation, incidence of anastomotic leaks, and incidence of Adverse 
Events (AEs) and Serious AEs (SAEs). 
Additional objectives include: 
• 
Evaluation of N1539 treatment impact on overall postoperative recovery course, including 
total opioid consumption, length of hospital stay, pain control, cost of hospital stay, return of 
bowel function, mobilization, and satisfaction with pain medication. 
Methodology:   
This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study evaluating the 
safety and efficacy of preoperative dosing with N1539 30 mg in adult subjects undergoing open or 
laparoscopic colorectal surgery.  The initial study cohort will enroll approximately 50 subjects 
randomized (1:1) to N1539 30 mg or placebo; additional study cohorts may be enrolled following 
review of initial study observations. 
Adult subjects, age 18 to 80 years inclusive, scheduled to undergo colorectal surgery that is expected 
to result in inpatient hospitalization for at least 48-72 hours, will be screened for participation at up to 
20 study sites in the United States.  Screening will occur within 28 days before study drug 
administration.  After signing the informed consent, medical history, physical examination, laboratory 
testing, 12-lead electrocardiogram (ECG), pregnancy testing, and vital sign measurements will be 
completed during the screening visit. 
Study sites will follow an Enhanced Recovery After Surgery (ERAS) protocol pre-, peri-, and 
postoperatively (see Appendix C.1).  On the day of surgery (DOS; Day 1), subjects will be evaluated 
to ensure they remain eligible for participation in the study.  Subjects with confirmed eligibility will 
be stratified by incision type (open vs laparoscopic) and randomized to either N1539 30 mg or placebo 
treatment within 12 hours prior to surgery and will be administered the first dose of study drug 
approximately 30 minutes prior to the start of surgery (defined as time of first incision).  The start time 
of first dose of study drug administration (Dose 1) will be used to schedule subsequent doses.  
Following surgery (end of surgery defined as the time of last suture; referenced as Hour 0), subjects 
will receive a standardized care regimen per the specified ERAS protocol, including rescue analgesia, 
mobilization, and diet advancing guidelines (see Appendix C.1).  Subjects will continue to receive 
study drug every 24-hours from Dose 1 so long as IV analgesia is clinically appropriate or until 
discharge, whichever comes first. Subjects will stay at the study center for at least 48-72 hours after 
surgery or so long as inpatient care is clinically appropriate.  A final dose of study drug may be 
administered up to 4 hours early in subjects who are scheduled to be discharged.  Subjects who do not 
receive a dose of study drug for > 28 hours following their previous dose of study drug should be 
considered off treatment, and should not receive further doses of study drug.   


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 SYNOPSIS (PAGE 2 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Subjects may be discharged from the study center based on their clinical status, with safety assessments 
performed at the earlier of 1 day (24 hours) following their last study dose (LSD+1) or at the time of 
discharge.  Subjects will be provided standard of care analgesic regimen for pain management after 
discharge from the study center. 
All treated subjects will be followed through 30 days after discharge.  All subjects will return to the 
study center to complete follow-up visit 1 (FUV-1) at 5-21 days post-discharge, with follow-up visit 2 
(FUV-2) completed by telephone 30 days post-discharge. 
Safety assessments will include monitoring of AEs, wound healing assessment, vital signs, and clinical 
laboratory tests. 
Assessments of efficacy will include total opioid consumption, pain intensity according to an 11-point 
numeric pain rating scale (NPRS; 0 - 10) on first ambulation, time to first analgesic rescue, time to 
return of bowel function (including time to first flatus or bowel sounds, and first bowel movement), 
time to mobilization (including time to first assisted mobilization out of hospital bed and time to first 
independent mobilization out of hospital bed), patient global assessment of pain control, brief pain 
inventory, subject satisfaction, time to hospital discharge (including time to hospital discharge order 
written and time to actual hospital departure), incidence of nasogastric (NG) tube insertion, length of 
stay, incidence of hospital readmission post initial discharge, and total cost of hospitalization. 
Number of subjects to be enrolled:  The initial study cohort is planned to enroll approximately 50 
subjects; 25 subjects to be randomized to placebo, and 25 subjects to be randomized to N1539 30 mg.  
Additional study cohorts may be enrolled following review of initial study observations. 
Number of study sites:  Up to 20 sites 
Study country location:  United States 
 
 


Recro Pharma, Inc. 
Protocol REC-17-024 Amendment 002 
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SYNOPSIS (PAGE 3 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Criteria for inclusion:  Subjects must meet all of the following criteria to be considered eligible to 
participate in the study: 
1. Voluntarily provide written informed consent. 
2. Be able to understand the study procedures, comply with all study procedures, and agree to 
participate in the study program. 
3. Male or female 18 to 80 years of age, inclusive. 
4. Be planned to undergo primary (no repeat procedures) open or laparoscopic colorectal surgery 
(laparoscopic expected to require a ≥ 5 cm incision) with bowel resection and/or anastomosis, 
and be expected to require IV analgesia, remain in an inpatient setting for at least 48-72 hours, 
and receive at least two doses of study drug. 
5. Be classified as American Society of Anesthesiology (ASA) physical status category 1, 2, or 3. 
6. Female subjects are eligible only if all of the following apply: 
• Not pregnant or planning/attempting to become pregnant during the study (female subjects 
of child bearing potential [FOCBP] must have a negative urine pregnancy test before 
surgery); 
• Not lactating; 
• Commits to the use of an acceptable form of birth control for the duration of the study 
through FUV-2; OR 
Be unable to become pregnant due to bilateral oophorectomy or tubal ligation, 
postmenopausal status (1-year post last menstrual period) or sterility of male partner while 
in a monogamous relationship; OR 
Be in a monogamous relationship with a same sex partner with no intention of becoming 
pregnant through any means. 
7. Have a body mass index <40 kg/m2.  
8. For oncology cases, all of the following criteria must be met:  
• Have a histologically confirmed diagnosis of colorectal cancer with a primary solid tumor 
confined to the primary organ, without evidence of local, regional, or distal spread;  
• Have a performance status such that they can carry on normal activities of daily life 
without limitations. 
 


Recro Pharma, Inc. 
Protocol REC-17-024 Amendment 002 
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SYNOPSIS (PAGE 4 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Criteria for exclusion:  Subjects who meet any of the following criteria will be excluded from 
participating in the study: 
1. Have a known allergy or hypersensitivity to eggs, meloxicam, aspirin, other non-steroidal anti-
inflammatory drugs (NSAIDs), or any excipient of N1539 or placebo. 
2. Planned surgical procedure from incision to closure is expected to be longer than 10 hours. 
3. Planned surgical procedure includes a resection beyond the peritoneal reflection, is related to 
an acute bout of diverticulitis, or is associated with an emergency procedure. 
4. Have a history of myocardial infarction within the preceding 12 months.  
5. Have, as determined by the investigator or the sponsor’s medical monitor, a history or clinical 
manifestations of significant renal (GFR<60 mL/min/1.73 m2), hepatic, cardiovascular, 
metabolic, neurologic, psychiatric, respiratory, or other condition that would preclude 
participation. 
6. Have a clinically significant abnormal clinical laboratory tests value according to the judgment 
of the investigator. 
7. Have active or recent (within 6 months) gastrointestinal ulceration or bleeding, with exception 
of events related to an ulcerative colitis diagnosis. 
8. Have a known bleeding disorder which may be worsened with the administration of an 
NSAID.  
9. Have evidence of a clinically significant 12 lead ECG abnormality per the judgment of the 
investigator. 
10. Have a recent history of alcohol or prescription/illicit drug abuse. 
11. Have received chronic opioid therapy (daily use of opioids for 30 days or longer) or > 5 days 
with opioid use, within 30 days prior to screening  


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SYNOPSIS (PAGE 5 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Criteria for exclusion (continued) 
12. Unable to discontinue medications, that have not been at a stable dose for at least 7 days prior 
to the scheduled surgical procedure, within 5 half-lives of the specific prior medication (or, if 
half-life is not known, within 48 hours) before dosing with study medication, with exception of 
medications utilized for surgical preparation 
13. Be unable to discontinue herbal medications/supplements associated with an increased 
bleeding risk at least 7 days prior to surgery through LSD+1/discharge, including but not 
limited to:  gingko biloba, garlic, ginger, ginseng, hawthorn, fish oil (omega-3-fatty acid), dong 
quai, feverfew, vitamin E.  
14. Be receiving lithium or a combination of furosemide with either an angiotensin converting 
enzyme inhibitor or an angiotensin receptor blocker 
15. Be currently receiving treatment with oral meloxicam (Mobic®) or another NSAID within 
48 hours prior to surgery. 
16. Have received any investigational product within 30 days before dosing with study medication. 
17. Have previously received N1539/IV meloxicam  
18. Have undergone major surgery in the last 3 months that could interfere with study assessments. 
19. Have undergone or be expected to undergo radiation therapy, chemotherapy, or other 
biological therapy for cancer treatment, within 60 days prior to screening through FUV-2. 
Investigational product:  N1539 30 mg 
Reference therapy:  Placebo 
Duration of treatment:  Each subject is expected to receive at least two doses of study drug during the 
treatment phase of the study, with the first dose (Dose 1) administered approximately 30 minutes prior 
to surgery start and additional doses administered every 24±1 hours from Dose 1 until discharge or 
until IV analgesia is no longer clinically appropriate, whichever comes first.  A final dose of study drug 
may be administered up to 4 hours early in subjects who are scheduled to be discharged.  Subjects who 
do not receive a dose of study drug for > 28 hours following their previous dose of study drug should 
be considered off treatment, and not receive further study dosing.  Subjects will be asked to return for 
FUV-1 to complete end of study assessments, with a safety follow-up by phone at FUV-2. 


Recro Pharma, Inc. 
Protocol REC-17-024 Amendment 002 
CONFIDENTIAL 
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SYNOPSIS (PAGE 6 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Criteria For Evaluation 
Safety:  
The safety endpoints will include the following: 
1. Incidence of treatment-emergent AEs and SAEs (including AEs of interest and opioid related 
AEs) 
2. Incidence of anastomotic leaks  
3. Change from baseline in laboratory tests; incidence of abnormal clinical laboratory tests 
4. Change from baseline in vital signs 
5. Assessment of surgical wound healing 
Efficacy:  The efficacy endpoints will be: 
1. Total opioid consumption.   
2. Time to hospital discharge order written 
3. Pain intensity on first ambulation 
4. Time to actual hospital departure 
5. Time to first rescue analgesia use 
6. Time to return of bowel function, including time to first bowel sound or first flatus, and time to 
first bowel movement 
7. Time to mobilization, including time to first assisted mobilization out of hospital bed and first 
independent mobilization out of hospital bed 
8. Patient Global Assessment (PGA) of pain control  
9. Brief Pain Inventory  
10. Subject assessment of satisfaction with pain medication 
11. Hospital length of stay (LOS)  
12. Incidence of postoperative NG tube insertion  
13. Incidence of hospital readmission  
14. Total cost of hospitalization 
Exploratory endpoints include: 
1. Change in inflammatory markers  
 


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CONFIDENTIAL 
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SYNOPSIS (PAGE 7 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-024 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety and 
Efficacy of Preoperative N1539 In Colorectal Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Statistical methods: 
Sample size determination:  The initial sample size of 50 subjects was selected empirically without a 
formal power calculation.  
An unblinded data review will be performed after approximately 40-50 subjects are enrolled and have 
completed study assessments through initial hospital discharge. An independent statistician will 
perform the analysis.  Details will be discussed in the analysis plan to be prepared for this study. 
Following enrollment and review of this initial cohort, if study data warrant, additional subject cohorts 
may be enrolled to further evaluate safety in this setting, or may explore other endpoints. 
Study populations:   
Intent-to-Treat (ITT) Analysis Set: The ITT set will include all eligible subjects who were randomized.  
The ITT subjects may or may not receive randomized treatment and may or may not have the 
scheduled surgery.  
Safety Analysis Set:  The safety analysis set will include all subjects treated with study drug.  
Efficacy Analysis Set: The efficacy analysis set will include all subjects in the safety analysis set who 
underwent the scheduled surgery and had NG tube removed prior to Hour 24.   
Safety analysis:  The Medical Dictionary for Regulatory Activities (Version 20 or higher) will be used 
to classify all AEs with respect to system organ class and preferred term.  AEs will be summarized for 
by treatment group.  Changes in vital signs and clinical laboratory tests at each post dosing time point 
will be summarized by treatment group using descriptive statistics without formal statistical tests.  The 
number and proportion of subjects with abnormal wound healing observations will be summarized at 
each time point by treatment group.    
Efficacy analysis:  Efficacy parameters will be summarized for each study treatment.  Difference 
between the groups will be evaluated using analysis of covariance (ANCOVA) models that include 
main effect of treatment and investigational sites for all continuous variables; Cox proportional hazards 
analysis will be used to evaluate treatment effect in time to event parameters; and the Cochran-Mantel-
Haenszel analysis controlling for investigational sites will be used to assess the differences in groups 
for the categorical parameters. 


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TABLE OF CONTENTS 
 
ARTICLE I. CONTENTS 
SYNOPSIS (PAGE 1 OF 7) ........................................................................................................... 3 
TABLE OF TABLES ................................................................................................................... 15 
LIST OF ABBREVIATIONS ....................................................................................................... 16 
1. 
INTRODUCTION ............................................................................................................ 19 
2. 
STUDY OBJECTIVE ....................................................................................................... 20 
3. 
INVESTIGATIONAL PLAN ........................................................................................... 21 
3.1. 
Overall Study Design .................................................................................................. 21 
3.2. 
Rationale for Study Design and Control Groups ........................................................ 22 
4. 
STUDY POPULATION ................................................................................................... 23 
4.1. 
Inclusion Criteria ........................................................................................................ 23 
4.2. 
Exclusion Criteria ....................................................................................................... 23 
4.3. 
Discontinuation of Subjects ........................................................................................ 25 
4.3.1. 
Procedures for Withdrawal ......................................................................................... 25 
4.3.2. 
Replacement of Subjects ............................................................................................. 25 
4.4. 
Lifestyle Guidelines .................................................................................................... 25 
4.4.1. 
Confinement ................................................................................................................ 25 
4.4.2. 
Diet .............................................................................................................................. 25 
5. 
TREATMENTS ................................................................................................................ 26 
5.1. 
Surgical Procedure and Perioperative Care ................................................................ 26 
5.2. 
Administration of Study Medication .......................................................................... 26 
5.3. 
Identity of Study Medication ...................................................................................... 26 
5.4. 
Method of Assigning Subjects to Treatment Groups .................................................. 26 
5.5. 
Selection of Doses....................................................................................................... 27 


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5.6. 
Selection of Timing of Dose ....................................................................................... 27 
5.7. 
Blinding and Unblinding of Study Medications ......................................................... 27 
5.8. 
Treatment Compliance ................................................................................................ 27 
5.9. 
Drug Accountability.................................................................................................... 28 
5.10. 
Packaging, Labeling, and Storage ............................................................................... 28 
5.11. 
Prior and Concomitant Medications ........................................................................... 28 
5.12. 
Prohibited Medications ............................................................................................... 28 
5.13. 
Concomitant Interventions and Procedures ................................................................ 29 
5.14. 
Rescue Medication ...................................................................................................... 29 
6. 
STUDY PROCEDURES .................................................................................................. 30 
6.1. 
Demographic and Efficacy Assessment...................................................................... 30 
6.1.1. 
Demographics ............................................................................................................. 30 
6.1.2. 
Medical History .......................................................................................................... 30 
6.1.3. 
Physical Examination.................................................................................................. 30 
6.1.4. 
Surgical Information ................................................................................................... 30 
6.1.5. 
Concomitant Medications and Opioid Use ................................................................. 30 
6.1.6. 
Pain Intensity (PI) on Ambulation .............................................................................. 31 
6.1.7. 
Cost of Hospitalization ............................................................................................... 31 
6.1.8. 
Time to Events ............................................................................................................ 31 
6.1.9. 
Patient Global Assessment (PGA) of Pain Control .................................................... 31 
6.1.10. 
Brief Pain Inventory .................................................................................................... 31 
6.1.11. 
Subject Satisfaction with Postoperative Pain Medication .......................................... 32 
6.1.12. 
Postoperative NG Tube Insertion................................................................................ 32 
6.1.13. 
Hospital Readmission ................................................................................................. 32 
6.2. 
Safety Assessments Description ................................................................................. 32 
6.2.1. 
Clinical Laboratory Tests ............................................................................................ 32 
6.2.2. 
Vital Sign Measurements ............................................................................................ 33 
6.2.3. 
12-Lead Electrocardiogram (ECG) ............................................................................. 33 


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6.2.4. 
Wound Evaluation ...................................................................................................... 33 
6.2.5. 
Anastomotic Leaks...................................................................................................... 33 
6.3. 
Assessments by Visit .................................................................................................. 34 
6.3.1. 
Screening Visit ............................................................................................................ 34 
6.3.2. 
Day 1 - Check-In ......................................................................................................... 34 
6.3.3. 
Day 1 - Randomization and Surgery ........................................................................... 34 
6.3.4. 
Inpatient Treatment ..................................................................................................... 35 
6.3.5. 
LSD+1 ......................................................................................................................... 35 
6.3.6. 
Discharge .................................................................................................................... 36 
6.3.7. 
Follow-Up Visit 1 (FUV-1) ........................................................................................ 36 
6.3.8. 
Follow-Up Visit 2 (FUV-2) ........................................................................................ 36 
6.4. 
Appropriateness of Assessments................................................................................. 36 
6.5. 
Clinical Stopping Rules .............................................................................................. 36 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................................... 37 
7.1. 
Definition of an Adverse Event .................................................................................. 37 
7.2. 
Definition of a Serious Adverse Event ....................................................................... 37 
7.3. 
Recording and Evaluating Adverse Events and Serious Adverse Events ................... 38 
7.3.1. 
Assessment of Intensity .............................................................................................. 38 
7.3.2. 
Assessment of Causality ............................................................................................. 39 
7.3.3. 
Assessment of Outcome .............................................................................................. 39 
7.4. 
Follow-up of Adverse Events and Serious Adverse Events ....................................... 40 
7.5. 
Prompt Reporting of Serious Adverse Events to the Sponsor .................................... 40 
7.6. 
Regulatory Reporting Requirements ........................................................................... 41 
7.7. 
Special Reporting Situations: Pregnancy .................................................................... 41 
8. 
STATISTICAL METHODOLOGY ................................................................................. 43 
8.1. 
Determination of Sample Size .................................................................................... 43 
8.2. 
Study Endpoints .......................................................................................................... 43 
8.2.1. 
Safety Endpoints ......................................................................................................... 43 


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8.2.2. 
Efficacy Endpoints ...................................................................................................... 43 
8.3. 
General Considerations for Statistical Analysis ......................................................... 44 
8.3.1. 
Analysis Datasets ........................................................................................................ 44 
8.3.2. 
Test Hypothesis and P Value Justification .................................................................. 44 
8.3.3. 
Procedures for Handling Missing Data ....................................................................... 44 
8.3.4. 
Definitions for Assessment Windows ......................................................................... 45 
8.3.5. 
Derived Variables ....................................................................................................... 45 
8.4. 
Study Population Summaries ...................................................................................... 45 
8.4.1. 
Disposition .................................................................................................................. 45 
8.4.2. 
Demographics and Surgical Characteristics ............................................................... 45 
8.4.3. 
Protocol Deviations ..................................................................................................... 45 
8.4.4. 
Treatment Compliance ................................................................................................ 45 
8.4.5. 
Prior and Concomitant Medications ........................................................................... 45 
8.5. 
Efficacy Analysis ........................................................................................................ 46 
8.5.1. 
Total Opioid Consumption ......................................................................................... 46 
8.5.2. 
PI on First Ambulation................................................................................................ 47 
8.5.3. 
Time to Event Endpoints ............................................................................................ 47 
8.5.4. 
Length of Stay (LOS).................................................................................................. 48 
8.5.5. 
PGA of Pain Control ................................................................................................... 48 
8.5.6. 
Brief Pain Inventory .................................................................................................... 48 
8.5.7. 
Subject Satisfaction for Postoperative Pain Medication ............................................. 48 
8.5.8. 
Incidence of Postoperative NG Tube Insertion ........................................................... 49 
8.5.9. 
Incidence of Hospital Readmission ............................................................................ 49 
8.5.10. 
Cost of Hospitalization ............................................................................................... 49 
8.5.11. 
Exploratory Analysis:  Inflammatory Markers ........................................................... 49 
8.5.12. 
Subgroup Analyses for Efficacy ................................................................................. 49 
8.6. 
Safety and Tolerability Evaluations ............................................................................ 49 
8.6.1. 
Extent of Exposure ...................................................................................................... 49 


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8.6.2. 
Adverse Events ........................................................................................................... 50 
8.6.3. 
Opioid Related AEs .................................................................................................... 50 
8.6.4. 
AEs of Interest ............................................................................................................ 50 
8.6.5. 
Incidence of Anastomotic Leaks ................................................................................. 50 
8.6.6. 
Clinical Laboratory Tests ............................................................................................ 50 
8.6.7. 
Vital Sign Measurements ............................................................................................ 50 
8.6.8. 
Wound Evaluation ...................................................................................................... 51 
8.6.9. 
Subgroup Analyses for Safety Endpoints ................................................................... 51 
9. 
STUDY ADMINISTRATION.......................................................................................... 52 
9.1. 
Regulatory and Ethical Considerations ....................................................................... 52 
9.1.1. 
Regulatory Authority Approval .................................................................................. 52 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval .................................................... 52 
9.1.3. 
Informed Consent........................................................................................................ 53 
9.1.4. 
Investigator Reporting Requirements ......................................................................... 54 
9.2. 
Study Monitoring ........................................................................................................ 54 
9.3. 
Quality Assurance ....................................................................................................... 54 
9.4. 
Study and Site Closure ................................................................................................ 54 
9.5. 
Records Retention ....................................................................................................... 55 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 .................................... 55 
9.5.2. 
Financial Disclosure.................................................................................................... 55 
9.5.3. 
Access to Original Records ......................................................................................... 55 
9.5.4. 
Archiving of Study-Related Documents ..................................................................... 55 
9.6. 
Provision of Study Results and Information to Investigators ..................................... 56 
9.7. 
Information Disclosure and Inventions ....................................................................... 56 
9.7.1. 
Ownership ................................................................................................................... 56 
9.7.2. 
Confidentiality ............................................................................................................ 56 
9.7.3. 
Publication .................................................................................................................. 56 
9.7.4. 
Data Management ....................................................................................................... 57 


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9.7.5. 
Data Security ............................................................................................................... 57 
9.8. 
Subject Tracking ......................................................................................................... 57 
10. 
REFERENCES ................................................................................................................. 58 
APPENDIX A: OVERVIEW OF STUDY SCHEDULE .......................................................... 59 
APPENDIX B: INVESTIGATOR OBLIGATIONS ................................................................. 60 
APPENDIX C: STUDY-SPECIFIC INFORMATION ............................................................. 62 
APPENDIX C.1: ENHANCED RECOVERY AFTER SURGERY (ERAS) PROTOCOL ..... 62 
APPENDIX C.2: PAIN INTENSITY ASSESSMENT ............................................................. 65 
APPENDIX C.3: PATIENT GLOBAL ASSESSMENT (PGA) OF PAIN CONTROL ........... 66 
APPENDIX C.4: SUBJECT SATISFACTION WITH PAIN MEDICATION ......................... 67 
APPENDIX C.5: BRIEF PAIN INVENTORY (BPI) – SHORT FORM .................................. 68 
APPENDIX D: AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL STATUS 
CLASSIFICATION SYSTEM ......................................................................... 70 
 
 
TABLE OF TABLES 
Table 1:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics ......................... 47 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ANCOVA 
Analysis of covariance 
BMI 
body mass index 
BP 
Blood Pressure 
BPI 
Brief Pain Inventory 
BPM 
Beats per minute 
CFR 
(United States) Code of Federal Regulations 
ºC 
degrees Centigrade 
CL 
Clearance 
CMH 
Cochran-Mantel-Haenszel 
eCRF 
Electronic case report form 
CRP 
C-reactive protein 
DBP 
Diastolic Blood Pressure 
DOS 
Day of surgery 
Dose 1 
Start time of first dose of study drug injection 
ECG 
Electrocardiogram 
ERAS 
Enhanced recovery after surgery 
FOCBP 
Female of Childbearing Potential 
FUV-1 
Follow-up visit 1 
FUV-2 
Follow-up visit 2 
GCP 
Good Clinical Practice 
H 
Hour 
HCl 
Hydrochloride 
Hour 0 
Time of end of surgery (i.e., time of last suture) 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IP 
Investigational Product 
ITT 
Intend-to-treat 
IV 
Intravenous 
Kg 
Kilogram 


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Abbreviation 
Definition 
L 
Liter 
LSD 
Last study dose 
m2 
square meters 
Mg 
Milligram 
Min 
Minute 
mITT 
Modified intend-to-treat 
mL 
Milliliter 
mm Hg 
millimeters of mercury 
N1539 
Injectable NanoCrystal® Colloidal Dispersion (NCD) 
Meloxicam 
NCD 
NanoCrystal Colloidal Dispersion 
NF 
National Formulary 
NG 
Nasogastric 
NPRS 
Numeric Pain Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OOB 
Out of bed 
PGA 
Patient Global Assessment 
pH 
negative log of hydrogen ion concentration 
PI 
Pain Intensity 
PID 
Pain Intensity Difference 
PK 
Pharmacokinetic 
POD (PODx) 
Postoperative Day (Postoperative day x) 
PRN 
Q1H 
Q4H 
Q8H 
As needed 
Every hour 
Every 4 hours 
Every 8 hours 
Q24H 
Every 24 hours 
SAR 
suspected adverse reaction 
SAE 
serious adverse event 
SBP 
Systolic Blood Pressure 
SpO2 
peripheral oxygen saturation 
SSAR 
Serious suspected adverse reaction 
SUSAR 
Serious unexpected suspected adverse reaction 
UDS 
Urine Drug Screen 


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Abbreviation 
Definition 
µL 
Microliter 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VD 
Volume of distribution 
WBC 
white blood cell 
 


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1. 
INTRODUCTION 
Since the year 2000, when the Joint Commission revised their standards for the assessment and 
management of pain, the treatment of pain has taken an increasingly significant position in 
medical care.  Often referred to as the “fifth vital sign”, subjects must now be routinely evaluated 
for pain symptoms so that therapy may be appropriately adjusted. 
While this increased focus has brought more attention to the issue of subject comfort and quality 
of life, our range of tools has remained largely the same.  Current medications run the gamut in 
duration of activity, ranging from acute medications that provide relief for 1-2 hours, to 
alternative formulations which can provide as much as 72 hours of analgesia.  At the same time, 
these dosage forms commonly rely on a similar set of active ingredients, which often work 
through the same opioid pathway to provide relief (morphine, oxycodone, fentanyl) 
(Swarm, 2007).  The result, while there is generally not a ceiling on the effect provided by opiate 
medications, the use of high doses, and multiple opiate medications may lead to an increased 
occurrence of adverse events, which may force a decision between symptoms and side effects 
N1539 was initially developed as an injectable form of meloxicam for the short-term 
management of moderate to severe acute pain using proprietary NanoCrystal® technology.  
N1539 was acquired by Recro Pharma, Inc. (Recro) in April 2015, at which time, Recro assumed 
its development. 
Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the enolic acid class that 
possesses anti-inflammatory, analgesic, and antipyretic activities, which are believed to be 
related to the inhibition of cyclooxygenase (COX) and subsequent reduction in prostaglandin 
biosynthesis (Turck, 1997; Del Tacca, 2002; Mobic 2016).  
Meloxicam has been marketed for over a decade as the oral agent, Mobic.  Mobic tablets and 
suspension are indicated for the relief of the signs and symptoms of osteoarthritis and rheumatoid 
arthritis and the relief of the signs and symptoms of pauciarticular or polyarticular course 
juvenile rheumatoid arthritis in patients 2 years or older.    
Meloxicam has a slow onset of action, largely due to poor water solubility, and is not currently 
approved for the treatment of acute pain.  It has a prolonged absorption, with the time of 
maximum observed plasma concentration (tmax) being approximately 5-6 hours following oral 
administration (Degner, 1997; Turck, 1997), which is consistent with its poor aqueous solubility.  
By increasing the dissolution rate of the active meloxicam moiety, the proprietary NanoCrystal 
technology should provide a faster onset of action of meloxicam, thus providing a suitable 
treatment of acute pain via the intravenous (IV) route 
Prior evaluations of N1539 have included postoperative dosing, before and after the onset of pain 
symptoms.  While administration of N1539 postoperatively has been well tolerated with a 
favorable safety and efficacy profile.  It is unknown whether any differences in surgical outcome 
or hospitalization course may be evident following preoperative dosing, where the use of N1539 
could further reduce the requirement for opioid analgesia.  This study is designed to evaluate the 
safety and efficacy of preoperative dosing with N1539 in subjects undergoing open or 
laparoscopic colorectal surgery, prior to expanding into larger subject enrollment.     
See the N1539 Investigator’s Brochure for more information about the compound. 


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2. 
STUDY OBJECTIVE 
The primary objective of this study is to evaluate the safety and tolerability of preoperative 
dosing of N1539 30 mg in subjects undergoing colorectal surgery, including clinical laboratory 
tests, wound healing evaluation, incidence of anastomotic leaks, and incidence of Adverse 
Events (AEs) and Serious AEs (SAEs). 
Additional objectives include: 
• Evaluation of N1539 treatment impact on overall postoperative recovery course, 
including total opioid consumption, length of hospital stay, pain control, cost of hospital 
stay, return of bowel function, mobilization, and satisfaction with pain medication. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study evaluating 
the safety and efficacy of preoperative dosing with N1539 30 mg in adult subjects undergoing 
open or laparoscopic colorectal surgery.  The initial study cohort will enroll approximately 
50 subjects randomized (1:1) to N1539 30 mg or placebo; additional study cohorts may be 
enrolled following review of initial study observations. 
Adult subjects, age 18 to 80 years inclusive, scheduled to undergo colorectal surgery that is 
expected to result in inpatient hospitalization for at least 48-72 hours, will be screened for 
participation at up to 20 study sites in the United States.  Screening will occur within 28 days 
before study drug administration.  After signing the informed consent, medical history, physical 
examination, laboratory testing, 12-lead electrocardiogram (ECG), pregnancy testing, and vital 
sign measurements will be completed during the screening visit. 
Study sites will follow an Enhanced Recovery After Surgery (ERAS) protocol pre-, peri-, and 
postoperatively (see Appendix C.1).  On the day of surgery (DOS; Day 1), subjects will be 
evaluated to ensure they remain eligible for participation in the study.  Subjects with confirmed 
eligibility will be stratified by incision type (open vs laparoscopic) and randomized to either 
N1539 30 mg or placebo treatment within 12 hours prior to surgery and will be administered the 
first dose of study drug approximately 30 minutes prior to the start of surgery (defined as time of 
first incision).  The start time of first dose of study drug administration (Dose 1) will be used to 
schedule subsequent doses.  
Following surgery (end of surgery defined as the time of last suture; referenced as Hour 0), 
subjects will receive a standardized care regimen per the specified ERAS protocol, including 
rescue analgesia, mobilization, and diet advancing guidelines (see Appendix C.1).  Subjects will 
continue to receive study drug every 24-hours from Dose 1 so long as IV analgesia is clinically 
appropriate or until discharge, whichever comes first.  Subjects will stay at the study center for at 
least 48-72 hours after surgery or so long as inpatient care is clinically appropriate.  A final dose 
of study drug may be administered up to 4 hours early in subjects who are scheduled to be 
discharged.  Subjects who do not receive a dose of study drug for > 28 hours following their 
previous dose of study drug should be considered off treatment, and should not receive further 
doses of study drug.   
Subjects may be discharged from the study center based on their clinical status, with safety 
assessments performed at the earlier of 1 day (24 hours) following their last study dose (LSD+1) 
or at the time of discharge.  Subjects will be provided standard of care analgesic regimen for pain 
management after discharge from the study center. 
All treated subjects will be followed through 30 days after discharge.  All subjects will return to 
the study center to complete follow-up visit 1 (FUV-1) at 5-21 days post-discharge, with follow-
up visit 2 (FUV-2) completed by telephone 30 days post-discharge. 
Safety assessments will include monitoring of AEs, wound healing assessment, vital signs, and 
clinical laboratory tests. 


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Assessments of efficacy will include total opioid consumption, pain intensity according to an 
11-point numeric pain rating scale (NPRS; 0 - 10) on first ambulation, time to first analgesic 
rescue, time to return of bowel function (including time to first flatus or bowel sounds, and first 
bowel movement), time to mobilization (including time to first assisted mobilization out of 
hospital bed and time to first independent mobilization out of hospital bed), patient global 
assessment of pain control, brief pain inventory, subject satisfaction, time to hospital discharge 
(including time to hospital discharge order written and time to actual hospital departure), 
incidence of nasogastric (NG) tube insertion, length of stay, incidence of hospital readmission 
post initial discharge, and total cost of hospitalization. 
3.2. 
Rationale for Study Design and Control Groups 
This study will evaluate the safety and efficacy of repeated dosing with N1539 with the first dose 
of N1539 administered prior to colorectal surgery.  Previous research has demonstrated the 
safety and efficacy of single and repeated doses of N1539 administered after surgery in a range 
of postoperative populations, including open hysterectomy, bunionectomy, and abdominoplasty, 
along with a range of major surgeries including orthopedic and abdominal surgeries.   
This study will further explore the safety and efficacy of N1539 when administered 
preoperatively on a once daily schedule, in a population of subjects undergoing colorectal 
surgery.  Preoperative dosing is anticipated to reduce the need for postoperative opioid 
analgesics, thereby improving the postoperative recovery course as evidenced by length of stay, 
return of bowel function, and pain control satisfaction.  However, it is unknown whether 
preoperative dosing may have other consequences on the safety of treated subjects.  The 
inclusion of a placebo control group will support the comparison of safety results observed in 
N1539 treated subjects. 
As the first preoperative evaluation of N1539, this study will initially enroll a limited cohort of 
approximately 50 subjects.  Following review of observations in the initial cohort, additional 
cohorts may be enrolled in this study to further evaluate the safety of N1539 in this setting, or to 
evaluate other endpoints.  Appropriate IRB approval will be obtained before enrolling additional 
cohorts in this study beyond the proposed initial cohort.   


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Voluntarily provide written informed consent. 
2. Be able to understand the study procedures, comply with all study procedures, and agree 
to participate in the study program. 
3. Male or female 18 to 80 years of age, inclusive. 
4. Be planned to undergo primary (no repeat procedures) open or laparoscopic colorectal 
surgery (laparoscopic expected to require a ≥ 5 cm incision) with bowel resection and/or 
anastomosis, and be expected to require IV analgesia, remain in an inpatient setting for at 
least 48-72 hours, and receive at least two doses of study drug. 
5. Be classified as American Society of Anesthesiology (ASA) physical status category 1, 2 
or 3. 
6. Female subjects are eligible only if all of the following apply: 
• Not pregnant or planning/attempting to become pregnant during the study (female 
subjects of child bearing potential [FOCBP] must have a negative urine 
pregnancy test before surgery); 
• Not lactating; 
• Commits to the use of an acceptable form of birth control for the duration of the 
study through FUV-2; OR 
Be unable to become pregnant due to bilateral oophorectomy or tubal ligation, 
postmenopausal status (1-year post last menstrual period), or sterility of male 
partner while in a monogamous relationship; OR 
Be in a monogamous relationship with a same sex partner with no intention of 
becoming pregnant through any means. 
7. Have a body mass index <40 kg/m2.  
8. For oncology cases, all of the following criteria must be met:  
• Have a histologically confirmed diagnosis of colorectal cancer with a primary 
solid tumor confined to the primary organ, without evidence of local, regional, or 
distal spread;  
• Have a performance status such that they can carry on normal activities of daily 
life without limitations. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the study: 


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1. Have a known allergy or hypersensitivity to eggs, meloxicam, aspirin, other non-steroidal 
anti-inflammatory drugs (NSAIDs), or any excipient of N1539 or placebo. 
2. Planned surgical procedure from incision to closure is expected to be longer than 10 
hours. 
3. Planned surgical procedure includes a resection beyond the peritoneal reflection, is 
related to an acute bout of diverticulitis, or is associated with an emergency procedure. 
4. Have a history of myocardial infarction within the preceding 12 months.  
5. Have, as determined by the investigator or the sponsor’s medical monitor, a history or 
clinical manifestations of significant renal (GFR<60 mL/min/1.73 m2), hepatic, 
cardiovascular, metabolic, neurologic, psychiatric, respiratory, or other condition that 
would preclude participation. 
6. Have a clinically significant abnormal clinical laboratory tests value according to the 
judgment of the investigator. 
7. Have active or recent (within 6 months) gastrointestinal ulceration or bleeding, with 
exception of events related to an ulcerative colitis diagnosis. 
8. Have a known bleeding disorder which may be worsened with the administration of an 
NSAID.  
9. Have evidence of a clinically significant 12 lead ECG abnormality per the judgment of 
the investigator. 
10. Have a recent history of alcohol or prescription/illicit drug abuse. 
11. Have received chronic opioid therapy (daily use of opioids for 30 days or longer) or > 5 
days with opioid use, within 30 days prior to screening.  
12. Unable to discontinue medications, that have not been at a stable dose for at least 7 days 
prior to the scheduled surgical procedure, within 5 half-lives of the specific prior 
medication (or, if half-life is not known, within 48 hours) before dosing with study 
medication, with exception of medications utilized for surgical preparation. 
13. Be unable to discontinue herbal medications/supplements associated with an increased 
bleeding risk at least 7 days prior to surgery through LSD+1/discharge, including but not 
limited to:  gingko biloba, garlic, ginger, ginseng, hawthorn, fish oil (omega-3-fatty acid), 
dong quai, feverfew, vitamin E.  
14. Be receiving lithium or a combination of furosemide with either an angiotensin 
converting enzyme inhibitor or an angiotensin receptor blocker. 
15. Be currently receiving treatment with oral meloxicam (Mobic®) or another NSAID 
within 48 hours prior to surgery.  
16. Have received any investigational product within 30 days before dosing with study 
medication. 
17. Have previously received N1539/IV meloxicam. 
18. Have undergone major surgery in the last 3 months that could interfere with study 
assessments. 


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19. Have undergone or be expected to undergo radiation therapy, chemotherapy, or other 
biological therapy for cancer treatment, within 60 days prior to screening through FUV-2. 
4.3. 
Discontinuation of Subjects 
4.3.1. 
Procedures for Withdrawal 
A subject may be discontinued from the study by the investigator or the sponsor at any time if 
either determines that it is not in the subject’s best interest to continue participation.  Subjects 
who withdraw consent to continue treatment should be encouraged to complete the discharge 
assessments prior to leaving the study center.  Subjects will be encouraged to return for FUV-1 
and to agree to be followed through FUV-2.  The date the subject is withdrawn and the primary 
reason for discontinuation will be recorded in the subject’s electronic case report form (eCRF). 
4.3.2. 
Replacement of Subjects 
Discontinued subjects will not be replaced in the study.  However, the study will enroll an 
adequate number of subjects to meet the target size of 50 subjects in the safety population for 
evaluation. 
4.4. 
Lifestyle Guidelines 
4.4.1. 
Confinement 
Prior to the surgical procedure (Day 1), subjects will arrive at the study site in sufficient time to 
prepare for the procedure and confirm eligibility to participate in the study.  Prior to the surgical 
procedure, qualifying subjects will be stratified and randomized and should receive the first dose 
of study drug approximately 30 minutes prior to surgery.  Subjects may continue to receive study 
drug every 24 hours so long as IV analgesia is clinically appropriate or until time of discharge, 
whichever comes first.  Subjects may be discharged from the study center when appropriate 
based on clinical status.    
Subjects will follow a standardized postoperative care regimen during their hospitalization as 
defined in the study ERAS (Appendix C.1) 
4.4.2. 
Diet 
Subjects will be diet restricted before and after surgery as defined in the study ERAS  
(Appendix C.1). 


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5. 
TREATMENTS 
5.1. 
Surgical Procedure and Perioperative Care 
On Day 1, day of surgery, subjects will undergo colorectal surgery.  Disallowed surgical 
procedures for inclusion in this study include repeat procedures or re-resections, resections 
beyond the peritoneal reflection, surgeries associated with acute bouts of diverticulitis, and 
surgeries associated with an emergency procedure. 
Surgeries should be completed using an appropriate anesthesia and analgesic regimen per the 
clinical practice of the surgeon within the guidelines of the study ERAS (Appendix C.1).  
Disallowed medications are described in Section 5.12. 
Venous thromboembolism prophylaxis before and after surgery will be administered according 
to standard practice, based on the subject’s individual needs, and at the discretion of the 
investigator and surgeon, taking into consideration known drug interactions and 
contraindications with NSAIDs.   
Time of surgery start (time of first incision) and end of surgery (time of last suture; Hour 0) will 
be captured in the eCRF. 
5.2. 
Administration of Study Medication 
Appropriately qualified study personnel will prepare all doses of study drug according to the 
treatment schedule, for administration in this study.  Additional details on study dose preparation 
and administration will be provided in the study specific pharmacy manual. 
All doses of study drug will be administered as an IV bolus over approximately 15 seconds.  
Start time of IV push should be recorded in the subject’s eCRF.   
Each subject is expected to receive at least two doses of study drug during their participation in 
the study.  Randomized subjects will receive their first dose of study drug (Dose 1) 
approximately 30 minutes prior to the start of surgery.  Additional doses of study drug will be 
administered every 24±1 hours from Dose 1 until discharge or until IV analgesia is no longer 
clinically appropriate, whichever is first.  A final dose of study drug may be administered up to 4 
hours early in subjects who are scheduled to be discharged.     
5.3. 
Identity of Study Medication 
N1539 will contain 30 mg meloxicam in each 1 mL of solution, as well as excipients including: 
povidone, sodium deoxycholate (deoxycholic acid), sucrose, and water for injection. 
Placebo will contain:  soybean oil, egg yolk phospholipids, glycerin, fluorescein sodium, sodium 
folate, edetate disodium, benzyl alcohol, polysorbate 80, dextrose and water for injection.  
Hydrochloric acid and/or sodium hydroxide may be used for pH adjustment. 
5.4. 
Method of Assigning Subjects to Treatment Groups 
A computer-generated randomization scheme will be prepared prior to study initiation.  Eligible 
subjects will be randomized in a 1:1 ratio to IV treatment with N1539 30 mg or placebo.  A 
block randomization will be generated stratified by center and planned incision type (open vs. 


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laparoscopic).  Investigators and site staff will not be aware of the size of the block.  All doses of 
study drug administered will be according to the original assignment. 
5.5. 
Selection of Doses 
Doses of N1539 have been selected following review of safety, efficacy and pharmacokinetic 
data from 11 previous clinical studies.  Clinical studies have evaluated doses of N1539 ranging 
from 5 to 180 mg.  Findings in the Phase 2 program for N1539 supported the use of a 30 mg dose 
administered via IV push once daily (every 24 hours).  These findings were verified in two well 
controlled Phase 3 studies of N1539 30 mg administered to subjects with moderate to severe pain 
following bunionectomy and abdominoplasty surgeries.  Both studies demonstrated a significant 
effect of N1539 30 mg for pain reduction compared with placebo.  The safety of N1539 30 mg 
has been further evaluated in a 721 subject, placebo controlled postoperative safety study where 
dosing with N1539 30 mg was observed to have a similar safety profile with placebo. 
The current study has been planned to evaluate the safety and efficacy of preoperative dosing 
with N1539 30 mg in a repeated dose setting compared with placebo.     
5.6. 
Selection of Timing of Dose 
Randomized subjects will be administered doses of study drug every 24 hours.  This interval has 
been demonstrated to maintain analgesia throughout the dosing interval in a range of Phase 2 and 
3 clinical studies.  The 24-hour dosing interval has been selected based on the pain relief and 
pharmacokinetic profile of N1539 established in previous clinical studies.  Administration of the 
first dose of study drug prior to the surgical procedure will be evaluated to determine its effect on 
postoperative outcomes.  The start time each dose is administered will be recorded in the 
subject’s eCRF.   
5.7. 
Blinding and Unblinding of Study Medications 
All doses of study drug will be prepared by an appropriately qualified member(s) of the 
healthcare team at the research center, for administration according to the subject’s 
randomization.   
Doses of study drug will be administered by staff members who will be blinded to the treatment 
assignment. 
The study blind may be broken only if the safety of a subject is at risk and the treatment plan for 
that subject depends on which study medication he or she received.  Unless the subject is at 
immediate risk, the investigator must make diligent attempts to contact the sponsor before 
unblinding the subject’s data.   
If a subject’s data are unblinded without the prior knowledge of the sponsor, the investigator 
must notify the sponsor as soon as possible and no later than the next business morning.  All 
circumstances surrounding a premature unblinding must be clearly documented. 
5.8. 
Treatment Compliance 
Blinded study personnel will administer each dose of study medication.  The exact date and time 
each dose is administered will be recorded in the subject’s eCRF.   


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5.9. 
Drug Accountability 
The investigator (or designee) will sign for the study medications when they are received.  The 
study medication must be handled and stored as described and dispensed only to those subjects 
formally entered into the study. 
At the completion of the study, and after reconciliation of all delivery and usage records, any 
unused study medication supplied by the sponsor will be returned to the sponsor (or designee) or 
destroyed per written instructions from the sponsor. 
5.10. 
Packaging, Labeling, and Storage 
Study medication will be provided in study labeled packaging for preparation for use in this 
study. 
N1539 will be provided in single use vials containing 30 mg per mL.   
Placebo will be provided in single use vials. 
Directions for preparation of study medication will be provided as pharmacy instructions prior to 
initiation of the study. 
Study medication should be stored at the study site at 20° to 25°C (68° to 77°F), although a 
range of 15ºC to 30ºC (59ºF to 86ºF) will be permitted.  Study medication should be protected 
from light. 
All study medication at the study site(s) should be stored in a locked area with restricted access.  
A temperature log or chart should be maintained to monitor the environment at the study site. 
5.11. 
Prior and Concomitant Medications 
All medications and other treatments taken by subjects within 5 days before the first dose of 
study drug and during the study will be recorded in the eCRF. 
All medications that have not been at a stable dose for at least 14 days prior to the scheduled 
procedure will be prohibited within five half-lives of the specific prior medication (or, if half-life 
is unknown, within 48 hours) before the surgical procedure, with exception of medications 
utilized for surgical preparation. 
5.12. 
Prohibited Medications 
The following medications or drug classes will be prohibited during the study: 
• Any NSAIDs other than study drug (ketorolac, ibuprofen, diclofenac, etc.) are prohibited 
from 48 hours prior to surgery through LSD+1 
• Non-opioid analgesics (other than ERAS specific post procedure acetaminophen) are 
prohibited from the end of surgery through LSD+1. (see Appendix C.1) 
• Alvimopan 
• Short or long acting local anesthetic agents infiltrated into the incision or port sites. 
• Other analgesic agents not expressly permitted in the ERAS protocol (see Appendix C.1).   


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5.13. 
Concomitant Interventions and Procedures 
All interventions or procedures, whether diagnostic or therapeutic, will be recorded in the eCRF, 
along with time, date, and reason for the intervention or procedure.  If an intervention or 
procedure is implemented to treat an AE, the event must be recorded as an AE, along with all 
relevant information. 
5.14. 
Rescue Medication 
During the study, inpatient and following discharge, pain symptoms that are not adequately 
controlled by dosing with study drug, may be treated with IV and PO opioids according to the 
standardized regimen defined in the study ERAS (Appendix C.1). 


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6. 
STUDY PROCEDURES 
The timing of study procedures are to be performed relative to Hour 0, end of surgery, defined as 
completion of surgical closure. 
A schedule of study procedures for overall study assessments and day-of-dosing assessments is 
provided in Appendix A. 
6.1. 
Demographic and Efficacy Assessment 
6.1.1. 
Demographics  
Demographics information will be collected during screening visit including age, sex, ethnicity, 
race, weight, height, and BMI. 
6.1.2. 
Medical History 
The investigator or designee will document each subject’s medical history during the screening 
visit.  Medical history will be updated on Day 1 when the subject reports for surgery, and the 
subject will be reviewed to confirm that they continue to meet the required study inclusion and 
exclusion criteria. 
6.1.3. 
Physical Examination 
The investigator or designee will perform a physical examination (HEENT, cardiovascular, 
respiratory, gastrointestinal, neurological, dermatologic, and musculoskeletal systems) during the 
screening visit, at check-in on Day 1, and at LSD+1.  Physical examination results collected 
within 7 days prior to the screening visit may be utilized to evaluate subject eligibility at 
screening.  Body weight and height will be measured, and BMI will be calculated during the 
screening visit only.   
The study Investigator may perform a physical examination (the extent of which is determined 
by the study investigator) at any time during the study if indicated by change in a subject’s 
medical history or condition. 
6.1.4. 
Surgical Information 
Information on the surgical procedure, including time of start and end of surgery, time into and 
out of recovery room, planned and actual incision type (open, laparoscopic, or laparoscopic 
converted to open), incision length, and any surgical complications will be recorded in the 
subject eCRF.  Surgery procedures will be grouped into surgery types for the purpose of 
analysis. 
6.1.5. 
Concomitant Medications and Opioid Use 
All medications utilized during the study will be captured as concomitant medications.  Opioid 
analgesics used from Hour 0 to discharge will be the primary efficacy endpoint and the dose of 
each opioid medication will be converted into their IV morphine equivalent dose (IVMED) for 
the total opioid consumption analysis.  Hence, each opioid medication used from Hour 0 to 
discharge will be captured separately in the eCRF. 


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Following discharge, subjects will be questioned regarding continued use of opioid analgesics 
during the FUV-1 and FUV-2 visits.   
6.1.6. 
Pain Intensity (PI) on Ambulation 
PI will be assessed by the study subject for their current pain according to an 11-point numeric 
pain rating scale (NPRS; 0 - 10) where 0 equates to no pain, and 10 equates to the worst pain 
imaginable, as described in Appendix C.2. 
PI will be assessed within 15 minutes prior to first ambulation.  Subjects will also utilize the 
NPRS to assess their worst pain intensity experienced during their first ambulation.  
6.1.7. 
Cost of Hospitalization 
Cost of hospitalization will be determined using UB-04 and/or similar hospital claim forms used 
for billing purposes.  Cost of hospitalization will be determined from the billing codes and/or 
procedure codes for all hospital care from the time of hospital admission until discharge. 
When available, hospital costs resulting from hospital readmissions during the follow-up period 
should be collected. 
6.1.8. 
Time to Events  
Following surgery, subjects will be questioned regarding the occurrence of first flatus and bowel 
movements, and study staff will be asked to document the first observed bowel sounds.  The 
times that these events first occur following the end of surgery (Hour 0) will be recorded.  
Time to rescue analgesia use will be determined from the first recorded time of opioid analgesic 
use in the subject’s medical record, beginning after surgery. 
Times to event pertaining to hospital discharge will include time that hospital discharge order 
was written or when discharge readiness was recorded in the subject chart, and actual departure 
time of hospital. 
Mobilization will be attempted per the postoperative schedule defined in the ERAS  
(Appendix C.1:).  Study staff will be asked to document the time of first successful postoperative 
mobilizations in the subject eCRF, including first assisted mobilization out of hospital bed, and 
first independent mobilization out of hospital bed. 
6.1.9. 
Patient Global Assessment (PGA) of Pain Control  
Subjects will be asked to evaluate their pain control during the preceding period according to the 
following scale: 0-poor, 1-fair, 2-good, 3-very good, or 4-excellent” (See Appendix C.3). 
The PGA of pain control will be completed at Hour 24 (± 2 hours) from Hour 0, every 24 hours 
(± 2 hours) thereafter until LSD+1 (Hour 48, Hour 72, etc.), and at LSD+1 (± 2 hours). 
6.1.10. 
Brief Pain Inventory 
The Brief Pain Inventory (BPI; short form; Appendix C.5) will be completed by all subjects to 
evaluate their pain control and functioning.   


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The BPI assessment will be completed at screening, Hour 24 (± 2 hours) from Hour 0, every 24 
hours thereafter (± 2 hours) until LSD+1, and at LSD+1 (± 2 hours). 
6.1.11. 
Subject Satisfaction with Postoperative Pain Medication 
Subjects will report their satisfaction with the medication they received to manage their 
postoperative pain according to a 7-point Likert scale including categories of: completely 
dissatisfied (1), mostly dissatisfied (2), somewhat dissatisfied (3), neither satisfied to dissatisfied 
(4), somewhat satisfied (5), mostly satisfied 6), and completely satisfied (7) (see Appendix C.4).  
The subject assessment of satisfaction will be assessed at LSD+1. 
6.1.12. 
Postoperative NG Tube Insertion 
All NG tubes inserted pre- or perioperatively should be removed at or before Hour 24.  Any NG 
tube inserted postoperatively will be recorded in the eCRF, along with time of insertion where 
appropriate.  
6.1.13. 
Hospital Readmission 
Following discharge, subjects will be asked to report any hospital readmissions to the study staff.  
Subjects will be questioned regarding any hospital readmissions during FUV-2.  
6.2. 
Safety Assessments Description  
6.2.1. 
Clinical Laboratory Tests 
During the screening visit, on Day 1 during check-in, and at LSD+1, subjects will have blood 
and urine samples collected for routine clinical laboratory testing.  Screening laboratory tests will 
be performed at a local laboratory; historic laboratory results collected within 7 days prior to the 
screening visit may be utilized for subject eligibility evaluation at screening visit.  Laboratory 
tests on Day 1 and at LSD+1 should be performed at the central laboratory.  Laboratory tests to 
be performed include: 
• hematology:  platelet count, hemoglobin, and hematocrit 
• clinical chemistry tests:  urea, glucose, creatinine, sodium, potassium, chloride, 
bicarbonate, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total bilirubin, direct bilirubin, and gamma-glutamyltransferase 
• coagulation tests:  prothrombin time, activated partial thromboplastin time, international 
normalized ratio  
Additional urine samples will be collected and tested as follows: 
• urine pregnancy testing at check-in on Day 1 for FOCBP.  
Additional blood samples will be collected from a cohort of subjects for exploratory analysis of 
inflammatory markers; participation in this cohort will be optional.  Blood samples will be 
collected at check-in prior to surgery on Day 1, and once daily thereafter (POD1, POD2, etc.; 
may be collected at any time on the stated POD) until LSD+1, for analysis of inflammatory 
markers including, but not limited to: c-reactive protein (CRP), tumor necrosis factor alpha 
(TNF-α), interleukin (IL) 1B, IL-4, IL-6, IL-8, IL-10, and IL-18. 


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Screening laboratory results, and Day 1 urine pregnancy results, will be used for assessing 
eligibility for randomization.   
6.2.2. 
Vital Sign Measurements 
Resting vital signs will include blood pressure, pulse, and peripheral oxygen saturation (SpO2), 
should be collected at the screening visit, at check-in prior to surgery on Day 1, and at LSD+1.  
Resting tests must be obtained after resting (seated/supine) for ≥ 5 minutes.  Historic vital signs 
results collected within 7 days prior to the screening visit may be utilized for subject eligibility 
evaluation at screening visit. 
Additional vital signs may be collected during the study according to standard practice and 
clinical status.  Any clinically significant changes in vital signs after study drug treatment should 
be captured as AEs at the discretion of the investigator. 
6.2.3. 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be completed for all subjects at screening.  Historic ECG results collected 
within 7 days prior to the screening visit may be utilized for evaluation of subject eligibility; 12-
lead ECG will be used to exclude subjects with a clinically significant abnormal ECG. 
6.2.4. 
Wound Evaluation 
Surgical wound healing will be evaluated by the investigator at time of discharge and at FUV-1 
to determine whether healing is following a normal course in the opinion of the investigator.  
The investigator will evaluate the healing of the wound using an 11-point scale (0-10) where a 
score of 0 is “Completely unsatisfied”, and a score of 10 is “Completely satisfied”.   
6.2.5. 
Anastomotic Leaks 
Following the end of surgery, subjects will be monitored for any occurrence of anastomotic 
leaks.  Any incidence of anastomotic leaks will be reported in the eCRF. 


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6.3. 
Assessments by Visit 
6.3.1. 
Screening Visit 
Subjects meeting the eligibility criteria listed in Section 4 may be enrolled in the study after the 
nature and purpose of the protocol have been explained to them, and they have voluntarily 
granted written informed consent to participate.  All subjects will have a screening evaluation 
within 28 days before surgery (Day 1).  After informed consent is obtained, the following 
procedures will be performed at the screening visit for all subjects: 
• Review of inclusion/exclusion criteria eligibility (Section 4.1 and Section 4.2) 
• Demographics and medical history (Section 6.1.1 and Section 6.1.2) 
• Physical examination including height, weight and BMI (may utilize historical results 
collected within 7 days prior to screening visit; Section 6.1.3) 
• Measurement of resting vital signs (may utilize historical results collected within 7 days 
prior to screening visit; Section 6.2.2) 
• 12-lead ECG (may utilize historical results collected within 7 days prior to screening 
visit; Section 6.2.3) 
• Clinical laboratory tests (may utilize historical results collected within 7 days prior to 
screening visit; Section 6.2.1) 
• Brief Pain Inventory (Section 6.1.10) 
6.3.2. 
Day 1 - Check-In  
The following assessments will be conducted on the day of admission (Day 1, prior to surgery) 
for all subjects:  
• Medical history update (Section 6.1.2) 
• Physical examination (Section 6.1.3) 
• Clinical laboratory tests (Section 6.2.1) 
• Urine pregnancy test (FOCBP only; Section 6.2.1) 
• Inflammatory marker sample collection (Section 6.2.1) 
• Measurement of resting vital signs (Section 6.2.2) 
Subjects who continue to meet eligibility criteria will be randomized and undergo surgery per 
Section 5.1. 
6.3.3. 
Day 1 - Randomization and Surgery 
The following assessments will be conducted on Day 1 prior to surgery: 
• Randomization to treatment within 12 hours prior to surgery (Section 5.4) 
• Study drug administration per randomization assignment approximately 30 minutes prior 
to start of surgery (Section 5.2) 


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• Undergo surgery per Section 5.1. 
6.3.4. 
Inpatient Treatment 
The following assessments will be conducted during inpatient treatment from Hour 0, end of 
surgery (time of last suture), until LSD+1: 
• Study drug administration per randomization; time of Dose 1 will be used to schedule 
subsequent doses (Section 5.2) 
• PI assessment on first ambulation (Section 6.1.6) 
• Monitoring of rescue analgesia usage (Section 6.1.5) 
• Monitoring of bowel function (Section 6.1.8) 
• Monitoring of mobilization (Section 6.1.8) 
• PGA of pain control (collected Q24H until LSD+1 Section 6.1.9) 
• Brief Pain Inventory (collected Q24H until LSD+1 Section 6.1.10) 
• Monitoring of AEs (Section 7) 
• Monitoring of all concomitant medications (Section 6.1.5) 
• Inflammatory marker sample collection (once daily until LSD+1; Section 6.2.1) 
6.3.5. 
LSD+1  
The following assessments will be conducted for all subjects 24 hours (± 2 hours) following the 
last study dose (LSD+1); if a subject is ready for discharge less than 24 hours following the last 
study dose, LSD+1 procedures should be performed prior to discharge: 
• Physical examination (Section 6.1.3) 
• PGA of pain control (Section 6.1.9) 
• Brief Pain Inventory (Section 6.1.10) 
• Subject satisfaction with postoperative pain medication (Section 6.1.11) 
• Clinical laboratory tests (Section 6.2.1) 
• Measurement of resting vital signs (Section 6.2.2) 
• Monitoring of AEs and concomitant medications (Section 7) 


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6.3.6. 
Discharge 
The following assessments will be conducted for all subjects within 4 hours prior to discharge: 
• Time hospital discharge order was written and time of actual departure from hospital 
(Section 6.1.8) 
• Wound evaluation (Section 6.2.4) 
• Monitoring of AEs and concomitant medications (Section 7) 
6.3.7. 
Follow-Up Visit 1 (FUV-1) 
The following procedures will be conducted for all subjects during FUV-1, conducted 5-21 days 
post-LSD. 
• Wound evaluation (Section 6.2.4) 
• Monitoring of AEs and concomitant medications (Section 7) 
6.3.8. 
Follow-Up Visit 2 (FUV-2) 
The following procedures will be conducted for all subjects during FUV-2, conducted by 
telephone contact 30±4 days post-LSD: 
• Monitoring for hospital readmission (Section 6.1.13) 
• Monitoring of AEs and concomitant medications (Section 7) 
6.4. 
Appropriateness of Assessments 
The efficacy measures utilized in this study are appropriate to support the objectives of the study.  
The timing of assessments is intended to evaluate efficacy throughout the dosing interval. 
Safety measures used in this study are standard for clinical trials of investigational medications.  
6.5. 
Clinical Stopping Rules 
This study will be discontinued if it is determined that there is a significant safety risk posed 
towards study subjects.  Potential safety risks will be evaluated continuously throughout the 
course of enrollment in the study.  


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7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an adverse event (AE) or serious adverse event (SAE) as provided in this 
protocol.  During the study, when there is a safety evaluation, the investigator or site staff will be 
responsible for detecting AEs and SAEs, as detailed in this section of the protocol. 
7.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not 
considered causally associated with the use of the study drug. Any abnormal laboratory value 
deemed clinically significant by the investigator, regardless of causal relationship, must be 
reported as an AE. 
Examples of an AE include the following: 
• Significant or unexpected worsening or exacerbation of the condition or indication under 
study 
• Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency or intensity of the condition (eg, abnormal physical examination 
finding) 
• Signs, symptoms, or clinical sequelae of a suspected interaction 
• Signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE, unless 
nonserious or serious sequelae occur) 
The following examples are not considered AEs: 
• Medical or surgical procedure (eg, endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) (including 
laboratory values) present or detected at the start of the study that do not worsen 
• The disease or disorder being studied, or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless they become more severe or occur with a greater 
frequency than expected for the subject’s condition  
All AEs, whether volunteered, elicited, or noted on physical examination, and regardless of 
causality, will be assessed and recorded in the eCRF beginning after administration of study drug 
through end of the study (ie, Day 30).  
7.2. 
Definition of a Serious Adverse Event 
A SAE is defined as any event that meets the following criteria: 
• Results in death 


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• Is immediately life-threatening (ie, presents an immediate risk of death from the event as 
it occurred; this does not include an AE had it occurred in a more serious form may have 
caused death).   
• Results in persistent or significant incapacity or substantial disruption of the ability to 
perform normal life functions.   
• Results in hospitalization. 
•  Results in prolongation of an existing hospitalization. 
•  Is a congenital anomaly or birth defect (in the offspring of a subject using the study drug 
regardless of time to diagnosis). 
•  Is considered an important medical event. 
Medical and scientific judgment should be exercised in determining whether an AE is serious 
when considering important medical events that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the subject or may require medical or 
surgical intervention to prevent any of the outcomes listed that define a SAE. Examples of such 
medical events that may also be considered serious include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of a SAE. 
Social or convenience admission to a hospital or prolongation of a hospitalization for social or 
convenience reasons not associated with the occurrence of an AE does not meet the definition of 
a SAE. 
SAEs will be assessed and recorded in the eCRF after the signing of informed consent through 
the end of the study (ie, Day 30). If an investigator becomes aware of a SAE or death that occurs 
more than 30 days after the subject receives study drug and the investigator considers the event 
to be related to the study drug, he/she is obligated to report the SAE to the sponsor. 
7.3. 
Recording and Evaluating Adverse Events and Serious Adverse 
Events 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, or other clinical information. In such cases, the diagnosis, not the individual signs or 
symptoms, should be documented as the AE or SAE. 
7.3.1. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study, using his or her clinical judgment. The intensity of each AE and SAE recorded in the 
eCRF should be assigned to one of the following categories: 
• Mild: an event that is easily tolerated by the subject, causes minimal discomfort, and does 
not interfere with everyday activities 


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• Moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities 
• Severe:  an event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with a SAE. Severity is a term used to 
describe the intensity of a specific event, and both AEs and SAEs can be assessed as severe. 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 the subject’s or event’s outcome or 
on action criteria usually associated with events that pose a threat to a subject’s life or 
functioning (see Section 7.2). 
7.3.2. 
Assessment of Causality 
The investigator must record the causal relationship of each event in the eCRF, and additionally 
for SAEs, on the SAE reporting form.  An investigator's causality assessment is the 
determination of whether there exists a reasonable possibility that the study drug caused or 
contributed to an AE.  
• Related: There is evidence to suggest a causal relationship between the study drug and 
the AE.   
• Not related: The AE is due to underlying or concurrent illness or effect of another drug or 
event and is not related to the study drug (eg, has a more likely alternate etiology and / or 
a temporal relationship does not suggest a causal relationship).   
Even in situations in which minimal information is available for the initial SAE report, it is 
important that the investigator always make an assessment of causality for every event before 
transmitting the SAE reporting form and completing the AE eCRF page(s). The causality 
assessment is one of the criteria used when determining regulatory reporting requirements. The 
investigator may change his or her opinion of causality in light of follow-up information and 
amend the SAE reporting form and AE eCRF page(s) accordingly. 
7.3.3. 
Assessment of Outcome 
All AEs and SAEs must be followed until they are resolved, the condition stabilizes, the events 
are otherwise explained, or the subject is lost to follow-up. The investigator will assess the 
outcome of the event(s) by using the following terms: 
• Resolved:  The event resolved and the subject returned to baseline.  
• Resolving:  At last observation, the event was improving. 
• Resolved with sequelae:  The event resolved but the subject is left with residual problems 
(eg, functional deficits)  
• Not resolved: At the last observation, the event was unchanged.  
• Unknown:  There were no observations after the onset (initial observation or report) of 
the event, and the status of the event is unknown. 
• Death (Fatal):  To be selected for the one AE, which in the judgement of the investigator 
was the primary cause of death.  


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7.4. 
Follow-up of Adverse Events and Serious Adverse Events 
After the occurrence of an AE or SAE, the investigator is required to follow each subject 
proactively and provide further information on the subject’s condition. All AEs and SAEs 
documented at a previous visit or contact that are designated as ongoing will be reviewed at 
subsequent visits or contacts until the event resolves, the condition stabilizes, the event is 
otherwise explained, or the subject is lost to follow-up. Any additional events that are relevant to 
the ongoing event will be documented. 
The investigator will ensure that follow-up information relevant to SAEs is provided to the 
sponsor and includes results of any additional laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to clarify the nature 
of the event, the cause of the event, or both. 
New or updated information will be recorded on the originally completed SAE reporting form 
and entered into the eCRF pages, with all changes signed and dated by the investigator. The 
updated SAE reporting form should be resubmitted to the sponsor within the time frames 
outlined in Section 7.5. 
7.5. 
Prompt Reporting of Serious Adverse Events to the Sponsor 
Once the investigator determines that an event meets the protocol definition of an SAE, he or she 
must notify the sponsor within 24 hours. 
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE, WHICH OCCURS 
DURING THE COURSE OF THIS STUDY, REGARDLESS OF RELATIONSHIP TO 
STUDY DRUG, MUST BE REPORTED TO THE SPONSOR IMMEDIATELY (within 24 
hours). 
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY eMAIL 
TO THE FOLLOWING SPONSOR CONTACT: 
 
Medical Safety Recro Pharma, Inc. 
Telephone: 484-395-2470 
eFax: 484-395-2472 
eMail: AE@recropharma.com 
 
In the initial eMail, the investigator must provide to the sponsor the following eCRF pages, 
completed to the greatest extent possible: 
• AE record 
• Medical history 
• Prior and concomitant medications 
Also, the following documents are to be forwarded: any laboratory results, diagnostic test results, 
or medical reports relevant to the SAE. 
E-mail transmission is the preferred method to transmit SAE information. In rare circumstances 
and in the absence of e-mail capacity, notification by fax or telephone is acceptable, with a copy 


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of the SAE reporting form sent by overnight mail. Initial notification via telephone does not 
replace the need for the investigator to complete the SAE reporting form and eCRF pages within 
the time frames outlined. 
If the investigator does not have all information regarding an SAE, he or she must not wait to 
receive additional information before notifying the sponsor of the event. The form must be 
updated when additional information is received. Follow-up information received on all SAEs 
must be forwarded to the sponsor by using the same procedure and timelines as for an initial 
report. 
7.6. 
Regulatory Reporting Requirements 
The investigator must promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 7.5 “Prompt Reporting of Serious Adverse Events to the Sponsor.” The 
sponsor has a legal responsibility to notify, as appropriate, both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. Prompt 
notification of SAEs by the investigator to the appropriate project contact for SAE receipt is 
essential so that SAEs that are either unexpected or observed with increasing occurrence, be 
reported and legal obligations and ethical responsibilities regarding the safety of other subjects 
are met. 
For the purposes of IND safety reporting, expectedness of the SAE will be assessed by the 
sponsor.  A SAE is considered unexpected if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
The sponsor will determine whether the SAE meets regulatory reporting criteria (ie, 7- or 15-day 
report) in compliance with local and regional law. If so, the sponsor (or the sponsor’s 
representative) will report the event to the appropriate regulatory authorities. The sponsor will 
report SAEs to the central IRB/EC and the investigator will be report SAE to their local to 
institutional review board (IRB)/EC. Investigator letters are prepared according to sponsor policy 
and are forwarded to the investigators as necessary. An investigator letter is prepared for any 
SAE that is attributable to study drug, serious, and unexpected. The purpose of the investigator 
letter is to fulfill specific regulatory and Good Clinical Practice (GCP) requirements regarding 
the product under investigation. 
The investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the IRB or IEC. 
7.7. 
Special Reporting Situations: Pregnancy  
Any subject who becomes pregnant during the study must discontinue further study drug 
administration and should be followed through delivery or termination of the pregnancy.  A 
subject should be instructed to also notify the investigator immediately if she becomes pregnant 
within 30 days after receiving study drug.  The sponsor must be notified of all pregnancies 
reported to the investigator (see Section 7.5 for contact information). 
Any uncomplicated pregnancy that occurs in a subject during this clinical study will be reported 
for tracking purposes only. All subject pregnancies that are identified during or after this study, 


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where the estimated date of conception is determined to have occurred within 30 days of 
receiving study drug need to be reported, followed to conclusion (delivery or termination), and 
the outcome reported, even if the subject is discontinued from the study. The investigator should 
report all pregnancies within 24 hours using the Pregnancy Report/Outcome Form, according to 
the usual timelines and directions for SAE reporting provided in Section 7.5. Monitoring of the 
pregnancy should continue until conclusion of the pregnancy; and follow-up detailing the 
outcome of the pregnancy submitted using the Pregnancy Report/Outcome Form. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Likewise, elective abortions without complications are not considered AEs.  
Any SAEs associated with pregnancy (eg, congenital abnormalities/birth defects/spontaneous 
miscarriages or any other serious events) must additionally be reported as such using the SAE 
report form according to the usual timelines and directions for SAE reporting provided in 
Section 7.5. 


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8. 
STATISTICAL METHODOLOGY 
The following outlines some of the key elements of the data analysis approach.  A formal 
statistical analysis plan (SAP) will be developed for this study in which statistical models, data 
derivation methods and rules will be described in details.  A separate SAP will also be prepared 
for the planned interim analysis for this study. 
8.1. 
Determination of Sample Size 
The initial sample size of 50 subjects was selected empirically without a formal power 
calculation. 
An unblinded data review will be performed after approximately 40-50 subjects are enrolled and 
have completed study assessments through initial hospital discharge.  An independent statistician 
will perform analysis.  Details will be discussed in the analysis plan to be prepared for this study. 
Following enrollment and review of this initial cohort, if study data warrant, additional cohorts 
may be enrolled to further evaluate safety in this setting, or may to explore other endpoints.   
8.2. 
Study Endpoints 
8.2.1. 
Safety Endpoints 
The safety endpoints will include the following: 
1. Incidence of treatment-emergent AEs and SAEs (including AEs of interest and opioid 
related AEs) 
2. Incidence of anastomotic leaks  
3. Change from baseline in laboratory tests; incidence of abnormal clinical laboratory tests 
4. Change from baseline in vital signs 
5. Assessment of surgical wound healing 
8.2.2. 
Efficacy Endpoints 
The efficacy endpoints will include:  
1. Total opioid consumption   
2. Time to hospital discharge order written 
3. Pain intensity on first ambulation 
4. Time to actual hospital departure 
5. Time to first rescue analgesia use 
6. Time to return of bowel function, including time to first bowel sounds or first flatus, and 
time to first bowel movement  
7. Time to mobilization, including time to first assisted mobilization out of hospital bed and 
time to first independent mobilization out of hospital bed 
8. PGA of pain control 


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9. Brief Pain Inventory  
10. Subject assessment of satisfaction with pain medication 
11. Hospital length of stay (LOS) 
12. Incidence of postoperative NG tube insertion 
13. Incidence of hospital readmission. 
14. Total cost of hospitalization 
 Exploratory endpoints include: 
1. Change in inflammatory markers  
8.3. 
General Considerations for Statistical Analysis 
8.3.1. 
Analysis Datasets  
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include all eligible subjects who were 
randomized.  The ITT subjects may or may not receive randomized treatment and may or may 
not have the scheduled surgery. 
Safety Set:  The safety set will include all treated subjects and will be used for safety and 
tolerability assessments.   
Efficacy analysis set will include all safety analysis set subjects who had the scheduled surgery.  
Subjects whose surgery was cancelled, whose surgery was changed will be excluded from the 
efficacy analysis, or who required NG tube use (placed perioperatively) beyond Hour 24.   
Efficacy analysis set will be the primary population for efficacy evaluation, but additional 
sensitivity analysis may be performed based on the ITT analysis set. 
8.3.2. 
Test Hypothesis and P Value Justification 
Each efficacy analysis will be performed to assess the differences between the 2 treatment 
groups; difference will be derived by N1539 30 mg vs Placebo.     
The null hypothesis is that there is not difference between the examined treatment groups.  The 
alternative hypothesis is that the treatment groups are different.  Differences between the 
2 groups will be evaluated via 2-sided tests at the 0.05 level of significance.  
Nominal p-value will be reported as is.  
Details for study-wise Type 1 error control, including interim analyses, final co-primary efficacy 
endpoints analyses, and final secondary efficacy endpoints, will be discussed in the formal SAP. 
8.3.3. 
Procedures for Handling Missing Data  
Unless indicated otherwise (see Section 8.3.5), no imputation will be done for missing data.  
However, AEs with missing severity assessments will be tabulated as “severe,” and AEs with 
missing relationship assessments will be tabulated as “related” for the purpose of analysis; and 
the missing data will be presented in data listing as is. 


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8.3.4. 
Definitions for Assessment Windows 
For the purpose of data analysis, baseline measures for a given parameter will be the last 
measurements taken before the subject receives the first dose of study medication.  End of Study 
Visit will be the last follow-up (FUV-2) to be conducted 30 ± 4 days post-discharge. 
8.3.5. 
Derived Variables 
Detailed rules to be used to derive various efficacy parameters will be documented in the 
statistical analysis plan, including method to compute time to events and censoring rules for time 
to event endpoints, imputation of partial/incomplete time of analgesic medications start and/or 
stop times, and computing scores for BPI at domain and sub-dimension level.    
8.4. 
Study Population Summaries 
Population summaries will be provided for the safety analysis set included in this study. 
8.4.1. 
Disposition 
The summary tables will provide frequency counts for subject disposition (all treated subjects, 
subjects who completed the study, number and proportion of subjects who discontinued 
treatment; number and proportion of subjects who discontinued from the study, and reason for 
discontinuation of study drug treatment and reason for discontinuation of study) by treatment 
group and study overall.   
Disposition in terms of number of subjects excluded from each analysis sets (ITT, safety, 
efficacy) will also be provided by treatment groups and study overall. 
8.4.2. 
Demographics and Surgical Characteristics 
The demographic summary will include descriptive statistics for age, sex, race, weight, height, 
and BMI for the overall and by treatment group. 
Surgery characteristics will include surgery information, such as surgery description and surgery 
duration (hr).  
8.4.3. 
Protocol Deviations 
All protocol deviations will be identified.  Tabulation may be provided if data warrant. 
8.4.4. 
Treatment Compliance 
Doses of study medication will be administered by study personnel to study subjects while 
subjects are confined to the study site.  The time of administration of study medication will be 
documented within each subject’s eCRF.  No formal summary of treatment compliance will be 
produced. 
8.4.5. 
Prior and Concomitant Medications 
All prior and concomitant medications will be tabulated for the overall study population.  Prior 
and concomitant medications will be coded to the therapeutic drug classes and generic drug 


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names using the World Health Organization (WHO) Drug classifications version 1Q2017 or 
higher. 
8.5. 
Efficacy Analysis 
8.5.1. 
Total Opioid Consumption 
All concomitant medications will be coded according to WHO Drug library.  Opioid medications 
will be identified per ATC level 2 and level 3.  The dose from each identified opioid record will 
then be converted to IV Morphine Equivalent Dose (IVMED) in mg; examples of IVMED of 
some commonly used analgesics are provided in Table 1. 
All analgesic medications will be mapped to the following time periods based on the start 
date/time and stop date/time:  Hour 0 to discharge, Hour 0-24, Hour 0-48, Hour 24-48,  
Hour 0-72, and Hour 48-72.   
Total opioid consumptions in IVMED (mg) per subject will be determined for each interval.  A 
summary table will be prepared to provide group descriptive statistics, including sample size, 
mean, standard deviation, minimum, median, and maximum.  Difference between treatment 
groups will be evaluated using an ANCOVA model that will include main effect of treatment 
and investigational site.  Nominal p-values will be reported as is. 
 
 


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Table 1:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics  
Generic Opioid Name 
1 Unit 
Route 
IV MED (mg) 
Morphine 
mg 
IV 
1 
Morphine 
mg 
PO 
0.333 
Methadone 
mg 
IV 
1 
Methadone 
mg 
PO 
0.333 
Nalbuphine 
mg 
IV 
1 
Nalbuphine 
mg 
PO 
0.333 
Buprenorphine 
mg 
IV 
25 
Fentanyl 
µg (mcg) 
IV 
0.1 
Sufentanil 
µg (mcg) 
IV 
1.00 
Alfentanil 
µg (mcg) 
IV 
0.02 
Hydromorphone 
mg 
IV 
6.67 
Hydromorphone 
mg 
PO 
1.3 
Codeine 
mg 
PO 
0.05 
Meperidine 
mg 
PO 
0.025 
Pentazocine 
mg 
PO 
0.1 
Oxycodone 
mg 
PO 
0.5 
Hydrocodone 
mg 
PO 
0.3 
8.5.2. 
PI on First Ambulation 
NPRS scores will be summarized by assessment time point.  The difference between groups will 
be analyzed by ANCOVA model that include the main effect of treatment and investigational 
sites.  Least-squares means (LSmeans) and standard error (SE) of the LSmeans will be 
calculated; difference in LSmeans between groups, corresponding 95% CI, and p-value from 
2-sample t-test will be derived.   
8.5.3. 
Time to Event Endpoints 
There are 7 time to event endpoints to be reported in this study, all events will be calculated as 
the elapsed time relative to the recorded end of surgery (Hour 0): 


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1) Time to hospital discharge order written 
2) Time to actual hospital discharge 
3) Time to first dose of rescue analgesia 
4) Time to first flatus or bowel sounds 
5) Time to first bowel movement 
6) Time to first assisted mobilization 
7) Time to first independent mobilization 
Time to event endpoints will be derived for each subject.  Subjects without the event will be 
censored at time of last evaluation during inpatient treatment phase.  Differences between the 
groups in time to event endpoints will be analyzed using the Cox proportional hazards analysis 
model that include the main effects of treatment and investigational sites; proportion of subjects 
censored will be presented and the time to event percentiles (25%, 50%, and 75% tiles) will be 
estimated.  The data will be graphically display using a Kaplan-Meier (KM) survival curve by 
treatment group.  
8.5.4. 
Length of Stay (LOS) 
Length of stay will be defined as days from the date of admission to the date of actual hospital 
discharge.  LOS will be tabulated with descriptive statistics by treatment groups and difference 
between the groups in the LOS will be evaluated using ANCOVA model that include main effect 
of treatment and investigational sites.     
8.5.5. 
PGA of Pain Control 
The number and percent of subjects in each global pain control category (0-poor, 1-fair, 2-good, 
3-very good, or 4-excellent) will be tabulated by treatment group.  The difference between the 
groups in global pain control will be evaluated based on proportion of subjects rating their pain 
control as good, very good, or excellent using the CMH test controlling for investigational site.   
8.5.6. 
Brief Pain Inventory 
Responses to each BPI parameter will be tabulated at each time point by treatment group, 
including score for each question (referred to as the item score), score for each domain (referred 
to as the domain score), and score for each subdomain (referred to as the sub-dimension score), 
change from baseline in item score, domain score, and sub-dimension score (Cleeland 2009). 
Differences between the treatment groups in domain score, sub-dimension score, and item score, 
as well as change from baseline in scores will be analyzed by ANCOVA model that includes 
treatment and investigational sites, and baseline score as a covariate.     
8.5.7. 
Subject Satisfaction for Postoperative Pain Medication 
Subjects will be categorized as dissatisfied (completely dissatisfied [1], mostly dissatisfied [2], or 
somewhat dissatisfied [3]), neither satisfied or dissatisfied (4), or satisfied (somewhat satisfied 
[5], mostly satisfied [6], or completely satisfied [7]) with postoperative pain medication.  The 
number and percent of subjects in each category will be tabulated by treatment group.  The 
difference between the groups in satisfaction with postoperative pain medication will be 


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evaluated based on proportion of subjects rating their satisfaction as dissatisfied (ratings of 1, 2, 
and 3), neither (rating 4), or satisfied (ratings of 5, 6, and 7) using the CMH test controlling for 
investigational site. 
8.5.8. 
Incidence of Postoperative NG Tube Insertion  
The proportion of subjects requiring postoperative NG tube insertion will be summarized by 
treatment group.  Differences between the groups will be evaluated using CMH test controlling 
for investigational site or Fisher’s exact test.   
8.5.9. 
Incidence of Hospital Readmission  
The incidence of all-cause hospital readmission will be reported during or prior to FUV-2.  
Hospital readmission will be summarized as the proportion of subjects with at least one 
readmission within the follow-up period by treatment group.  If data permits causality of hospital 
readmission will also be examined.  Differences between the groups will be examined using 
Fisher’s exact test. 
8.5.10. 
Cost of Hospitalization 
Cost of hospitalization will be calculated using UB-04 and/or similar hospital claim forms used 
for billing purposes.  Cost of hospitalization will be the cost of all hospital care from the charge 
of hospital admission until discharge.  When available, hospital costs resulting from hospital 
readmissions during the follow-up period should be collected. 
Cost of hospitalization will be summarized by treatment group for the primary admission, and 
for all related readmissions if data are available. 
8.5.11. 
Exploratory Analysis:  Inflammatory Markers 
Inflammatory markers will be analyzed for each collected sample.     
8.5.12. 
Subgroup Analyses for Efficacy 
Subgroups to be analyzed for efficacy may include: race, gender, age, and surgery type.  The 
analysis within a subgroup will follow the same analysis approach for the overall.  The subgroup 
analysis will focus on the primary efficacy endpoint total opioid use from Hour 0 to discharge; 
subgroup analysis on secondary efficacy endpoint will be performed if data warrants.  Potential 
covariates (such as incision type, surgery duration, and incision length) will be evaluated if data 
permits.   
8.6. 
Safety and Tolerability Evaluations 
8.6.1. 
Extent of Exposure 
Evaluation of the extent of exposure for the treatment period will be assessed via number of 
doses taken prior to discharge.  A summary of the number of subjects receiving increasing 
numbers of doses of study drug will be prepared. 


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8.6.2. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 20 or higher) will be used to classify 
all AEs with respect to system organ class and preferred term. 
Three types of summaries will be produced for the AE summary: 
1. an overall summary of AEs: number of subjects with at least one event and number of 
events for all AEs, and SAEs 
2. a summary table of AEs and SAEs by system organ class and preferred term and severity  
3. a summary table of AEs and SAEs by preferred terms in descending order of total 
incidence 
AEs will be tabulated by treatment group.  AEs that lead to premature discontinuation from the 
study or to death will be listed separately via data listings.    
8.6.3. 
Opioid Related AEs 
A summary of opioid related AEs will be generated for events including, but not limited to: 
somnolence, respiratory depression, hypoventilation, hypoxia, dry mouth, nausea, vomiting, 
constipation, sedation, confusion, pruritus, urinary retention, and postoperative ileus.  
A separate summary of opioid related SAEs may be generated if data warrant. 
8.6.4. 
AEs of Interest 
A summary of AEs of interest will be generated including: cardiovascular events, thrombotic 
events, bleeding-related events, renal events, hepatobiliary events, injection site related events, 
and wound healing related events. 
A separate summary of SAEs of interest may be generated if data warrant. 
8.6.5. 
Incidence of Anastomotic Leaks  
The incidence of anastomotic leaks will be summarized by the proportion of subjects 
experiencing the event in each treatment group. 
8.6.6. 
Clinical Laboratory Tests 
Laboratory values will be collected at screening, Day 1 during check-in, and at 
LSD+1/discharge; locally performed screening laboratory results will not be included in the 
study database or summaries and listings.  Observed values at each time point, and change from 
baseline will be summarized by treatment group without formal statistical testing 
Number (%) subjects with abnormal clinical test results relative to the lab normal range at each 
time point and shift tables may also be prepared if data warrant.  Number (%) subjects with 
clinically significant changes in laboratory test post dosing will also be tabulated.   
8.6.7. 
Vital Sign Measurements 
Resting vital sign values will be summarized by treatment group without formal statistical 
testing.  Incidence of clinically important changes from baseline will be identified and tabulated 
if data permits. 


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8.6.8. 
Wound Evaluation 
The investigator assessment scores of satisfaction with wound healing at each time point 
collected will be summarized by treatment group.  Wound healing status and incidence of 
abnormal wound healing will be summarized by treatment group.  
8.6.9. 
Subgroup Analyses for Safety Endpoints 
Subgroups to be analyzed for safety may include: race, gender, age, and surgery type.  The 
subgroup analysis will focus on the incidence of adverse event; subgroup analysis on other safety 
endpoints will be performed if data warrants. 
 


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9. 
STUDY ADMINISTRATION 
9.1. 
Regulatory and Ethical Considerations 
9.1.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country specific regulatory requirements before any site may 
initiate the study in that country. 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted according to GCP; US 21 Code of Federal Regulations (CFR) 
Part 50 (Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR Part 54 
(Financial Disclosure); International Conference on Harmonization (ICH) Guidance for Industry, 
E6 GCP: Consolidated Guidance; the Nuremberg Code; and, where applicable the principles of 
the Declaration of Helsinki (Recommendations guiding Medical Doctors in Biomedical Research 
Involving Human Subjects), and with the NH&MRC National Statement on Ethical Conduct in 
Human Research (2007).   
9.1.2.1. 
Ethics Committees 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
site’s informed consent form, and any other information that will be presented to potential 
subjects (e.g., advertisements or information that supports or supplements the informed consent 
form) are reviewed and approved by the appropriate IRB or IEC.  The investigator agrees to 
allow the IRB or IEC direct access to all relevant documents.  The IRB or IEC must be 
constituted in accordance with all applicable regulatory requirements.  The sponsor will provide 
the investigator with relevant documents or data needed for IRB or IEC review and approval of 
the study.  Before investigational products can be shipped to the site, the sponsor must receive 
copies of the IRB or IEC approval, the approved informed consent form, and any other 
information that the IRB or IEC has approved for presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IRB or IEC has 
approved for presentation to potential subjects is amended during the study, the investigator is 
responsible for ensuring that the IRB or IEC reviews and approves, where applicable, these 
amended documents.  The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form, including obtaining IRB or IEC 
approval of the amended form, before new subjects consent to take part in the study using the 
new version of the form.  The investigator must promptly forward to the sponsor copies of the 
IRB or IEC approval of the amended informed consent form or other information and the 
approved amended informed consent form or other information.  IRB or IEC approval of the 
consent forms must be obtained in addition to the approval given for the clinical study.  
Regulatory review and approval may be required in some countries before IRB or IEC approval 
can be sought. 
9.1.2.2. 
General Considerations 
The ethical standards defined within GCP are intended to ensure the following: 


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• Human subjects are provided with an adequate understanding of the possible risks of 
their participation in the study, and they have a free choice to participate or not. 
• The study is conducted with diligence and in conformance with the protocol in such a 
way as to ensure the integrity of the findings. 
• The potential benefits of the research justify the risks. 
Recro Pharma, Inc. is the sponsor of study REC-17-024.  The sponsor is responsible for all of the 
following: 
• selecting qualified investigators 
• providing investigators with the information they need to conduct the investigation 
properly 
• ensuring proper monitoring of the investigation 
• ensuring that appropriate regulatory agencies and all participating investigators are 
properly informed of significant new information regarding AEs or risks associated with 
N1539 
9.1.3. 
Informed Consent 
The sponsor will provide investigators with a sample informed consent form for this study.  
Investigators are encouraged to use the sample form; however, they may adapt the information to 
suit the needs of their institution, if necessary (although it must reflect the required elements of 
informed consent specified in 21 CFR Part 50.25).  The final informed consent form must be 
accepted by the sponsor and approved by the IRB or IEC.  Investigators must provide the 
sponsor with an unsigned copy of the final informed consent form before and after it is approved 
by the IRB or IEC.  If any new information becomes available that might affect subjects’ 
willingness to participate in the study, or if any amendments to the protocol require changes to 
the informed consent form, the sponsor will provide investigators with a revised informed 
consent form.  The IRB or IEC must provide written approval of any revisions to the informed 
consent form in advance of its use. 
Investigators must provide subjects with all the information necessary to make an informed 
decision about their participation in the study, including the nature and intended purpose of the 
study, possible benefits, and possible risks. 
All information in the informed consent form should be provided in a language (whether written 
or spoken) that is as nontechnical as practical and that is understandable to the subjects. 
Before written informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study.  All questions must be answered to the 
satisfaction of the subject (or his or her legally authorized representative). 
Before a subject undergoes procedures specific to the protocol, the informed consent form must 
be signed and dated by the subject (or his or her legally authorized representative) and any other 
signatories as required by the IRB or IEC. 
If a subject (or legally authorized representative) cannot read, a short form approved by the IRB 
or IEC may be used.  Only the short form itself is to be signed by the subject or the 


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representative.  However, the witness shall sign both the short form and a copy of the summary, 
and the person obtaining the consent shall sign the copy of the summary in accordance with 
21 CFR 50.27 (b2). 
After all required signatures have been obtained, a copy of the informed consent form should be 
provided to the subject, and the original must be kept on file at the site and made available for 
review by the sponsor.  Documentation of the informed consent discussion must be noted in the 
subject’s case history. 
9.1.4. 
Investigator Reporting Requirements 
The investigator is responsible for completing and maintaining adequate and accurate eCRFs and 
source documentation.  Source documentation constitutes original records (first point of entry, 
either hard copy or electronic), which may include progress notes, medication administration 
records, operation reports, laboratory reports, discharge summaries, and so on.   
9.2. 
Study Monitoring 
The sponsor is responsible for ensuring the proper conduct of the study with regard to subject 
protection, ethics, protocol adherence, site procedures, and integrity of the data.  At regular 
intervals during the study, the sponsor’s study monitors will contact the study site via visits to 
the site, telephone calls, and letters in order to review study progress and eCRF completion and 
to address any concerns or questions regarding the study conduct.  During monitoring visits, the 
following aspects of study conduct will be carefully reviewed: subjects’ informed consent 
documents, subject recruitment procedures, subjects’ compliance with the study procedures, 
source-data verification, drug accountability, use of concomitant therapy by subjects, AE and 
SAE documentation and reporting, and quality of data. 
9.3. 
Quality Assurance 
The sponsor, a regulatory authority, or an IRB representative may visit the study site at any time 
during the study or after completion of the study to perform audits or inspections.  The purpose 
of a sponsor audit or regulatory inspection is to examine systematically and independently all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements.  Investigators should contact the sponsor immediately if contacted by a regulatory 
agency about an inspection at their site. 
9.4. 
Study and Site Closure 
If the sponsor, investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that the study should be halted or that the study site should be 
closed, this action may be taken after appropriate consultation between the sponsor and 
investigator.  Conditions that may warrant termination of the study include, but are not limited 
to, the following: 
• discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 


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• submission of knowingly false information from the research facility to the sponsor, 
study monitor, or regulatory agencies 
• failure of the investigator to comply with GCP (e.g., ICH guidelines, regulatory agency 
guidelines) 
• insufficient adherence to protocol requirements or an unacceptably high rate of missing, 
erroneous, or improperly collected data 
• evidence from the blinded data of sufficient technical problems with the study that one 
could believe with a high degree of certainty that subjects are being exposed to the 
investigational drug without a realistic expectation of evaluable data 
• a decision on the part of the sponsor to suspend or discontinue testing evaluation or 
development of the product 
• failure of the investigator to enroll subjects into the study at an acceptable rate 
9.5. 
Records Retention 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 (the 
Health Insurance Portability and Accountability Act of 1996 privacy regulation).  The 
investigator shall ensure that study subjects authorize the use and disclosure of protected health 
information in accordance with the privacy regulations of the Health Insurance Portability and 
Accountability Act and in a form satisfactory to the sponsor. 
9.5.2. 
Financial Disclosure 
Financial disclosure is required for this study. 
9.5.3. 
Access to Original Records 
Regulatory authorities expect that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source documentation 
(see examples in Section 9.1.4) to ensure data integrity.  “Original” in this context is defined as 
the first documentation of an observation and does not differentiate between hard-copy and 
electronic records. 
9.5.4. 
Archiving of Study-Related Documents 
Records related to this clinical study must be retained either for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  The sponsor 
will notify the investigator as to when these documents no longer need to be retained for this use. 


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9.6. 
Provision of Study Results and Information to Investigators 
When a clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigators. 
In addition, details of the study treatment assignment will be provided to the investigators to 
enable them to review the data to determine the outcome of the study for their subjects. 
The sponsor may list and summarize the results from coded samples by subject number in the 
clinical study report.  In this event, the investigator and study staff would have access to the 
research results and would be able to link the results to a particular subject.  The investigator and 
study staff would be directed to hold this information confidentially. 
9.7. 
Information Disclosure and Inventions 
9.7.1. 
Ownership 
All information provided by the sponsor and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of Recro Pharma, 
Inc. 
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by site staff during the course of or as a 
result of the study are the sole property of Recro Pharma, Inc. and are hereby assigned to Recro 
Pharma, Inc. 
If a written contract is executed between Recro Pharma, Inc. and the study site for the conduct of 
the study and that contract includes ownership provisions inconsistent with this statement, that 
contract’s ownership provisions shall apply rather than this statement. 
9.7.2. 
Confidentiality 
All information provided by Recro Pharma, Inc. and all data and information generated by the 
site as part of the study (other than a subject’s medical records) will be kept confidential by the 
investigator and other site staff.  This information and data will not be used by the investigator or 
other site personnel for any purpose other than conducting the study.  These restrictions do not 
apply to the following:  1) information that becomes publicly available through no fault of the 
investigator or site staff, 2) information that must be disclosed in confidence to an IEC or IRB 
solely for the evaluation of the study results, 3) information that must be disclosed in order to 
provide appropriate medical care to a study subject, or 4) study results that may be published as 
described in Section 9.7.3.  If a written contract for the conduct of the study is executed and that 
contract includes confidentiality provisions inconsistent with this statement, that contract’s 
confidentiality provisions shall apply rather than this statement. 
9.7.3. 
Publication 
For multicenter studies, the first publication or disclosure of study results shall be a complete, 
joint, multicenter publication or disclosure coordinated by Recro Pharma, Inc.  Thereafter, any 
secondary publications will reference the original publication(s).  If no multicenter publication is 
submitted for publication within 18 months of study database hard lock, then the site shall be 
free to disclose its own results, subject to sponsor rights under Section 9.7.1. 


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Before submitting material for publication, presentation, or use for instructional purposes, or 
before otherwise disclosing the study results generated by the site (collectively, a “publication”), 
the investigator shall provide Recro Pharma, Inc. with a copy of the proposed publication and 
allow Recro Pharma, Inc. a period of at least 90 days to review the proposed publication.  
Proposed publications shall not include either Recro Pharma, Inc. confidential information (other 
than the study results) or the personal data (such as name or initials) of any subject. 
At Recro Pharma, Inc.’s request, the submission or other disclosure of a proposed publication 
will be delayed a further 90 days to allow Recro Pharma, Inc. to seek patent or similar protection 
of any inventions, know-how, or other intellectual or industrial property rights disclosed in the 
proposed publication. 
If a written contract is executed for the conduct of the study and that contract includes 
publication provisions inconsistent with this statement, that contract’s publication provisions 
shall apply rather than this statement. 
9.7.4. 
Data Management 
The investigator (or designee) will enter subject data by using the eCRF defined by Recro 
Pharma, Inc. Clinical data management will be performed in accordance with applicable Recro 
Pharma, Inc. standards and data-cleaning procedures.  Database freeze will occur when data 
management quality-control procedures are completed.   
In addition, validated laboratory data will be transmitted electronically from the clinical 
laboratory to Recro Pharma, Inc. or its designee. 
The investigator or designee must record all required data using the previously specified data 
collection method defined by Recro Pharma, Inc.  An explanation must be documented for any 
critical data points.  The investigator must sign and date a declaration in the eCRF attesting that 
he or she is responsible for the quality of all data recorded and that the data represent a complete 
and accurate record of each subject’s participation in the study. 
9.7.5. 
Data Security 
Access to the data will be strictly controlled. 
9.8. 
Subject Tracking 
Drug accountability logs, a subject identification log (to be retained by the investigator only), 
and a subject enrollment log may be used to track subject participation in the study. 


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10. 
REFERENCES 
Cleeland CS.  The Brief Pain Inventory User Guide.  University of Texas MD Anderson Cancer 
Center; 2009.  Retrieved from: https://www.mdanderson.org/documents/Departments-and-
Divisions/Symptom-Research/BPI_UserGuide.pdf 
Degner F, Turck D, Pairet M. Pharmacological, pharmacokinetic and clinical profile of 
meloxicam. Drugs Today. 1997;33(10):739-58. 
Del Tacca M, Colucci R, Fornai M, Blandizzi C. Efficacy and tolerability of meloxicam, a COX-
2 preferential nonsteroidal anti-inflammatory drug. Clin Drug Invest. 2002;22(12):799-818. 
Mobic (meloxicam) Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc., 
Ridgefield, CT. Revised 06/2016. 
Swarm R. et al. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain.  Journal of 
the National Comprehensive Cancer Network. 2007 Sept; 5(8):726-51 
Turck D, Busch U, Henizel G, Narjes H. Clinical pharmacokinetics of meloxicam. Arzneim-
Forsch/Drug Res. 1997;47(I):253-8. 
 
 
 
 
 
 


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APPENDIX A: 
OVERVIEW OF STUDY SCHEDULE 
 
Screening 
(Day -21 to 
Day -1) 
Treatment Period  
Day 1 - Day of Last Study Dose (LSD) 
End of 
Treatment 
(LSD+1a) 
Hospital 
Discharge 
Follow-Up Visit 1 
(5-21 days  
post-discharge) 
Follow-Up Visit 2 
(30 ± 4 days  
post-discharge) 
Prior to 
Surgery 
Surgery 
(End of 
Surgery=Hour 0) 
Hour 24 & Q24Hr after 
Hour 0 Until LSD 
(Including LSD) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
  
 
  
 
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
Physical Examination 
Xc 
X 
 
 
 X 
 
  
 
Pregnancy Test (FOCBP only) 
 
Xurine 
 
 
 
 
 
 
Clinical Laboratory Testsb 
Xc 
X 
 
 
X 
 
 
 
Inflammatory Markers 
 
X 
 
X - Once Daily 
X 
 
 
 
Vital Signsd 
X 
X 
 
 
X 
 
 
 
12 Lead ECG 
Xc 
 
 
 
 
 
 
 
Surgical Procedure 
 
 
X 
 
 
 
 
 
Study Drug Administration 
 
 
Xe 
Q24 from Dose 1 
 
 
 
 
PI Assessment 
 
 
 
On first ambulationf 
 
 
 
 
Monitoring Bowel Function 
 
 
 
X 
X 
 
 
 
PGA of Pain Control 
 
 
 
X 
X 
 
 
 
BPI Assessment 
X 
 
 
X 
X 
 
 
 
Subject Satisfaction 
 
 
 
 
X 
 
 
 
Wound Evaluation 
 
 
 
 
 
X 
X 
 
Incidence of Readmission 
 
 
 
 
 
 
 
X 
Prior and Concomitant Medication 
X  
Adverse Event Monitoring 
 
X  
a If a subject is prepared for discharge less than 24 hours following the last study dose, LSD+1 procedures should be completed prior to discharge.  
b Laboratory tests will be performed locally at screening and centrally at Day 1 prior to surgery and LSD+1.  
c Historic results collected within 7 days prior to screening may be utilized for eligibility assessment purposes 
d Vital signs (VS) include: resting blood pressure, resting pulse, and SpO2. Tests must be obtained after resting (seated/supine) for ≥ 5 minutes.   
e Dose 1 is to be administered approximately 30 minutes prior to first incision. Subsequent doses may be administered every 24±1 hours from Dose 1. 
f PI will be assessed within 15 minutes prior to first ambulation, and for the worst pain experienced during first ambulation. 


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APPENDIX B: 
INVESTIGATOR OBLIGATIONS 
As an investigator, you are responsible for ensuring that the study is conducted according to the 
protocol, the signed Statement of Investigator, and all applicable regulations. 
Debarment 
Individuals ineligible to conduct or be involved with clinical studies, including those ineligible as 
a result of debarment under the Generic Drug Enforcement Act of 1992, will not be allowed to 
conduct or work on studies sponsored by Recro Pharma, Inc.  You are required to disclose 
immediately to the sponsor, in writing, if any person involved in the conduct of the study is 
debarred pursuant to a hearing by FDA under this antifraud law or if any proceeding for 
debarment is pending or is (to the best of your knowledge) threatened. 
Institutional Review Board 
You are required to obtain initial and continuing review and approval by an IRB or IEC that 
complies with the requirements specified in 21 CFR Part 56.  Before initiating the trial, you must 
have written approval from the IRB or IEC for the protocol, informed consent form, subject 
recruitment procedures (e.g., advertisements), and any other written information to be provided 
to the subjects.  You must submit the Investigator’s Brochure and any updates to the IRB or IEC 
for review.  The IRB or IEC must also provide written approval of any amendments to the 
protocol that affect the conduct of the study and any changes to the informed consent form in 
advance of use.  If the duration of the study is longer than 1 year, reapproval by the IRB or IEC 
must be obtained on a yearly basis (or at more frequent intervals if required by the IRB or IEC).  
All IRB or IEC approvals must be forwarded to the sponsor. 
You must provide reports of all SAEs from your site to the IRB or IEC.  You are also responsible 
for providing the IRB or IEC with Safety Reports of any SAEs from any other study conducted 
with the study medication.  The latter will be provided to you by the sponsor. 
Confidentiality and Safety of Subjects 
You are responsible for protecting the rights, safety, and welfare of subjects under your care and 
for the control of the drug(s) under investigation. 
You are responsible for keeping a record of all screened subjects, including full names and last 
known addresses.  All subjects will be identified on the eCRFs by subject number.  Demographic 
information including date of birth, sex, and race will also be recorded on the eCRFs.  
Confidentiality of subject data will be maintained in accordance with local laws. 
In addition to your responsibilities for reporting AEs identified during the course of a subject’s 
participation in the study, you must also report any SAEs that occur within 30 days after the last 
dose of study medication (regardless of relationship to study medication) and any serious adverse 
drug reactions (SAEs for which you consider that there is a reasonable possibility that the study 
medication caused the response) that you become aware of at any time (even if the event occurs 
more than 30 days after the subject’s last exposure to study medication).  This obligation is in 
addition to any protocol-specified requirement for reporting AEs occurring after the last dose of 
study medication.  Please refer to Sections 7.7 and 7.8 of this protocol for contact information 
and SAE reporting requirements. 


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Study-Related Records 
You are required to maintain complete and accurate study documentation in compliance with 
current GCP standards and all applicable federal, state, and local laws, rules, and regulations 
related to the conduct of a clinical study. 
You are required to make all study documentation promptly available for inspection, review, or 
audit at your study site upon request by the sponsor, its representatives, or any appropriate 
regulatory agencies. 
Accountability of the Investigational Product 
You or your designee (ie, the pharmacist) is responsible for accountability of the investigational 
product at the site.  You or your designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and the return to the sponsor or alternative 
disposition of any unused product.  These records must include dates; quantities; batch, serial, or 
lot numbers; and expiration dates (if applicable). 
You should ensure that the investigational product is used only in accordance with the protocol. 


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APPENDIX C: 
STUDY-SPECIFIC INFORMATION 
APPENDIX C.1: ENHANCED RECOVERY AFTER SURGERY (ERAS) 
PROTOCOL 
Preoperative 
Patient Education:   
• Subject education (which may include discussion and a written handout) describing pre-, 
peri-, and postoperative care and expectations should be provided ahead of surgery. 
Diet:   
• Encourage hydration 2 days prior to surgery.  
• Encourage carbohydrate loading preoperative which may include: ClearFast, Ensure 
Clear®, clear juices, or Gatorade® up to 2-6 hours prior to surgery (per 
surgeon/anesthesiologist standard fluids cut off time). 
Bowel Prep:   
• Clear liquids with mechanical bowel prep as indicated by surgery type. 
• Antibiotics as indicated by surgeon. 
Motility:   
• Use of alvimopan is prohibited. 
Analgesia:   
• Gabapentin 300 mg PO once, administered approximately 30-90 minutes preoperatively. 
• Acetaminophen 650 mg PO or IV once, administered approximately 30-90 minutes 
preoperatively. 
• Study drug IV (per randomization assignment) administered approximately 30 minutes 
prior to the start of surgery. 
Anxiolysis:   
• Midazolam 2 mg IV once PRN. 
Perioperative 
Epidural:   
• No epidural medication will be utilized. 
Analgesia:   
• Perioperative analgesia should be maintained using IV opioids.   
• Prohibited perioperative therapies include NSAIDS, ketamine, transverse abdominis 
plane (TAP) blocks, lidocaine, and/or local instillation. 


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Nausea prophylaxis:   
• Dexamethasone IV up to 4 mg once and ondansetron IV 4 mg once 
        OR  
• Promethazine IV 25 mg once and a scopolamine transdermal patch 0.5 mg  
Fluids:   
• Target fluids 5-7 mL/kg/hr, as medical condition and intraoperative physiological status 
permits. 
Anesthesia:   
• Acceptable agents include nitrous oxide, isoflurane, sevoflurane or desflurane.    
• Total intravenous anesthesia is also acceptable. 
Neuromuscular blockade (NMB):   
• Institution specific standard of care for NMB and reversal agents.  
Postoperative 
Diet:   
• Clear liquids on day of surgery (DOS). 
• Advance diet to solids as tolerated starting on postoperative Day 1 (POD1). 
• Liquid protein supplements (ex. Boost®, Ensure®) available with each meal. 
Ambulation:   
• Out of bed (OOB) and ambulating on DOS 
• OOB at least 6 hours with ambulation 4 times daily starting on POD1. 
Analgesia:   
• All subjects will receive 650 mg of acetaminophen Q8H PO as tolerated until 24 hours 
following the last study dose.  
• IV morphine, or morphine patient controlled analgesia (PCA) should be available 
immediately postoperatively; PCA should be set for 1 mg morphine bolus on patient 
demand with 6-minute lockout, no basal infusion, which may be supplemented with 
morphine 1-2 mg IV bolus administered up to Q1H PRN.  
• If a PCA is not used, morphine IV boluses may be administered PRN; total morphine 
dose should not exceed 12 mg/hr. 
• Conversion to oral analgesia should be made once subjects are tolerating liquid intake.  
Oral analgesia regimen must be oxycodone 5mg Q4H PO PRN, with morphine 1-4 mg 
IV bolus administered up to Q1H available if needed for supplemental analgesia until 24 
hours after the last study dose.   
Twenty-four hours after the last study dose, patient analgesia will be managed as per site 
standard of care.  


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Pyrexia:   
• Cooling blankets may be utilized in the event of pyrexia (acetaminophen should not be 
utilized to manage pyrexia until 24 hours following the last study dose while subject is 
receiving routine dose of acetaminophen). 
Postoperative Nausea and Vomiting:   
• Ondansetron 4 mg IV or 8 mg PO PRN (avoid prophylactic use). 
Fluids:   
• Fluids to be managed per subjects’ individual needs.  
Motility:   
• Gum chewing is prohibited 
• Use of Alvimopan is prohibited. 
Tubes/Drains:   
• Orogastric/nasogastric tubes should be removed in the operating room or on DOS. 
• Urinary catheters should be removed on or before POD1. 
 
 


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APPENDIX C.2: PAIN INTENSITY ASSESSMENT 
Pain Intensity - Numerical Pain Rating Scale (NPRS) 
Pre-Ambulation (within 15 minutes prior to first ambulation): 
On a scale of 0-10, please rate your pain by marking an ‘X” in the appropriate box that 
best describes your pain NOW. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
worst 
imaginable 
pain 
 
On first ambulation 
On a scale of 0-10, please rate your pain by marking an ‘X” in the appropriate box that 
best describes your worst pain during current ambulation. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
worst 
imaginable 
pain 
 


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APPENDIX C.3: PATIENT GLOBAL ASSESSMENT (PGA) OF PAIN 
CONTROL  
 
A. The following question will be answered by subjects at Hour 24 from Hour 0 and every 
24 hours thereafter until LSD+1: 
“Overall, please rate how well your pain has been controlled during the last 24 hours?” 
 
 
Response to each question will be: (Check (√) one box) 
  Poor (0) 
 
  Fair (1) 
 
  Good (2) 
 
  Very Good (3) 
 
  Excellent (4) 
 
 
 
 
 


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APPENDIX C.4: SUBJECT SATISFACTION WITH PAIN MEDICATION 
The following question will be answered by all subjects at LSD+1: 
 
“Overall, please rate your satisfaction with the pain medication you received following 
your surgery.” 
 
Response to the question will be: (Mark (X) one box) 
 Completely Dissatisfied (1) 
 Mostly Dissatisfied (2) 
 Somewhat Dissatisfied (3) 
 Neither Dissatisfied nor satisfied (4) 
 Somewhat Satisfied (5) 
 Mostly Satisfied (6) 
 Completely Satisfied (7) 
 
 
 
 


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APPENDIX C.5: BRIEF PAIN INVENTORY (BPI) – SHORT FORM 
 
 
 
 
 
 


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APPENDIX D: 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM 
 
I 
Normal healthy patient 
 
II  
Patient with mild systemic disease; no functional limitation – e.g. smoker with well-
controlled hypertension 
 
III  
Patient with severe systemic disease; definite functional impairment – e.g. diabetes and 
angina with relatively stable disease, but requiring therapy 
 
IV 
Patient with severe systemic disease that is a constant threat to life – e.g. diabetes and 
angina and congestive heart failure; patients with dyspnea on mild exertion and chest 
pain 
 
V 
Unstable moribund patient who is not expected to survive 24 hours with or without 
operation 
 
VI 
Brain dead patient whose organs are removed for donation to another 
 
E 
Emergency operation of any type, which is added to any of the above six categories, an in 
ASA II E 
 

SAP_001.pdf: 
 
 
 
REC-17-024 
 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Evaluation of the 
Safety and Efficacy of Preoperative N1539 In Colorectal Surgery 
 
NCT03323385 
 
Statistical Analysis Plan 
 
30 April 2019 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
  REC-17-024 
Protocol Title:  
 
  A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety 
and Efficacy of Preoperative N1539 In Colorectal 
Surgery 
Date of Original 
Protocol 
June 01, 2017     
Date of Protocol 
Amendment 001 
August 30, 2017     
Date of Protocol 
Amendment 002 
November 16, 2017     
 
 
 


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 3 of 39 
 
TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS AND PHOURSASES .....................................................................5 
IN-TEXT TABLES ..........................................................................................................................8 
1. 
INTRODUCTION AND SCOPE .................................................................................9 
2. 
OVERVIEW OF STUDY OBJECTIVES AND ASSESSMENTS............................10 
2.1. 
Study Endpoints ..........................................................................................................12 
2.1.1. 
Safety Endpoints .........................................................................................................12 
2.1.2. 
Efficacy Endpoints ......................................................................................................12 
2.1.3. 
Exploratory Endpoints – Change in Inflammatory Markers ......................................12 
3. 
GENERAL CONSIDERATIONS ..............................................................................13 
3.1. 
Analysis Population ....................................................................................................13 
3.2. 
Test Hypothesis and P Value Justification .................................................................13 
3.3. 
Procedures for Handling Missing Data .......................................................................13 
3.4. 
Definitions and Derived Variables .............................................................................13 
3.4.1. 
Analysis Center ...........................................................................................................13 
3.4.2. 
Baseline .......................................................................................................................13 
3.4.3. 
Study Period and Analysis Visit .................................................................................14 
3.4.4. 
Subjects at Risk ...........................................................................................................16 
3.4.5. 
Opioid Consumption ...................................................................................................17 
3.4.6. 
Time to First Rescue ...................................................................................................21 
3.4.7. 
Time to First Ambulation and Associated Pain Intensity ...........................................22 
3.4.8. 
Time to Return of Bowel Function .............................................................................23 
3.4.9. 
Length of Hospital Stay Measured by Time to Hospital Discharge ...........................24 
3.4.10. 
Brief Pain Inventory (BPI)..........................................................................................24 
3.4.11. 
Patient Global Assessment of Pain Control (PGA) ....................................................26 
3.4.12. 
Subject Assessment of Satisfaction with Pain Medication .........................................27 
3.4.13. 
Healthcare Utilization Endpoints ................................................................................27 
4. 
STUDY POPULATION SUMMARIES ....................................................................28 


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Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 4 of 39 
 
4.1. 
Disposition ..................................................................................................................28 
4.2. 
Demographics and Baseline Characteristics ...............................................................29 
4.2.1. 
Other Medical History ................................................................................................29 
4.3. 
Protocol Deviations ....................................................................................................29 
4.4. 
Treatment Compliance ................................................................................................30 
4.5. 
Prior and Concomitant Medications ...........................................................................30 
5. 
EFFICACY ANALYSIS ............................................................................................31 
5.1. 
Opioid Consumptions .................................................................................................31 
5.1.1. 
Number (%) Subjects Opioid Free .............................................................................31 
5.1.2. 
ANCOVA Analysis of Total Opioid Consumption ....................................................31 
5.1.3. 
Rank Analysis of Total Opioid Consumption ............................................................32 
5.2. 
Time to First Rescue ...................................................................................................32 
5.3. 
Length of Hospital Stay Measured by Time to Discharge .........................................32 
5.4. 
Ambulation Assessments ............................................................................................33 
5.4.1. 
Time to First Ambulation Events ...............................................................................33 
5.4.2. 
Pain Before and the Worst Pain During Ambulation .................................................33 
5.5. 
Time to Return of Bowel Function .............................................................................34 
5.6. 
Patient Global Assessment (PGA) of Pain Control ....................................................34 
5.7. 
Brief Pain Inventory Questionnaire ............................................................................34 
5.8. 
Patient Satisfaction with Postoperative Pain Medication ...........................................35 
5.9. 
Health Care Utilization ...............................................................................................36 
5.10. 
Change in Inflammatory Markers (Exploratory Endpoint) ........................................36 
6. 
SAFETY AND TOLERABILITY EVALUATIONS ................................................37 
6.1. 
Extent of Exposure .....................................................................................................37 
6.2. 
Adverse Events ...........................................................................................................37 
6.3. 
Change in Laboratory Tests ........................................................................................37 
6.4. 
Wound Healing ...........................................................................................................39 
6.5. 
Vital Signs ..................................................................................................................39 
 


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Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 5 of 39 
 
LIST OF ABBREVIATIONS AND PHOURSASES 
Abbreviation 
Definition 
N1539 
Injectable NanoCrystal® Colloidal Dispersion (NCD) Meloxicam 
AE 
Adverse Event 
ADC 
Actual hospital discharge 
ANCOVA 
Analysis of Covariance 
ATC 
The Anatomical Therapeutic Chemical Classification System 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory 
CMH 
Cochran-Mantel-Haenszel  
CRP 
C-Reactive Protein 
DBP 
Diastolic Blood Pressure 
DOW 
Hospital Discharge Order Written 
eCRF 
Electronic case report form 
EOS 
End of Study (POD 30 ± 4 days) 
EOT 
End of Treatment Period (Discharge or LSD+1, whichever comes first) 
FSD 
First Dose of Study Drug 
FUV-1 
Follow-up Visit 1 
FUV-2 
Follow-up Visit 2 
Hour 0 
Time of End of Surgery (H0) 
ICH 
International Conference on Harmonization 
IL 
Interleukin 
ITT 
Intent-to-treat  
IV 
Intravenous 
IVMED 
IV Morphine Equivalent Dose (mg) 
Kg 
Kilogram 
KM 
Kaplan-Meier   
LOS 
Length of Stay 
LSD 
Last Dose Date/Time 
LSD+1 
24 hours after the last dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat  


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 6 of 39 
 
Abbreviation 
Definition 
mL 
Milliliter 
NG 
Nasogastric  
NPRS 
Numeric Pain Rating Scale 
OBAS 
Overall Benefit of Analgesic Score 
ODDS 
Opioid Distress Dimension Score (a sub domain of OBAS) 
PACU 
Post-Anesthesia Care Unit 
PCSC 
Potentially Clinically Significant Change 
PDD 
Post discharge day (24-hour period starting time of actual hospital discharge) 
PGA 
Patient Global Assessment   
PI 
Pain Intensity Score  
POD 
Postoperative day (determined by calendar date from surgery date) 
PSD 
Post-Surgery Day (a 24-hour period starting end of surgery) 
PT 
Preferred term 
REM 
Relationship with other people, Enjoyment of life, and Mood ((a subdimension 
of pain inference) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SOC 
System Organ Class 
SpO2 
Peripheral oxygen saturation 
TEAE 
Treatment emergent adverse event 
TNF-α 
Tumor Necrosis Factor alpha 
Time 0 
Time of First Dose (T0) 
TTE 
Time to Event 
TTADC 
Time to actual hospital discharge 
TTBS 
Time to first bowel sound 
TTDOW 
Time to hospital discharge order written 
TTFL 
Time to first flatus 
TTBM 
Time to first bowel movement  
µg 
Microgram 
µL 
Microliter 


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 7 of 39 
 
Abbreviation 
Definition 
WAW 
Walk, General Activities, Work (a subdimension of pain inference)  
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 8 of 39 
 
IN-TEXT TABLES 
 
Table 1:  Analysis Visit Using Post-Operative Day and Post-Surgery Day ..................................15 
Table 2:  Subjects at Risk for 12 Periods Defined for Opioid Consumption .................................16 
Table 3:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics ..........................17 
Table 4:  Definition of Opioid Consumption Intervals ..................................................................20 
Table 5:  Definition of BPI Dimension and Subdimension ...........................................................25 
Table 6:  Selected Laboratory Tests of Special Interest ................................................................38 
Table 7:  Definition of Potentially Clinically Significant Change (PCSC) in Selected 
Laboratory Tests of Special Interest ...........................................................................39 
 


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 9 of 39 
 
1. 
INTRODUCTION AND SCOPE 
Protocol REC-17-024 is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter 
study evaluating the safety and efficacy of preoperative dosing with N1539 30 mg in adult 
subjects undergoing open or laparoscopic colorectal surgery. The initial study cohort will enroll 
approximately 50 subjects randomized (1:1) to N1539 30 mg or placebo; additional study 
cohorts may be enrolled following review of initial study observations.   
This Statistical Analysis Plan (SAP) is intended to provide a more technical and detailed 
elaboration of the principal statistical features stated in the protocols.  The objective of the SAP is 
to reasonably assure that the statistical methodologies to be used for analysis are complete and 
accurate.   
In the development of this SAP, the following documents were used: 
• Protocol REC-17-024: Amendment 2, November 16, 2017  
• REC-17-024 eCRF Completion Guidelines: Version 4, date November 27, 2018 
The principles in the following guidance documents are followed in preparation of this SAP: 
• ICH E3 (1995): Structure and Content of Clinical Study Reports 
• ICH E6 (1996): Guideline for Good Clinical Practice 
• ICH E9 (1998): Statistical Principles for Clinical Trials 
In the event that a discrepancy is found between the descriptions in the statistical section of the 
protocol and this document, the description in this document supersedes the descriptions in the 
statistical section of the protocol. 
 
 
 


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 10 of 39 
 
2. 
OVERVIEW OF STUDY OBJECTIVES AND ASSESSMENTS   
The primary objective of this study is to evaluate the safety and tolerability of preoperative 
dosing of N1539 30 mg in subjects undergoing colorectal surgery, including clinical laboratory 
tests, wound healing evaluation, incidence of anastomotic leaks, and incidence of Adverse 
Events (AEs) and Serious AEs (SAEs). 
Additional objectives include: 
• Evaluation of N1539 treatment impact on overall postoperative recovery course, 
including total opioid consumption, length of hospital stay, pain control, cost of hospital 
stay, return of bowel function, mobilization, and satisfaction with pain medication. 
Each subject is expected to receive at least two doses of study drug during the treatment phase of 
the study, with the first dose (Dose 1) administered within 30 minutes prior to surgery start and 
additional doses administered every 24±1 hours from Dose 1 until discharge or until IV analgesia 
is no longer clinically appropriate, whichever comes first.  A final dose of study drug may be 
administered up to 4 hours early in subjects who are scheduled to be discharged.  Subjects who 
do not receive a dose of study drug for > 28 hours following their previous dose of study drug 
should be considered off treatment, and not receive further study dosing.  Subjects will be asked 
to return for FUV-1 to complete end of study assessments, with a safety follow-up by phone at 
FUV-2. 
Assessments of efficacy will include total opioid consumption, pain intensity according to an 11-
point numeric pain rating scale (NPRS; 0 - 10) on first ambulation, time to first analgesic rescue, 
time to return of bowel function (including time to first flatus or bowel sounds, and first bowel 
movement), time to mobilization (including time to first assisted mobilization out of hospital bed 
and time to first independent mobilization out of hospital bed), patient global assessment of pain 
control, brief pain inventory, subject satisfaction, time to hospital discharge (including time to 
hospital discharge order written and time to actual hospital departure), incidence of nasogastric 
(NG) tube insertion, length of stay, incidence of hospital readmission post initial discharge, and 
total cost of hospitalization. 
Study safety assessments will monitor adverse events, change in clinical laboratory tests and 
vital signs and wound healing assessments. Study procedure schedule (Protocol Appendix A) is 
included here for the convenience of review. 
 
 
 


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Statistical Analysis Plan 
 
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Page 11 of 39 
 
 


Protocol REC-17-024 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 12 of 39 
 
2.1. 
Study Endpoints  
2.1.1. 
Safety Endpoints 
The planned safety endpoints include the following: 
1. Incidence of treatment-emergent AEs and SAEs (including AEs of interest and opioid 
related AEs) 
2. Incidence of anastomotic leaks  
3. Change from baseline in laboratory tests; incidence of abnormal clinical laboratory tests 
4. Change from baseline in vital signs 
5. Assessment of surgical wound healing 
2.1.2. 
Efficacy Endpoints 
The planned efficacy endpoints include:  
1. Total opioid consumption   
2. Time to hospital discharge order written 
3. Pain intensity on first ambulation 
4. Time to actual hospital departure 
5. Time to first rescue analgesia use 
6. Time to return of bowel function, including time to first bowel sounds or first flatus, and 
time to first bowel movement  
7. Time to mobilization, including time to first assisted mobilization out of hospital bed and 
time to first independent mobilization out of hospital bed 
8. PGA of pain control 
9. Brief Pain Inventory  
10. Subject assessment of satisfaction with pain medication 
11. Hospital length of stay (LOS) 
12. Incidence of postoperative NG tube insertion 
13. Incidence of hospital readmission. 
14. Total cost of hospitalization 
2.1.3. 
Exploratory Endpoints – Change in Inflammatory Markers 
Inflammatory markers including, but not limited to: c-reactive protein (CRP), tumor necrosis 
factor alpha (TNF-α), interleukin (IL) 1B, IL-4, IL-6, IL-8, IL-10, and IL-18. 


Protocol REC-17-024 
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3. 
GENERAL CONSIDERATIONS  
3.1. 
Analysis Population 
The following analysis sets will be identified for this study. 
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include randomized subjects.  This 
dataset may also be referenced as the ‘Randomized Set’.  The ITT subjects may or may not 
receive randomized treatment.    
Safety Set:  The safety set will include all treated subjects and will be used for safety and 
tolerability assessments.   
Efficacy Set:  The efficacy population will consist of all subjects who receive at least one 
injection of study drug and have the scheduled surgery.  This is also referenced as the modified 
intent-to-treat (mITT) Analysis Set.  All efficacy evaluations will be based on the mITT 
population.  
3.2. 
Test Hypothesis and P Value Justification 
The null hypothesis is that there is no difference between N1539 30 mg and placebo groups.  The 
alternative hypothesis is that the treatment groups are different. 
Differences between N1539 30 mg dose and placebo group will be evaluated via a 2-sided 
2-sample t-test at the 0.05 level of significance.  Nominal p-values will be reported as is.     
3.3. 
Procedures for Handling Missing Data  
Missing data imputation rules for pain intensity will be discussed extensively in Section 3.4.  
No missing data imputation will be performed for safety parameters.  However, AEs with 
missing severity assessments will be tabulated as “severe,” and AEs with missing relationship 
assessments will be tabulated as “related” for the purpose of analysis; and the missing data will 
be presented in data listing as is. 
3.4. 
Definitions and Derived Variables 
3.4.1. 
Analysis Center  
This is a multicenter study; investigative centers will be included in the analysis model as a 
covariate. Centers with small enrollment may be pooled to form an analysis center.  The final 
decision on pooling will be made prior to database hard lock. 
3.4.2. 
Baseline   
Baseline will be the last measurements taken before the subject receives the study medication. If 
an unscheduled visit/assessment occurred before a subject receives the first dose of study 
drug; the unscheduled visit may be the Baseline if it is the last non-missing value before the 
first dose. 


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3.4.3. 
Study Period and Analysis Visit 
3.4.3.1. 
Study Periods 
The study duration for each subject is divided into 4 periods 
1. Screening Period: The duration from signing informed consent until before receiving the 
first dose of study drug will be described as the screening period.  The last measurement 
taken prior to receiving the first dose of study drug is the Baseline measurement. 
Hence, the Baseline measurement could be either a scheduled assessment or an 
unscheduled assessment. 
2. Peri-operative period: this period starts when the subject receives the first dose of study 
drug and ends at time of end of surgery (T0 to H0). 
3. Post-operative period: postoperative period starts at the end of surgery and ends when the 
subject is discharged from the hospital or when the subject has reached LSD+1 (ie, 24 
hours after the last dose) before being discharged from the hospital. 
4. Post discharge period: this period starts after the subject is discharged from the hospital 
through end of study.   
3.4.3.2. 
End of Treatment and End of Study 
The treatment period covers the duration from the date/time of the first dose of study drug (T0) 
through 24 hours after the last dose of study drug (LSD+1).  However, it is expected that, for the 
majority of subjects, the treatment period ends when the subject is discharged from the hospital. 
Hence, the treatment period would be described as the time period from the first dose (T0) through 
hospital discharge or LSD+1, whichever comes first. 
End of Treatment (EOT): end of study drug treatment for a subject is when the subject has the 
LSD+1 Visit or the subject was discharged from hospital, whichever comes first.  
Time of End of Treatment (EOT) for a subject could be mathematically expressed as  
Time of EOT =min (date/time of actual discharge, date/time of LSD+1), where min is 
the function of minimal. 
End of Study (EOS): end of study for a subject is when the subject completes the follow up visit 2 
(30 ± 4 days post-discharge).  All treated subjects who have EOS visits are considered to have 
completed the study. 
3.4.3.3. 
Time 0 and Hour 0  
Time 0 (T0) is referred to the date/time of first dose of study drug, whereas Hour 0 (H0) is 
referred to the date/time of End of Surgery.   T0 is used to schedule study drug dosing whereas 
H0 is used to map efficacy assessments (such as opioid consumptions) in a standardized time 
window.  
 
 


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3.4.3.4. 
Analysis Visits   
Efficacy data will be mapped to Analysis Visit using the following 2 benchmarks: 
1. Relative to the time of end of surgery (Hour 0). A 24-hour period is referred to as a 
Post-surgery Day (PSD).  PSD 1 is the first 24-hour period after end of surgery, PSD 2 is 
>24 and <=48 hours after end of surgery.  Hence, date and time of an assessment will be 
compared to the end of surgery time in order to determine the PSD of the assessment.  An 
example of this type of visit is the total opioid consumption.    
2. Relative to the surgery date. This analysis will be based on the assessment date only and 
will be referred to as the Post-operative Day (POD). A post-operative day is calendar date 
after surgery.  For instance, POD 1 is one calendar day after the surgery date; the time 
elapsed from end of surgery to the assessment time performed on POD 1 may not be 24-
hours. An example of this type of visit is the PGA analysis.    
Analysis visit (POD vs PSD) will be clearly spelled out for each efficacy endpoint. The 
difference between POD and PSD can be illustrated in the following 3 examples.  
1. In example 1 the assessment time was within 24 hours after the end of surgery, therefore 
it is assigned to PSD 1 for Post-surgery Day analysis; and the date of the assessment was 
the same day of surgery, therefore, the POD 0 is assigned as Surgery Day (POD 0). 
2. In example 2 the assessment time was within 24 hours after the end of surgery, therefore 
it is assigned to PSD 1 for Post-surgery Day analysis; but the date of the assessment was 
1 day after the date of surgery, therefore, the POD 1 is assigned for Post-operative Day 
Analysis. 
3. In example 3 the assessment time was >24 and less than 48 hours after the end of surgery, 
therefore it is assigned to PSD 2 for Post-surgery Day analysis; and the date of the 
assessment was 1 day after the date of surgery, therefore, the POD 1 is assigned for 
Post-operative Day Analysis. 
 
Table 1:  Analysis Visit Using Post-Operative Day and Post-Surgery Day  
Example 
End of Surgery Time 
Assessment Time 
Post-Surgery Day 
Post-Operative Day 
1 
2018-03-12T11:01 
2018-03-12T16:45 
PSD 1 
Surgery Day (POD 0) 
2 
2018-03-12T11:01 
2018-03-13T08:45 
PSD 1 
POD 1 
3 
2018-03-12T08:05 
2018-03-13T18:05 
PSD 2 
POD 1 
 
 
 


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3.4.4. 
Subjects at Risk  
A subject is at risk if the subject is still available for assessment.  This concept is used for several 
analyses that pertain to a period.  
• For example, for analysis of opioid consumption from Hour 48 to Hour 72 after end of 
surgery, if a subject has been discharged before Hour 48, this subject will be considered 
‘Not at risk’ for H48-72 hours opioid consumption.   
• Another example is the assessment of Brief Pain Inventory.  Subjects who responded 
‘No’ to the Question 1 [Throughout our lives, most of us have had pain from time to time 
(such as minor headaches, sprains, and toothaches). Have you had pain other than these 
everyday kinds of pain today?] will not be ‘at risk’ for pain intensity and pain 
interference.  
Table 2 provides examples of subjects at risk for 12 periods used in the opioid consumption 
analysis. 
Table 2:  Subjects at Risk for 12 Periods Defined for Opioid Consumption    
ID 
Interval / Period 
Subject at Risk 
1 
Total in Study 
mITT subject 
2 
Pre-operative Period 
mITT subject 
3 
Intra-operative Period 
mITT subject 
4 
T0 - H0 (Perioperative) 
mITT subject 
5 
T0 to T24 (Excluding Dose 2) 
mITT subject 
6 
H0 - H24 (PSD 1) 
mITT subject 
7 
H24 - H48 (PSD 2) 
mITT subject with in-patient duration ≥24 hours 
8 
H48 - H72 (PSD 3) 
mITT subject with in-patient duration ≥48 hours 
9 
H0 - H48 (PSD 1-2) 
mITT subject 
10 
H0 - H72 (PSD 1-3) 
mITT subject 
11 
H0 - EOT (postoperative) 
mITT subject 
12 
H0 – Actual hospital discharge 
mITT subject 
 
 
 


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3.4.5. 
Opioid Consumption  
3.4.5.1. 
Total Opioid Consumption in IVMED by Period 
All concomitant medications will be coded according to WHODrug library. Opioid medications 
will be identified per ATC level 2 and level 3.  The dose from each identified opioid record will 
then be converted to IV Morphine Equivalent Dose (IVMED) in mg; examples of IVMED of 
some commonly used analgesics are provided in Table 3. 
 
Table 3:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics  
Generic Opioid Name 
1 Unit 
Route 
IV MED (mg) 
Morphine 
mg 
IV 
1 
Morphine 
mg 
PO 
0.333 
Methadone 
mg 
IV 
1 
Methadone 
mg 
PO 
0.333 
Nalbuphine 
mg 
IV 
1 
Nalbuphine 
mg 
PO 
0.333 
Buprenorphine 
mg 
IV 
25 
Fentanyl 
µg (mcg) 
IV 
0.1 
Sufentanil 
µg (mcg) 
IV 
1.00 
Alfentanil 
µg (mcg) 
IV 
0.02 
Hydromorphone 
mg 
IV 
6.67 
Hydromorphone 
mg 
PO 
1.3 
Codeine 
mg 
PO 
0.05 
Meperidine 
mg 
PO 
0.025 
Pentazocine 
mg 
PO 
0.1 
Oxycodone 
mg 
PO 
0.5 
Hydrocodone 
mg 
PO 
0.3 
 
The eCRF page for opioid medications uses the following indications to identify study periods: 
• Surgical:  This period includes all opioids used pre-surgery as part of the surgery 
preparation and opioids used during the surgery.  


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• Pain Management: all opioids used during in-patient period defined as end of surgery 
to hospital discharge or LSD+1, whichever occurs first.  This corresponds to the post-
operative period defined in Section 3.4.3.1)  
• Prophylaxis: opioid taken in a preventive manner 
• Medical history: opioids taken for medical history events 
• Other: opioids that do not fall under any of the above 4 categories  
Opioids for medical history events are expected to be taken before the surgery.  Those records 
will be excluded from the total opioid consumption analysis. Similarly, the opioids with 
indication of ‘OTHER’ may be excluded. The opioid records with indication of MEDICAL 
HISTORY, or OTHER will be reviewed carefully and queried if there are any doubts/questions 
on records prior to exclusion. 
3.4.5.2. 
Missing Date/time Imputation for Opioid Records 
After all efforts to clean up the database, if date or time is missing for opioid medications, the 
following rules will apply during programming to create the analysis dataset.  
1. Missing Dates 
a. If both the start and the stop dates are unknown, the record will be queried and 
excluded if confirmed.   
b. If the start date is present but the stop date is missing, the stop date is set to be the 
start date and vice versa. 
2. Missing Time 
a. If the start date is equal to the stop date 
i. If the start time is missing but the stop time is present, the start time is set 
to be the stop time and vice versa. 
ii. When both the start and the stop times are missing  
o if the date is the surgery date: missing start and stop start time will be 
set to 1 minute after end of surgery.  
o If the date is after surgery date: missing start time will be set to 00:01 
and missing stop time will be set to 23:59 
b. When the start date is not equal to the stop date 
i. When start time is missing  
o if the start date = surgery date then missing start time will be set to 1 
minute after end of surgery 
o if the start date > surgery date the missing start time will be set to 
00:01 


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ii. When stop time is missing 
o If stop date = surgery date the missing stop time will be set to 1 minute 
after end of surgery 
o If stop date > surgery date the missing stop time will be set to 23:59 
After all the opioid records that have the appropriate start and stop times, the start and the stop 
relative time (hours) to Hour 0 (end of surgery) or discharge will be determined for each record 
in order to derive the total opioid consumption within a PSD.  Total dose will be calculated for 
the following 12 intervals (Table 4).   Note: if a record indicates that the start and stop time 
extends beyond one interval, the total dose from this record will be split into appropriate 
intervals using linear interpolation (hourly dose). 


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Table 4:  Definition of Opioid Consumption Intervals  
ID 
Interval  
Interval Description 
Interval Expression [1] 
1 
Total in Study 
From hospital admission to actual hospital discharge 
[ADM, ADC] 
2 
Pre-operative Period 
From hospital admission to surgery start  
[ADM, SGST) 
3 
Intra-operative Period 
From surgery start to surgery end  
[SGST, SGEN] 
4 
T0 - H0 
From first dose start time to end of surgery  
[FSD, SGEN] 
5 
T0 to T24 
From first dose start time to but not include the second dose start time  [FSD, SSD) 
6 
H0 - H24 (PSD 1) 
From surgery stop time to 24 hours after end of surgery  
(SGEN, SGEN+24] 
7 
H24 - H48 (PSD 2) 
From 24 hours after end of surgery to 48 hours after surgery  
(SGEN+24, SGEN+48] 
8 
H48 - H72 (PSD 3) 
From 48 hours after end of surgery to 72 hours after surgery  
(SGEN+48, SGEN+72] 
9 
H0 - H48 (PSD 1-2) 
From end of surgery to 48 hours after surgery 
(SGEN, SGEN+48] 
10 
H0 - H72 (PSD 1-3) 
From end of surgery to 72 hours after surgery 
(SGEN, SGEN+72] 
11 
H0 - EOT  
From end of surgery to end of treatment 
(SGEN, EOT] 
12 
H0 – Discharge  
From end of surgery to actual hospital discharge  
(SGEN, ADC] 
[1] The square brackets, [ ], means inclusive whereas the parentheses, ( ), means exclusive.   
Abbreviations for intervals:  
ADM: hospital admission date/time;  
SGST=surgery start date/time;  
SGEN=surgery stop date/time;  
FSD=study drug first dose start date/time; 
SSD=study drug second dose start date/time;  
ADC=actual hospital discharge date/time;  
EOT=end of treatment date /time, defined as hospital discharge date/time or LSD+1, whichever comes first 
LSD+1 is 24 hours after the last dose of study drug, hence, LSD+1 = last dose date/time + 24 hours   
 


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3.4.5.3. 
Opioid Free Subjects  
A subject who did not use any opioids is classified as an opioid free subject.  The status of opioid 
free (OPFREE = Yes/No/NA) will be determined for each period based on the following rules: 
1. If any opioid records are found in the opioid concomitant medication page for 
corresponding period regardless if the total dose was known or unknown, the subject is 
assigned OPFREE=No; otherwise, OPFREE=Yes 
2. If a subject is discharged from hospital (based on actual discharge date/time) prior to the 
start of a period (e.g., H48-H72 period), the subject is assigned to OPFREE=NA for this 
period (i.e., subjects is not at risk).  That is, OPFREE=NA when a subject is not At-Risk 
for an interval.  See Table 2 for more information.       
3.4.6. 
Time to First Rescue 
Rescue opioid (IV opioid or oral opioid analgesic) will be those opioid records with ‘Pain 
Management’ as the indication in the database.     
Time (hours) from end of surgery (H0) to the start time of the first rescue opioid will be 
calculated for each opioid record.  
Time (hours) = start date/time of analgesics – date/time of end of surgery (Hour 0)  
A rescue opioid record without start date and/or time (although those may have imputed 
date/time, see Section 3.4.5.2)  will be excluded in general with one exception, that is, this 
record will be included if this is the only record for this route of administration.  That is, if 
this is the only record of rescue for this route of administration, the imputed start missing 
date/time will be used.  See Section 3.4.5.2 for missing date/time imputation rules. 
Following the determination of the time from end of surgery (Hour 0) to the rescue start time for 
each rescue record the following data derivations will be performed:  
1. when a subject has both IV and oral rescue opioid records, the time to first rescue (IV or 
Oral) will be the first rescue record based on the start time, mathematically, it can be 
expressed as 
Time to first rescue = min (time to first IV rescue, time to first oral rescue) if both 
events have occurred.   
2. When a subject did not have any IV rescue opioid but had oral rescue opioid,  
a. Time to first rescue (IV or Oral) will be set to be the same as the time of first oral 
rescue  
b. This subject will be censored for time to first IV rescue.  The censored time will 
be date/time of first oral rescue.     
 
 


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3. When a subject did not have any Oral rescue opioid but had IV rescue opioid,  
c. the time to first rescue (IV or Oral) will be set to the time to first IV rescue opioid 
(subject is not censored) 
d. this subject will be censored to EOT for the time to first oral rescue analysis.    
4. When a subject does not have any rescue opioid records,  
e. This subject will be censored for all 3 time to rescue endpoints.  The censored 
time will be the time of EOT (see Section 3.4.3.2 for more information). 
3.4.7. 
Time to First Ambulation and Associated Pain Intensity  
Two types of ambulation are assessed: assisted ambulation vs unassisted (i.e., independent) 
ambulation.  The eCRF has the following collections for the first assisted ambulation and the 
first independent ambulation: 
1. Start date/time of the ambulation 
2. Duration of the ambulation 
3. Pain score prior to the ambulation (within 15 minutes prior to the ambulation), including 
the time of PI assessment.  
4. The worst pain score during the ambulation, including the time of PI assessment.  
The following rules will apply for partial date/time of an ambulation record when the ambulation 
occurred and time is unknown  
• If the assessment time for pre-ambulation PI score is available: set the start time of 
ambulation to be 15 minutes after the pre-ambulation PI assessment time 
• Otherwise if the worst pain score assessment time is present, the ambulation start time 
will be set to the time when the worst PI score was assessed. 
• Otherwise, subject is excluded from the time to first ambulation analysis. 
Time (hours) to first assisted ambulation and time to first independent ambulation will be 
determined as follows 
Time (hours) = start date/time of event – date/time of end of surgery (Hour 0) 
The following rules will apply: 
• When a subject did not have any assisted ambulation record, but this subject has a record for 
independent ambulation, this subject will not be censored for time to first assisted 
ambulation.  The time to first assisted ambulation will be set to the same as time to first 
independent ambulation for analysis. 
• When a subject has the first assisted ambulation record but this subject did not have any 
record for unassisted ambulation, this subject will be censored for time to first independent 
ambulation.  The censored time will be the time of EOT (see Section 3.4.3.2 for more 
information).  


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• When a subject did not have any ambulation event, this subject will be censored at time of 
EOT for both time to first assisted ambulation and time to first independent ambulation. 
Pain Intensity (PI) score prior to ambulation and the worst PI score during ambulation will be 
recorded on a scale of 0-10 where 0=no pain and 10=the worst imaginable pain.  Missing PI 
score will not be imputed.  Subjects with missing PI score will be excluded from the analysis of 
PI assessment.  
3.4.8. 
Time to Return of Bowel Function 
Return of bowel function will include 3 elements: 1) time to first bowel sound, 2) time to first 
flatus, and 3) time to first bowel movement; numerically, each event will be calculated as  
Time (hr) = date/time of event   – date/time of End of Surgery (Hour 0)  
The following assumption and rules will apply when an event is not captured on the eCRF. 
1) When the first bowel sound (BS) is not reported 
• If the first flatus is reported: the event of first bowel sound would be considered to 
have occurred as well; the date/time of first bowel sound is set to be the date/time 
of first flatus. The subject will NOT be censored. 
• If the first flatus is not reported but bowel movement is reported: the event of first 
bowel sound would be considered to have occurred; the date/time of first bowel 
sound is set to be the date/time of first bowel movement. The subject will NOT 
be censored. 
• If the first flatus and first bowel movement are not reported, the subject will be 
censored for time to first bowel sound analysis.  The censored time will be the 
time of EOT (see Section 3.4.3.2 for more information). 
2) First flatus (FL) is not reported: 
• If first bowel movement is reported: the event of first flatus would be considered 
to have occurred as well; the date/time of first flatus is set to be the same as the 
date/time of first bowel movement. The subject will NOT be censored. 
• If first bowel movement is not reported: the subject will be censored for time to 
first flatus analysis; censoring time will be the time of EOT (see Section 3.4.3.2 
for more information). 
3) If first bowel movement (BM) is not reported: the subject will be censored for time to 
first bowel movement analysis; the censoring time will be the time of EOT (see Section 
3.4.3.2 for more information).         
 
 


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3.4.9. 
Length of Hospital Stay Measured by Time to Hospital Discharge  
Length of hospital stay is assessed in 2 different forms: 
1. Time (hours) to hospital discharge order written (DOW) as follows: 
TTDOW (hours) = Date/Time of DOW – Date/time of End of surgery (Hour 0) 
2. Time (hours) to actual hospital discharge (ADC) as follows: 
     TTADC (hours) = Date/Time of ADC – Date/time of End of surgery (Hour 0) 
The following rules will apply when time of DOW or time of ADC are missing: 
1. If time of DOW is unknown but time of ADC is present, the time of DOW will be set to 
time of ADC and vice versa. 
2. If both time of DOW and time of ADC are missing, both times will be set to 23:59. 
3.4.10. 
Brief Pain Inventory (BPI)  
BPI short form is a questionnaire that assess the “sensory” dimension of pain (intensity, or 
severity) and the “reactive” dimension of pain (interference with daily function). 
1. Four items are used to capture the variability of pain over time: pain at its “worst,” 
“least,” “average,” and “now” (current pain).  
2. Seven items are used to measure how much pain interfered with various daily activities, 
including general activity, walking, work, mood, enjoyment of life, relations with others, 
and sleep.  The seven items are divided into two subdimensions of pain interference:  
a. an affective subdimension (REM: relations with others, enjoyment of life, and 
mood, items 9B, 9E, and 9G) and  
b. an activity subdimension (WAW: walking, general activity, and work, items 9A, 
9C, and 9D).  
• Please note that he author indicated the appropriate categorization of sleep 
within these two subdimensions was unclear; hence, the author suggested that 
item 9F score is included in the dimension of Interference score but excluded 
from both sub-dimensions REM and WAW.     
The items and the dimensions are illustrated graphically as follows.  Additional information 
about can be found in BPI User Guide1 (2009, Charles S. Cleeland). 
                                                          
1 The Brief Pain Inventory User Guide. Charles S. Cleeland, PhD. 2009 


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The BPI scores for each dimension and subdimension will be calculated for each subject as 
shown in Table 5. 
Table 5:  Definition of BPI Dimension and Subdimension  
Dimension 
Composite Score = Average Score of  
Interpretation 
Pain Severity 
Questions 3, 4, 5, 6.  All 4 questions must be 
answered. 
The high score indicates the severe 
average pain 
Interference 
All 7 scores in Question 9. At least 50% items 
(or 4 of the 7 scores) must be responded    
The high score indicates the greater 
pain interference 
REM 
Scores of 9B, 9E, and 9G.  At least 2 of the 3 
scores must be responded.    
The high score indicates the greater 
pain interference with patient’s 
affection with other people 
WAW 
Scores of 9A, 9C, and 9D. At least 50%, or 2 
of the 3 scores must be responded    
The high score indicates the greater 
pain interference with patient’s daily 
activities 
BPI 
Average scores of pain severity & pain 
interference.   
The high score indicates the patient 
had severe pain intensity and a 
greater pain interference 
 


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In addition, the BPI short form has two questions. 
Question 1: Throughout our lives, most of us had pain from time to time (such as minor 
headaches, sprains, and toothaches) Have you had pain other than those everyday kinds of pain 
today?  
Subjects must have a response ‘Yes’ to be included in the BPI analysis for a given visit.  In 
other words, BPI analysis will be performed based on the concept of ‘at Risk’.  Subjects 
who did not have pain will not be at risk for pain severity and pain interference 
assessments.  
Question 8: This question is about pain relief from the pain treatment.  Response from this 
question will be analyzed individually only (i.e., the response will not be included in the 
composite scores stated above. 
BPI scores at screening visit will be the baseline score; change from baseline will be calculated 
for each Post-Operative Day (POD, see Section 3.4.3.4) for subjects at risk.  Missing data will 
not be imputed for the analysis.  In addition, the last observation prior to discharge will also be 
included as ‘Prior to Discharge’ time point. 
 
3.4.11. 
Patient Global Assessment of Pain Control (PGA)  
PGA assessments will be mapped to Analysis Visit using the Post-Operative Day benchmark 
(see Section 3.4.3.4).   In addition, the last observation prior to discharge will also be included as 
‘Prior to Discharge’ time point. 
 
A study staff will ask subjects to respond to the following question: 
“Overall, please rate how well your pain has been controlled during the last 24 hours?”  
Poor (0) 
Fair (1) 
Good (2) 
Very Good (3) 
Excellent (4) 
Subjects with ratings of 2 (good), 3 (very good) or 4 (excellent) will be grouped as subjects with 
acceptable pain control for PGA analysis.  
 
 


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3.4.12. 
Subject Assessment of Satisfaction with Pain Medication     
At LSD+1 Visit subjects will report their satisfaction with the pain medication they received to 
manage their postoperative pain according to a 7-point Likert scale including categories of: 
completely dissatisfied (1), mostly dissatisfied (2), somewhat dissatisfied (3), neither satisfied to 
dissatisfied (4), somewhat satisfied (5), mostly satisfied 6), and completely satisfied (7). 
Based on the response, subjects will be grouped into 3 groups:  
1) Not satisfied if ratings are 1, 2, or 3;  
2) Neutral if rating is 4 
3) Satisfied if ratings are 5, 6, or 7 
3.4.13. 
 Healthcare Utilization Endpoints     
The following 3 events endpoints will be assessed for each subject:  
1. Incidence (Yes vs No) being re-admitted to hospital, including all cause readmissions 
2. Incidence (Yes vs No) of postoperative NG tube insertion 
3. Incidence (Yes vs No) of postoperative anastomotic leak 
Total cost of hospitalization is also captured on the eCRF. 
Missing date related to the endpoints associated with healthcare utilization will not be imputed.  
Subjects will be excluded for missing data.    
 


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4. 
STUDY POPULATION SUMMARIES 
4.1. 
Disposition 
A summary table (Table 14.1.1.1) will provide frequency counts for subject disposition, 
including 
• randomized (ITT),  
• all treated subjects (Safety),  
• mITT Subjects (Efficacy),  
• Subjects completed study, 
• Subjects prematurely discontinued the study  
o reasons for early termination  
• Reasons for subject no longer continuing study drug. 
 
Primary reason for early termination of study includes 
1) Adverse Event 
2) Study Non-compliance  
3) Physician Decision 
4) Sponsor Decision 
5) Subject Decision 
6) Lost to Follow-Up 
7) Other 
 
Primary reason for subject no longer continuing study drug treatment includes 
1) IV Access Removed 
2) Subject Discharged 
3) Adverse Event 
4) Physician Decision 
5) Subject Decision 
6) Other 
A summary table (Table 14.1.1.2) will provide enrollment by site, including ITT analysis set, 
Safety analysis set, and mITT analysis set for each treatment group and overall.  The site with 
overall highest ITT enrollment will display first. 


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4.2. 
Demographics and Baseline Characteristics 
The demographic summary will include descriptive statistics for age, age group (age <65, age 
>=65), sex, race, ethnicity, height (cm), weight (kg) and BMI (kg/m2) at baseline for overall and 
by treatment group.  
Baseline characteristics and patient population characteristics will include: 
1) primary indication for surgery 
2) surgery type 
3) actual incision type 
4) incision length (cm)  
5) time (hours) from first dose to surgery start  
6) surgery duration (hours) 
7) time (minutes) stayed in the PACU 
Demographics and baseline characteristics will be tabulated for safety analysis set (Table 
4.1.2.1). If the mITT set is not the same as the Safety Analysis set, a second table for the mITT 
analysis set (Table 14.1.2.2) will also be provided.  No formal inferential tests will be 
performed. 
4.2.1. 
Other Medical History 
All medical history data will be available in SDTM dataset without formal data summary and 
data listing. 
4.3. 
Protocol Deviations 
All protocol deviations will be identified and will be classified as either an ‘Important Protocol 
Deviation’ or ‘Protocol Deviation’. 
Important Protocol Deviation: An Important Protocol Deviation is a protocol deviation that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being. Examples may include: 
➢ Failure to meet all entry criteria; 
➢ Non-compliant with study drug treatment regimen; 
➢ Did not receive randomized treatment; 
➢ Did not receive correct randomization treatment; 
➢ Use of prohibited concomitant medications; 
Protocol Deviation: Any alteration/modification, divergence or departure from the IRB-approved 
protocol.  A protocol deviation is an unanticipated or unintentional divergence or departure from 


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the expected conduct of an approved study that is not consistent with the current research 
protocol, or consent document. 
All protocol deviations will be tabulated by protocol type, protocol deviation category for each 
treatment group and study overall (Table 14.1.4). 
4.4. 
Treatment Compliance 
Doses of study medication will be administered to the study subjects under the observation of 
study personnel while confined to the study site.  The exact time of administration of study 
medication will be documented within each subject’s eCRF.  No formal summary of treatment 
compliance will be produced. 
A subject is expected to receive at least 2 doses of study drug.  All doses after dose 1 are to be 
given every 24 hours (± 1 hour, i.e., window=23-25 hours from previous dose).  The last dose 
could be given up to 4 hours earlier from previous dose (i.e., window=20-25 hours from previous 
dose) if the last dose is given on the day of discharge.   
Compliance relative to dosing window will be checked based on dosing interval (hours). 
Mathematically dosing interval will be derived as (date/time of dose(n+1) – date/time of dosen).   
Dosing interval will be calculated for each dose starting dose #2.  Dosing intervals outside the 
dosing window (23-25 hours or 20-25 if it is the last dose given on the day of discharge) will be 
considered non-compliance.  
Compliance data will be tabulated together with study drug total exposure (see Section 6.1). 
 
4.5. 
Prior and Concomitant Medications 
All prior and concomitant medications will be available in SDTM dataset without formal data 
summary and data listing. 


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5. 
EFFICACY ANALYSIS 
5.1. 
Opioid Consumptions 
Opioid consumption will follow at risk approach (see Section Table 2 for Subjects at Risk).  The 
following 12 periods will be included in the summary table. 
 
ID 
Interval  
1 
Total in Study  
2 
Pre-Operative 
3 
Intra-Operative 
4 
T0 - H0 
5 
T0 to T24  
6 
H0 - H24 (PSD 1)  
7 
H24 - H48 (PSD 2) 
8 
H48 - H72 (PSD 3) 
9 
H0 - H48 (PSD 1-2) 
10 
H0 - H72 (PSD 1-3) 
11 
H0 - EOT  
12 
H0 - Discharge 
 
The following 3 analyses will be included for each interval (Table 14.2.1.1). 
5.1.1. 
Number (%) Subjects Opioid Free 
A subject is opioid free if this subject did not use any opioid (IV or Oral) analgesic in this period 
(see Section 3.4.5.3).  Number (%) subjects opioid free (Yes/No) will be tabulated by treatment 
group. The denominator for each period should include all subjects at risk (see Table 2:  Subjects 
at Risk): 
Treatment group difference in proportion of subjects used rescue and 95% confidence intervals 
for the difference will be provided.  The difference will be evaluated using Cochran-Mantel-
Haenszel (CMH) test controlling for analysis center (CM general association statistic). 
5.1.2. 
ANCOVA Analysis of Total Opioid Consumption  
Total opioid consumptions in IVMED (mg) per subject will be determined for each interval.  
Subjects who did not use any rescue medication in a period (ie, opioid free =Yes in Section 


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5.1.1) will be set to zero ‘0’ for total opioid consumption analysis.  Subjects with OPFREE=NA 
at a given interval will be excluded from the analysis for this interval. 
A summary table will be prepared to provide group descriptive statistics, including sample size, 
mean, standard deviation, minimum, median, and maximum.  Difference between treatment 
groups will be evaluated using an ANCOVA model that will include main effect of treatment 
and analysis center.  LS means from each group and difference in LS means and corresponding 
95% CI for the difference and nominal p-values will be reported in the summary table. 
5.1.3. 
Rank Analysis of Total Opioid Consumption  
Total opioid consumptions may not be normally distributed, hence, the statistical assumption for 
parametric analysis using ANCOVA specified in Section 5.1.2 above may not be held.  A 
confirmatory analysis using CMH ANOVA (Row Mean Scores Differ) on rank (a nonparametric 
approach) will also be performed for total opioid consumption.  The test will control for analysis 
center.   A single set of rank will be produced within each time point across treatment groups 
using Nplus1 and ties=mean method.  P-value from the CMH test will be presented. 
5.2. 
 Time to First Rescue  
There are 3 time-to-first rescue events in this study associated with opioid analgesic: 
• Time from hour 0 to first use of IV or Oral rescue analgesic  
• time from hour 0 to first use of IV rescue analgesic 
• time from hour 0 to first use of Oral rescue analgesic 
A summary table (Table 14.2.1.2) will include the following statistics for each of the event. 
• number (%) subjects with and without (censored) event,  
• Kaplan-Meier product limit estimates of quartiles of time to first event (25%, 50%, and 
75% tiles and 95% CIs)   
• KM means (SE) of time to first event  
• the log rank test for homogeneity between the treatment groups.   
• Differences between the groups in time to event will be further analyzed using Cox 
proportional hazards analysis model that include the main effects of treatment and 
analysis center.  Hazard ratio (N1539 30 mg / placebo) and 95% CIs and p-value from 
Wald’s chi-square test for treatment and analysis center will be presented.   
Kaplan-Meier survival curves will be presented for each treatment group.  
 
5.3. 
Length of Hospital Stay Measured by Time to Discharge  
Time to DOW and Time to ADC (see Section 3.4.9) will be summarized by treatment group.  
The summary table (Table 14.2.2.1) will include  


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• number (%) subjects with and without (censored) event,  
• Kaplan-Meier product limit estimates of quartiles of time to first event (25%, 50%, and 
75% tiles and 95% CIs) and  
• KM restricted means (SE) of time to first event  
• the log rank test for homogeneity between the treatment groups.   
• Differences between the groups in time to event will be further analyzed using Cox 
proportional hazards analysis model that include the main effects of treatment and 
analysis center.  Hazards ratio (N1539 30 mg / placebo) and 95% CIs and p-value from 
Wald’s chi-square test for treatment and analysis center will be presented.   
Kaplan-Meier survival curves will be presented for each treatment group. 
5.4. 
Ambulation Assessments 
5.4.1. 
Time to First Ambulation Events  
A summary table (Table 14.2.3.1) will include the following statistics for time to first assisted 
ambulation and time to first independent ambulation. 
• number (%) subjects with and without (censored) event,  
• Kaplan-Meier product limit estimates of quartiles of time to first event (25%, 50%, and 
75% tiles and 95% CIs) and  
• KM restricted means (SE) of time to first event  
• the log rank test for homogeneity between the treatment groups.   
• Differences between the groups in time to event will be further analyzed using Cox 
proportional hazards analysis model that include the main effects of treatment and 
analysis center.  Hazard ratio (N1539 30 mg / placebo) and 95% CIs and p-value from 
Wald’s chi-square test for treatment and analysis center will be presented.   
Kaplan-Meier survival curves will be presented for each treatment group.  
5.4.2. 
Pain Before and the Worst Pain During Ambulation 
PI score will be tabulated by treatment and ambulation type with descriptive statistics (Table 
14.2.3.2.1 – First Assisted Ambulation; Table 14.2.3.2.2 – First Independent Ambulation). 
Difference between the groups will be evaluated using an ANOVA model that include treatment 
and investigator center.  Difference between the treatment groups in LSM and 95% CI for the 
difference will be provided along with p-value for the effect of treatment and analysis center. 
A sensitivity analysis using CMH ANOVA (Row Mean Scores Differ) on rank controlling for 
investigator center will also be provided.     


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5.5. 
Time to Return of Bowel Function  
There are 3 surrogate events associated with the return of normal bowel function: 
• Time from hour 0 to first bowel sound (TTBS)   
• time from hour 0 to first flatus (TTFL) 
• time from hour 0 to first bowel movement (TTBM)  
All 3 parameters will be summarized by treatment group (Table 14.2.4); the summary table will 
include the following statistics for each of the 3 events. 
• number (%) subjects with and without (censored) event,  
• Kaplan-Meier product limit estimates of quartiles of time to first event (25%, 50%, and 
75% tiles and 95% CIs) and  
• KM means (SE) of time to first event  
• the log rank test for homogeneity between the treatment groups.   
• Differences between the groups in time to event will be further analyzed using Cox 
proportional hazards analysis model that include the main effects of treatment and 
analysis center.  Hazard ratio (N1539 30 mg / placebo) and 95% CIs and p-value from 
Wald’s chi-square test for treatment and analysis center will be presented.   
Kaplan-Meier survival curves will be presented for each treatment group.  
5.6. 
Patient Global Assessment (PGA) of Pain Control  
All PGA assessments collected on eCRF will be mapped to POD 1, POD 2, ...etc. for analysis.  
Hence, the number of subjects at each time point (POD 1, POD 2, POD 3, …., etc.) will expect 
to decrease as subjects discharged from the hospital.  A timepoint of Prior to Discharge (EOT) 
will be included for all subjects which will be the last PGA assessment during hospital stay. 
Number (%) subjects by PGA ratings will be tabulated along with mean (SD) of the rating by 
treatment and time point (Table 14.2.5).  Proportion of subjects with acceptable pain control 
[including ratings of 2 (good), 3 (very good) or 4 (excellent)] vs proportion of subjects with non-
positive response [including ratings of 0 (poor) or 1 (fair)] will be compared between treatment 
groups using CMH test (general association) controlling for analysis center.     
5.7. 
Brief Pain Inventory Questionnaire  
BPI dimension scores and sub-dimension (see Section 3.4.10 for parameter derivation method) 
and score from each item will be tabulated. 
Baseline (screening visit) BPI data for the all subjects at risk at baseline will be tabulated 
separately (Table 14.2.6.1) with descriptive summary; difference between the groups at baseline 
will be assessed using 1-way ANOVA.   


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Post baseline BPI data will be tabulated for each POD by treatment. Number of subjects at risk 
(ie, subjects with pain) at each POD may vary depending on the response to Question No. 1; 
hence, number (%) of subjects with pain (ie, subjects at risk for pain severity and pain 
interference) will be tabulated and evaluated using a CMH test (controlling for investigational 
site) at each time point.  Difference between the groups at each POD in domain and sub-domain 
score will be assessed using ANCOVA model that includes the main effect of treatment, analysis 
site, and baseline score as covariate. The summary table will present the estimated LSM, 
difference in LSM and 95% CI for the difference, and p-value for treatment effect, analysis site 
effect and the baseline effect.  
A sensitivity analysis using CMH ANOVA (Row Mean Scores Differ) on rank controlling for 
analysis center will also be provided.  
The analysis for BPI will be performed for each question individually and at dimension and 
subdimension level as well (Tables 14.2.6.2 to 14.2.6.8).        
BPI analysis will be based on POD analysis visit. A timepoint of Prior to Discharge (EOT) will 
be included for all subjects which will be the last BPI assessment during hospital stay. 
5.8. 
Patient Satisfaction with Postoperative Pain Medication  
Number (%) subjects by satisfaction ratings will be tabulated along with mean (SD) and median 
of the rating by treatment (Table 14.2.7).  Proportion of subjects who are satisfied or not 
satisfied or neutral (see Section 3.4.12)  will be compared between treatment groups using CMH 
test (general association) controlling for analysis center.     
 
 


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5.9. 
Health Care Utilization   
Health care utilization related parameters include: 
1. Subjects with >=1 all cause hospital readmission  
2. Subjects with >=1 postoperative NG Tube insertion  
3. Subjects with >=1 incidence of anastomotic leak  
4. Total cost of hospitalization 
A summary table (Table 14.2.8.1) will include descriptive statistics of subjects (%) for first 3 
parameters, and another summary table (Table 14.2.8.2.2) will provide descriptive summary of 
total cost of hospitalization, including n mean, standard deviation, median, minimum, maximum. 
No inferential statistics will be provided. 
5.10. 
Change in Inflammatory Markers (Exploratory Endpoint)   
A summary table (Table 14.2.9) will include descriptive statistics of n mean, standard deviation, 
median, minimum, maximum for each measured inflammatory marker or number (%) of subjects 
by each category.  Results will also be tabulated relative to normal range showing number of 
subjects (%) in each category (normal, high, low, etc.).  Change from baseline will be measured 
by creating shift (Baseline – Visit) category (Normal – Normal, Normal – High, Normal – Low, 
etc.). 
The table will include only those subjects who agreed to participate this portion of the study.  No 
inferential statistics will be provided.  
 


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6. 
SAFETY AND TOLERABILITY EVALUATIONS 
6.1. 
Extent of Exposure 
The extent of exposure will be assessed by number of doses taken.  The summary will provide 
number of subjects (%) who had 1, 2, 3, …. etc. doses of study drug in the study.  Percentage 
will be calculated based on total number of treated subjects in each treatment group 
(Table 14.3.1). 
1. The exposure table will also include dosing compliance (see Section 4.4) information 
based on based on a subset of subjects who had ≥ doses of study drug.  The compliance 
data will include number of subjects (%) with all doses taken within dose interval and 
number subjects (%) with >=1 dose that was dosed outside the dosing interval will be 
tabulated by treatment group.    
2. In addition, number of subjects and total number of doses that are dosed <23 hours, <22 
hours, <21 hours, and <20 hours from the previous dose will also be identified. 
 
6.2. 
Adverse Events 
Adverse events reported post dosing through the final follow-up (30 ± 4 days post-discharge) 
will be considered as treatment emergent adverse events (TEAEs).  The Medical Dictionary for 
Regulatory Activities (Version 20.1) will be used to classify all AEs with respect to system 
organ class and preferred term. 
The following summary tables will be produced for the TEAEs. All data summaries will provide 
number (%) subjects as well as total number of events in each category. 
1. a topline summary of TEAEs (Table 14.3.2.1) 
2. a summary table by preferred term in descending order of total incidence (Table 14.3.2.2) 
3. a detailed summary table by system organ class, preferred term and severity 
(Table 14.3.2.3.1) 
4. a detailed summary table by system organ class, preferred term and relationship 
(Table 14.3.2.3.2) 
5. a table of serious TEAEs by system organ class and preferred term (Table 14.3.2.4) 
6.3. 
Change in Laboratory Tests 
Safety laboratory tests are scheduled to be performed at check-in and at hospital discharge.  
Additional unscheduled laboratory tests would be performed as clinical indicates.  Central lab 
will be provided by PPD Global Central Labs. 
Incidence of potentially clinically significant change (PCSC) in clinical laboratory values will be 
identified for selected laboratory tests of special interest.    


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Table 6:  Selected Laboratory Tests of Special Interest 
Lab Category 
Description (Code) 
Chemistry 
Alkaline Phosphatase (ALP) 
 
Alanine Aminotransferase (ALT) 
 
Aspartate Aminotransferase (AST) 
 
Blood Urea Nitrogen (BUN) 
 
Direct Bilirubin (DBILI) 
 
Total Bilirubin (TBILI) 
 
Gamma Glutamyl Transferase (GAMMAGT) 
 
Serum Creatinine (CREATIN) 
 
 
Hematology 
Hematocrit (HCT) 
 
Hemoglobin (HGB) 
 
Platelet (PLT) 
 
 
Coagulation 
Activated Partial Thromboplastin Time (APTT) 
 
Thromboplastin Time (PT) 
 
Prothrombin time International Normalized Ratio (PTINR) 
 
A summary table will provide number (%) of subjects with abnormal results that meet the 
criteria in Table 7 post baseline. All post baseline lab tests (scheduled plus unscheduled) will be 
included in the analysis. If a subject had more than 1 lab draw and all results are abnormal, this 
subject is counted only in this lab test but all events will be counted in the ‘total’ events.    This 
analysis will be performed twice: once to include all subjects in the safety analysis set (Table 
14.3.3.1) and second time to include only the subjects with normal baseline (Table 14.3.3.2).   
 
 


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Table 7:  Definition of Potentially Clinically Significant Change (PCSC) in Selected 
Laboratory Tests of Special Interest 
Category 
Test Code 
Category for post baseline result [1] 
Hematology tests 
HGB, PLT, HCT 
1) Shift from Normal to Abnormal, Low 
2) Shift from Normal to Abnormal, High 
 
Renal function 
tests [2] 
BUN, 
Serum creatinine 
1) > 1 to < 1.5 times of ULN 
2) ≥ 1.5 to < 3 times of ULN 
3) ≥ 3 times of ULN 
 
Liver function 
tests [2]  
ALT, AST, GGT, 
ALP 
1) > 1 to < 3 times of ULN 
2) ≥ 3 to < 10 times of ULN 
3) ≥ 10 times of ULN 
 
 
Bilirubin (Total and 
Direct) 
1) >1 to < 1.5 times of ULN 
2) ≥ 1.5 to <2 times of ULN 
3) ≥ 2 to < 2.5 times of ULN 
4) ≥ 2.5 to < 3 times of ULN 
5) ≥ 3 times of ULN 
 
Coagulation tests 
PTT, PT, INR 
1) Shift from Normal to Abnormal, Low 
2) Shift from Normal to Abnormal, High 
 
[1] ULN = Upper limit of normal range; LLN = Lower limit of normal range. 
 
6.4. 
Wound Healing 
Wound healing progress will be assessed at hospital discharge and at follow-up visit 1 (5-21 days 
post-discharge).  Wound evaluation assessments will include investigator satisfaction score 
(0=completely unsatisfied and 10=completely satisfied).    
The summary table (Table 14.3.4) will include number (percent) subjects in each response 
category; Group mean, median, and standard deviation will also be provided. Differences 
between the groups will be assessed using Cochran-Mantel-Haenszel ANOVA (Row Mean 
Scores) on response controlling for analysis centers.   
6.5. 
Vital Signs 
Vital signs will be collected at screening, check-in visit, and LSD+1 Visit.  Vital signs at each 
time point and change from baseline at LSD+1 visit will be summarized by treatment group 
(Table 14.3.5) with descriptive statistics without inferential statistics.