Clinical trial NCT02720692
Conditions: Pain, Post-operative
Keywords: Pain Analgesia N1539 Phase 3
Sponsor: Baudax Bio
Start date: 2016-03-01; Completion date: 2017-05-01
Enrollment: 722 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of N1539 in a variety of post-surgical conditions.

Detailed description:

Arms: arm 1: N1539 (Intravenous meloxicam) 30mg every 24 hours for up to 7 doses. arm 2: IV Placebo every 24 hours for up to 7 doses.
Interventions: intervention 1: N1539 intervention 2: Intravenous Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 
REC-15-017 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Evaluation of the Safety of N1539 Following Major Surgery 
 
NCT02720692 
 
Clinical Study Protocol – Amendment 003 
 
13 July 2016 


PROTOCOL REC-15-017 Amendment 003 
CONFIDENTIAL 
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13 July 2016 
 
 
CLINICAL STUDY PROTOCOL 
Compound Name: 
Injectable NanoCrystal Colloidal Dispersion Meloxicam (N1539) 
Protocol Number: 
REC-15-017 – Amendment 003 
Protocol Title:  
 A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Evaluation of the Safety of N1539 Following Major Surgery  
Date of Protocol: 
13 July 2016 
 
Study Designated 
Physician: 
Stewart McCallum, MD 
490 Lapp Rd 
Malvern, PA 19355 
Telephone: 484-395-2411 
Mobile: 610-888-3984 
Fax: 484-395-2471 
Email: smccallum@recropharma.com 
Contacts: 
Randy Mack 
SVP, Development 
490 Lapp Rd 
Malvern, PA 19355 
Telephone: 484-395-2406 
Email: rmack@recropharma.com 
 
 
 
 
 
 
Unauthorized copying or use of this information is prohibited. 
 


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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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SYNOPSIS (PAGE 1 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
Objective:  The primary objective of this study is to evaluate the safety and tolerability of N1539 
compared with placebo, as evaluated with physical examination, vital signs, clinical laboratory tests, 
ECGs, wound evaluation, postoperative opioid consumption, and incidence of Adverse Events (AEs) 
and Serious AEs (SAEs). 
Methodology:   
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, evaluation of the safety 
of N1539 in adult subjects undergoing major surgery.  The study will enroll approximately 700 
subjects. 
Adult subjects, age 18 to 80 years inclusive, requiring major surgery that is expected to result in 
inpatient hospitalization for at least 24-48 hours, will be screened for participation at 30-40 study sites 
in North America, Australia, and New Zealand.  Screening will occur within 28 days before study 
drug administration.  After signing the informed consent, medical history, physical examination, 
baseline laboratory testing, 12-lead electrocardiogram (ECG), pregnancy testing, and vital sign 
measurements will be completed during the screening visit. 
Study enrollment will include a cohort of approximately 30-40 subjects meeting criteria as high risk 
subjects, defined as age > 65 years with a glomerular filtration rate (GFR) of 60-89 mL/min/1.73 m2, 
as calculated using the Modification of Diet in Renal Disease (MDRD) equation (Appendix E). 
On the day of surgery (Day 1), subjects will undergo surgical procedure.  Following surgery, subjects 
will be evaluated to ensure their eligibility for randomization within six hours after surgery.  Eligible 
subjects will be randomized and treated with study drug for at least two study doses and will stay at 
the study center for at least 24-48 hours after treatment initiation or so long as inpatient care is 
clinically appropriate.  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 time of discharge.   
All treated subjects will be followed through 28 days following LSD.  All subjects will return to the 
study center to complete end of study assessments 7 days post-LSD (LSD+7), with a telephone safety 
follow-up 28 days post-LSD (LSD+28). 
Safety assessments will include monitoring of AEs, clinical laboratory tests, opioid consumption, vital 
sign measurements, wound evaluation, and ECGs. 


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 SYNOPSIS (PAGE 2 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
The following summarizes key activities for each phase of this study: 1) Pretreatment Phase, 
2) Treatment Phase, 3) Follow-up.   
1. Pretreatment Phase: 
a. Screening Period (Day -28 to Day -1):  Subjects will be consented and screened. 
b. Day of Surgery (Day 1):  
1) Pre-surgery:  Subjects will be admitted to the site and reassessed for eligibility for the 
study.  Pre-surgery activities will be conducted. 
2) Surgery:  Eligible subjects will undergo surgery using an appropriate anesthetic 
regimen according to the type of surgery. 
3) Postoperative Period:  Following surgery, subjects will be evaluated for eligibility for 
treatment. 
c. Randomization Qualification (Day 1):  Subjects will be eligible for randomization and 
study dosing if/when they meet all of the postoperative randomization criteria within six 
hours after surgery (Section 4.3).   
2. Treatment Phase (Hour 0 through Discharge) 
Once the subject meets postoperative randomization eligibility criteria, they will be 
randomized in a 3:1 ratio to IV treatment with N1539 30 mg or placebo, administered 
every 24 hours (±1 hour).      


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SYNOPSIS (PAGE 3 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
The time of first dose of study drug (Dose 1) will be recorded as Hour 0.  Subjects will be 
administered a study dose according to their randomization every 24 hours (from Hour 0) so 
long as IV analgesia is clinically appropriate or until they receive a maximum of 7 study doses.  
A final study dose may be administered up to 4 hours early in subjects who are scheduled to be 
discharged.  When inpatient care is no longer required, subjects may receive additional study 
doses under continued supervision of the investigator in an appropriate setting.  Subjects who 
do not receive a study dose for >28 hours following their previous study dose should be 
considered off treatment, and should not receive further study dosing.  Subjects may 
continue to receive standard of care analgesics per the discretion of the investigator, except for 
medications which may interact with meloxicam or interfere with the objectives of the study, 
as defined in Section 5.12.     
Subjects will undergo safety assessments at the earlier of LSD+1 day or at the time of 
discharge prior to leaving the study center.   
3. Follow-up: 
Subjects will be provided routine standard of care for pain management after discharge from 
the study center.  All subjects will be asked to return to the study center at LSD+7 days to 
complete end of study assessments.  Subjects will complete a final safety assessment by 
telephone at LSD+28 days.   
Number of subjects to be enrolled:  It is planned to enroll approximately 700 subjects; 175 subjects to 
be randomized to placebo, and 525 subjects to be randomized to N1539 30 mg.   
Study enrollment will include a cohort of approximately 30-40 subjects meeting criteria as high risk 
subjects, defined as age > 65 years with a GFR of 60-89 mL/min/1.73 m2 (using MDRD equation). 
Number of study sites:  30-40 
Study country location:  United States, Canada, Australia, and New Zealand 
 


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SYNOPSIS (PAGE 4 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
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. Male or female 18 to 80 years of age, inclusive. 
3. Be planned to undergo major elective surgery, and be expected to require intravenous 
analgesia, remain in an inpatient setting for at least 24-48 hours, and are expected to receive at 
least two study doses. 
4. Female subjects are eligible only if all of the following apply: 
• 
Not pregnant (female subjects of child bearing potential must have a negative serum 
pregnancy test at screening and negative urine pregnancy test before surgery); 
• 
Not breastfeeding; 
• 
Not planning to become pregnant during the study through telephone follow-up (LSD+28 
days); 
• 
Commits to the use of an acceptable form of birth control for the duration of the study 
through telephone follow-up (LSD+28 days): OR 
o Be unable to become pregnant due to postmenopausal status or sterility of male partner 
while in a monogamous relationship; OR 
o Be in a monogamous relationship with a same sex partner with no intention of 
becoming pregnant through any means 
5. Have a body mass index ≤40 kg/m2  
6. Be able to understand the study procedures, comply with all study procedures, and agree to 
participate in the study program. 
7. For oncology cases all of the following criteria must be met:  
• 
Have a histologically confirmed diagnosis of a primary solid tumor, affecting any one of 
the following organs: breast, skin, colon, prostate, uterus, ovaries, urethra, penis, or vulva; 
AND  
• 
Based on clinical, laboratory, radiologic, pathologic, and surgical findings, the tumor is 
confined to the primary organ, without evidence of local, regional or distal spread; AND 
• 
Have a performance status such that they are able to carry on normal activities of daily life 
without limitations 


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SYNOPSIS (PAGE 5 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
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 meloxicam or any excipient of N1539, aspirin, or 
other non-steroidal anti-inflammatory drugs (NSAIDs). 
2. Be scheduled to undergo cranial surgery, open heart procedure, any type of coronary artery 
bypass graft, organ transplant, or any other surgical procedure in which NSAIDs are 
contraindicated. 
3. Planned or actual admission to the intensive care unit at any time during study participation. 
4. Have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of > 2X the 
upper limit of normal (ULN), alkaline phosphatase (AP) >1.5X ULN, or total bilirubin > 1.2X 
ULN, a prothrombin time (PT) > 20% above ULN, or any laboratory abnormality that would 
place the subject at increased risk for study participation according to the judgment of the 
investigator at screening and/or prior to surgery. 
5. Have a history of myocardial infarction within the preceding 12 months  
6. Have history of HIV, or hepatitis B or C at screening. 
7. 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. 
8. Have active or recent (within 6 months) gastrointestinal ulceration or bleeding 
9. Have a known bleeding disorder which may be worsened with the administration of a NSAID.  
10. Have evidence of a clinically significant 12 lead ECG abnormality according to the judgment 
of the investigator. 
11. Have a history of alcohol abuse (regularly drinks > 4 units of alcohol per day; 8 oz. beer, 3 oz. 
wine, 1 oz. spirits) or prescription/illicit drug abuse within the previous 5 years. 
12. Have positive results on the urine drug screen for cocaine or PCP, or alcohol breath test at 
screening, and/or prior to surgery.  


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SYNOPSIS (PAGE 6 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
Criteria for Exclusion (cont): 
13. Unable to discontinue medications, that have not been at a stable dose for at least 14 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. 
14. Be unable to discontinue herbal medications 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 
15. Be receiving lithium or a combination of furosemide with either an angiotensin converting 
enzyme inhibitor or an angiotensin receptor blocker  
16. Be currently receiving treatment with oral meloxicam (Mobic®) or another NSAID within 
7 days prior to surgery. 
17. Have received any investigational product within 30 days before dosing with study medication. 
18. Have previously received N1539 in clinical trials, or had 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 the  
LSD+28 visit. 
Post-Operative Randomization Criteria: 
Administration of Dose 1 should be completed within six hours of the end of surgery in subjects who 
meet the following criteria: 
1. Be able to achieve hemostasis and surgical incision closure, prior to Operating Room 
discharge.  
2. The surgical procedure did not require use of > 2 units of packed red blood cells or platelets. 
3. The surgical procedure from incision to closure was not longer than 12 hours. 
4. Subject is expected to have sufficient pain such that parenteral analgesia is clinically 
appropriate 
5. The subject has had no evidence of respiratory insufficiency, clinically significant hypotension, 
bradycardia, coagulopathy, or any other abnormality, during or following surgery that, in the 
investigator’s opinion, significantly increases the risks of study participation.  
Investigational product:  N1539 30 mg 
Reference therapy:  Placebo 


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SYNOPSIS (PAGE 7 OF 7) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-15-017 
Name of Study Drugs:   
Injectable NanoCrystal Colloidal 
Dispersion (NCD) Meloxicam (N1539) 
Protocol Title:  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Evaluation of the Safety 
of N1539 Following Major Surgery 
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3 
Duration of treatment:  Each subject is expected to receive at least two study doses during the 
treatment phase of the study, with additional doses administered every 24±1 hours from Hour 0 until 
discharge, until IV analgesia is no longer clinically appropriate, or until they have received 7 study 
doses.  A final study dose may be administered up to 4 hours early in subjects who are scheduled to be 
discharged.  When inpatient care is no longer required, subjects may receive additional study doses 
under continued supervision of the investigator in an appropriate setting.  Subjects who do not receive a 
study dose for >28 hours following their previous study dose should be considered off treatment, and 
not receive further study dosing.  Subjects will remain in the study center from the day of surgery (Day 
1) to at least 24 hours after randomization (Day 2) or when appropriate for discharge.  Subjects will be 
asked to return at LSD+7 days to complete end of study assessments, with a safety follow-up by phone 
at LSD+28. 
Criteria For Evaluation 
Safety:  
The safety endpoints will include the following: 
1) incidence of AEs and SAEs 
2) change from baseline in laboratory tests; incidence of abnormal clinical laboratory tests, 
including routine blood chemistry, hematology, coagulation tests, and urinalysis 
3) change from baseline in vital signs; incidence of clinically significant changes in vital signs 
4) incidence of clinically significant abnormal ECG findings 
5) incidence of abnormal wound healing 
6) total opioid consumption during 0-24, 24-48, and 0-48 hours post first dose of study drug 
Statistical methods: 
Sample size determination:  The sample size for this study was selected to support the required total 
exposure population for N1539. 
Study populations:   
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include all subjects who qualify for treatment 
following surgery.  The ITT subjects may or may not receive treatment.  
Safety Analysis Set:  The safety analysis set will include all subjects treated with study drug in the 
study.  
Safety analysis:  The Medical Dictionary for Regulatory Activities (Version 18 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 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 ECG findings will be summarized at each time point by treatment group.  
Safety data may be summarized by surgery type if data warrant.   


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TABLE OF CONTENTS 
SYNOPSIS (PAGE 1 OF 7) ............................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
INTRODUCTION ......................................................................................................16 
2. 
STUDY OBJECTIVE .................................................................................................17 
3. 
INVESTIGATIONAL PLAN .....................................................................................18 
3.1. 
Overall Study Design ..................................................................................................18 
3.2. 
Rationale for Study Design and Control Groups ........................................................19 
4. 
STUDY POPULATION .............................................................................................20 
4.1. 
Inclusion Criteria ........................................................................................................20 
4.2. 
Exclusion Criteria .......................................................................................................21 
4.3. 
Postoperative Randomization Criteria ........................................................................22 
4.4. 
Discontinuation of Subjects ........................................................................................22 
4.4.1. 
Procedures for Withdrawal .........................................................................................22 
4.4.2. 
Replacement of Subjects .............................................................................................22 
4.5. 
Lifestyle Guidelines ....................................................................................................23 
4.5.1. 
Confinement ...............................................................................................................23 
4.5.2. 
Diet .............................................................................................................................23 
5. 
TREATMENTS ..........................................................................................................24 
5.1. 
Surgical Procedure and Perioperative Care ................................................................24 
5.2. 
Administration of Study Medication ..........................................................................24 
5.3. 
Identity of Study Medication ......................................................................................24 
5.4. 
Method of Assigning Subjects to Treatment Groups .................................................25 
5.5. 
Selection of Doses ......................................................................................................25 
5.6. 
Selection of Timing of Dose .......................................................................................25 
5.7. 
Blinding and Unblinding of Study Medications .........................................................25 
5.8. 
Treatment Compliance ................................................................................................26 
5.9. 
Drug Accountability ...................................................................................................26 
5.10. 
Packaging, Labeling, and Storage ..............................................................................26 
5.11. 
Prior and Concomitant Medications ...........................................................................26 
5.12. 
Prohibited Medications ...............................................................................................26 
5.13. 
Concomitant Interventions and Procedures ................................................................27 


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5.14. 
Rescue Medication ......................................................................................................27 
6. 
STUDY PROCEDURES ............................................................................................28 
6.1. 
Demographic Assessments .........................................................................................28 
6.1.1. 
Demographics .............................................................................................................28 
6.1.2. 
Medical History ..........................................................................................................28 
6.1.3. 
Physical Examination .................................................................................................28 
6.2. 
Safety Assessments Description .................................................................................28 
6.2.1. 
Clinical Laboratory Tests ...........................................................................................28 
6.2.2. 
Vital Sign Measurements ............................................................................................29 
6.2.3. 
12-Lead Electrocardiogram (ECG) .............................................................................29 
6.2.4. 
Wound Evaluation ......................................................................................................29 
6.3. 
Assessments by Visit ..................................................................................................30 
6.3.1. 
Screening Visit ............................................................................................................30 
6.3.2. 
Day 1 (Check-In) ........................................................................................................30 
6.3.3. 
Day 1 (Randomization) ...............................................................................................31 
6.3.4. 
Treatment Phase - Day 1 to Discharge (Up to Day 7) ................................................31 
6.3.5. 
LSD+1 Day / Discharge..............................................................................................31 
6.3.6. 
Follow-Up Visit (LSD+7 Days ± 2) ...........................................................................31 
6.3.7. 
Follow-Up Telephone Contact (LSD+28 Days ± 4) ...................................................32 
6.4. 
Appropriateness of Assessments ................................................................................32 
6.5. 
Clinical Stopping Rules ..............................................................................................32 
7. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS 
SUSPECTED ADVERSE REACTIONS ...................................................................33 
7.1. 
Definition of an Adverse Event ..................................................................................33 
7.2. 
Definition of a Serious Adverse Event .......................................................................34 
7.2.1. 
Serious Adverse Events That Occur After Study Completion ...................................34 
7.3. 
Definition of a Suspected Adverse Reaction (SAR) ...................................................34 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR) ...................................34 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events ..................35 
7.5.1. 
Assessment of Intensity ..............................................................................................35 
7.5.2. 
Assessment of Causality .............................................................................................35 
7.5.3. 
Assessment of Outcome .............................................................................................36 
7.5.4. 
Assessment of Expectedness ......................................................................................36 


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7.6. 
Follow-up of Adverse Events and Serious Adverse Events .......................................36 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor ....................................37 
7.8. 
Regulatory Reporting Requirements ..........................................................................38 
7.9. 
Precautions ..................................................................................................................38 
8. 
STATISTICAL METHODOLOGY ...........................................................................39 
8.1. 
Determination of Sample Size ....................................................................................39 
8.2. 
Study Endpoints ..........................................................................................................39 
8.2.1. 
Safety Endpoints .........................................................................................................39 
8.3. 
General Considerations for Statistical Analysis .........................................................39 
8.3.1. 
Analysis Datasets ........................................................................................................39 
8.3.2. 
Test Hypothesis and P Value Justification .................................................................39 
8.3.3. 
Procedures for Handling Missing Data .......................................................................39 
8.3.4. 
Definitions for Assessment Windows ........................................................................40 
8.4. 
Study Population Summaries ......................................................................................40 
8.4.1. 
Disposition ..................................................................................................................40 
8.4.2. 
Demographics and Surgery Characteristics ................................................................40 
8.4.3. 
Protocol Violations .....................................................................................................40 
8.4.4. 
Treatment Compliance ................................................................................................40 
8.4.5. 
Prior and Concomitant Medications ...........................................................................40 
8.5. 
Safety and Tolerability Evaluations ............................................................................41 
8.5.1. 
Extent of Exposure .....................................................................................................41 
8.5.2. 
Adverse Events ...........................................................................................................41 
8.5.3. 
Clinical Laboratory Tests ...........................................................................................41 
8.5.4. 
Vital Sign Measurements ............................................................................................41 
8.5.5. 
Electrocardiograms .....................................................................................................41 
8.5.6. 
Wound Evaluation ......................................................................................................42 
8.5.7. 
Subgroup Analyses for Safety Endpoints ...................................................................42 
9. 
STUDY ADMINISTRATION ...................................................................................43 
9.1. 
Regulatory and Ethical Considerations ......................................................................43 
9.1.1. 
Regulatory Authority Approval ..................................................................................43 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................43 
9.1.3. 
Informed Consent .......................................................................................................44 
9.1.4. 
Investigator Reporting Requirements .........................................................................45 


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9.2. 
Study Monitoring ........................................................................................................45 
9.3. 
Quality Assurance .......................................................................................................45 
9.4. 
Study and Site Closure................................................................................................45 
9.5. 
Records Retention .......................................................................................................46 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996....................................46 
9.5.2. 
Financial Disclosure ...................................................................................................46 
9.5.3. 
Access to Original Records ........................................................................................46 
9.5.4. 
Archiving of Study-Related Documents .....................................................................46 
9.6. 
Provision of Study Results and Information to Investigators .....................................47 
9.7. 
Information Disclosure and Inventions ......................................................................47 
9.7.1. 
Ownership ...................................................................................................................47 
9.7.2. 
Confidentiality ............................................................................................................47 
9.7.3. 
Publication ..................................................................................................................47 
9.7.4. 
Data Management .......................................................................................................48 
9.7.5. 
Data Security ..............................................................................................................48 
9.8. 
Subject Tracking .........................................................................................................48 
10. 
REFERENCES ...........................................................................................................49 
APPENDIX A. OVERVIEW OF STUDY SCHEDULE ............................................................50 
APPENDIX B. INVESTIGATOR OBLIGATIONS ..................................................................51 
APPENDIX C. STUDY-SPECIFIC INFORMATION ...............................................................53 
Appendix C.1: Surgical Wound Status Assessment ....................................................................53 
APPENDIX D. BMI CALCULATION ......................................................................................54 
APPENDIX E. MDRD CALCULATION ..................................................................................55 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
BMI 
body mass index 
BP 
Blood Pressure 
BPM 
Beats per minute 
BSA-CF 
body-surface-area conversion factor 
CFR 
(United States) Code of Federal Regulations 
ºC 
degrees Centigrade 
CL 
Clearance 
eCRF 
Electronic case report form 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
ºF 
degrees Fahrenheit 
FOCBP 
Female subject of childbearing potential 
G 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
H 
Hour 
HCl 
Hydrochloride 
HR 
Heart Rate 
HREC 
Human Research Ethics Committee 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LSD 
Last study dose 
m2 
square meters 
MDRD 
Modification of Diet in Renal Disease 
Mg 
Milligram 
Min 
Minute 


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Abbreviation 
Definition 
mL 
Milliliter 
mm Hg 
millimeters of mercury 
NCD 
NanoCrystal Colloidal Dispersion 
NF 
National Formulary 
NSAID 
Nonsteroidal anti-inflammatory drug 
pH 
negative log of hydrogen ion concentration 
REB 
Research Ethics Board 
SAR 
suspected adverse reaction 
SAE 
serious adverse event 
SBP 
Systolic Blood Pressure 
SL 
Sublingual 
SPID 
Summed PID 
SpO2 
peripheral oxygen saturation 
SSAR 
Serious suspected adverse reaction 
SUSAR 
Serious unexpected suspected adverse reaction 
UDS 
Urine Drug Screen 
µg 
Microgram 
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® 2012).  
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 
This study is designed to evaluate the safety of dosing with IV N1539 in a range of surgical 
procedures with subjects experiencing postoperative pain.     
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 N1539 as 
evaluated with physical examination, vital signs, clinical laboratory tests, ECGs, wound 
evaluation, postoperative opioid consumption, and incidence of Adverse Events (AEs) and 
Serious AEs (SAEs). 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, evaluation of the 
safety of N1539 in adult subjects undergoing major surgery.  The study will enroll approximately 
700 subjects. 
Adult subjects, age 18 to 80 years inclusive, requiring major surgery that is expected to result in 
inpatient hospitalization for at least 24-48 hours, will be screened for participation at 30-40 study 
sites in North America, Australia, and New Zealand.  Screening will occur within 28 days before 
study drug administration.  After signing the informed consent, medical history, physical 
examination, baseline laboratory testing, 12-lead electrocardiogram (ECG), pregnancy testing, 
and vital sign measurements will be completed during the screening visit. 
Study enrollment will include a cohort of approximately 30-40 subjects meeting criteria as  
high risk subjects, defined as age > 65 years with a glomerular filtration rate (GFR) of 
60-89 mL/min/1.73 m2, as calculated using the Modification of Diet in Renal Disease (MDRD) 
equation (Appendix E).   
On the day of surgery (Day 1), subjects will undergo surgical procedure.  Following surgery, 
subjects will be evaluated to ensure their eligibility for randomization within six hours after 
surgery.  Eligible subjects will be randomized and treated with study drug for at least two study 
doses and will stay at the study center for at least 24-48 hours after treatment initiation or so long 
as inpatient care is clinically appropriate.  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 time of discharge.   
All treated subjects will be followed through 28 days following LSD.  All subjects will return to 
the study center to complete end of study assessments 7 days post-LSD (LSD+7), with a 
telephone safety follow-up 28 days post-LSD (LSD+28). 
Safety assessments will include monitoring of AEs, clinical laboratory tests, opioid consumption, 
vital sign measurements, wound evaluation, and ECGs. 
The following summarizes key activities for each phase of this study: 1) Pretreatment Phase, 
2) Treatment Phase, 3) Follow-up.   
1. Pretreatment Phase: 
a. Screening Period (Day -28 to Day -1):  Subjects will be consented and screened. 
b. Day of Surgery (Day 1):  
1) Pre-surgery:  Subjects will be admitted to the site and reassessed for 
eligibility for the study.  Pre-surgery activities will be conducted. 
2) Surgery:  Eligible subjects will undergo surgery using an appropriate 
anesthetic regimen according to the type of surgery. 
3) Postoperative Period:  Following surgery, subjects will be evaluated for 
eligibility for treatment. 


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c. Randomization Qualification (Day 1):  Subjects will be eligible for randomization 
and study dosing if/when they meet all of the postoperative randomization criteria 
within six hours after surgery (Section 4.3).   
2. Treatment Phase (Hour 0 through Discharge) 
Once the subject meets postoperative randomization eligibility criteria, they will be 
randomized in a 3:1 ratio to IV treatment with N1539 30 mg or placebo, administered 
every 24 hours (±1 hour).   
The time of first dose of study drug (Dose 1) will be recorded as Hour 0.  Subjects will be 
administered a study dose according to their randomization every 24 hours (from Hour 0) 
so long as IV analgesia is clinically appropriate or until they receive a maximum of 7 
study doses.  A final study dose may be administered up to 4 hours early in subjects who 
are scheduled to be discharged.  When inpatient care is no longer required, subjects may 
receive additional study doses under continued supervision of the investigator in an 
appropriate setting.  Subjects who do not receive a study dose for >28 hours following 
their previous study dose should be considered off treatment, and not receive further 
study dosing.  Subjects may continue to receive standard of care analgesics per the 
discretion of the investigator, except for medications which may interact with meloxicam 
or interfere with the objectives of the study, as defined in Section 5.12.     
Subjects will undergo safety assessments at the earlier of LSD+1 day or at the time of 
discharge prior to leaving the study center. 
3. Follow-up: 
Subjects will be provided routine standard of care for pain management after discharge 
from the study center.  All subjects will be asked to return to the study center at LSD+7 
days to complete end of study assessments.  Subjects will complete a final safety 
assessment by telephone at LSD+28 days. 
3.2. 
Rationale for Study Design and Control Groups 
This study will evaluate the safety of repeated dosing with N1539 administered following a 
range of major surgical procedures.  Previous research has demonstrated the safety and efficacy 
of single and repeated doses of N1539 when administered IV in pharmacokinetic studies and 
after open and laparoscopic abdominal surgeries.  Previous postoperative studies have identified 
30 and 60 mg doses of N1539 as efficacious in comparison to placebo and active control groups.  
However, differences in efficacy between the 30 and 60 mg N1539 dose levels have not been 
consistently observed.  As a result, the 30 mg dose of N1539 has been selected for additional 
safety and efficacy evaluation.  
This study will further explore the safety of dosing with N1539 30 mg IV on a once daily 
schedule in a population of subjects with pain following major surgery.   


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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. Male or female 18 to 80 years of age, inclusive. 
3. Be planned to undergo major elective surgery, and be expected to require intravenous 
analgesia, remain in an inpatient setting for at least 24-48 hours, and are expected to 
receive at least two study doses. 
4. Female subjects are eligible only if all of the following apply: 
• Not pregnant (female subject of child bearing potential must have a negative serum 
pregnancy test at screening and negative urine pregnancy test before surgery); 
• Not breastfeeding; 
• Not planning to become pregnant during the study through telephone follow-up 
(LSD+28 days); 
• Commit to the use of an acceptable form of birth control for the duration of the study 
through telephone follow-up (LSD+28 days); OR 
o Be unable to become pregnant due to postmenopausal status or sterility of 
male partner while in a monogamous relationship; OR 
o Be in a monogamous relationship with a same sex partner with no intention of 
becoming pregnant through any means 
5. Have a body mass index ≤40 kg/m2  
6. Be able to understand the study procedures, comply with all study procedures, and agree 
to participate in the study program. 
7. For oncology cases all of the following criteria must be met:  
• Have a histologically confirmed diagnosis of a primary solid tumor, affecting any one 
of the following organs: breast, skin, colon, prostate, uterus, ovaries, urethra, penis, or 
vulva; AND  
• Based on clinical, laboratory, radiologic, pathologic, and surgical findings, the tumor 
is confined to the primary organ, without evidence of local, regional or distal spread 
at any time during study participation; AND 
• Have a performance status such that they are able to carry on normal activities of 
daily life without limitations 


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4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the study: 
1. Have a known allergy or hypersensitivity to meloxicam or any excipient of N1539, 
aspirin, or other non-steroidal anti-inflammatory drugs (NSAIDs). 
2. Be scheduled to undergo cranial surgery, open heart procedure, any type of coronary 
artery bypass graft, organ transplant, or any other surgical procedure in which NSAIDs 
are contraindicated. 
3. Planned or actual admission to the intensive care unit at any time during study 
participation 
4. Have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of > 2X the 
upper limit of normal (ULN), alkaline phosphatase (AP) >1.5X ULN, or total bilirubin > 
1.2X ULN, a prothrombin time (PT) >20% above ULN, or any laboratory abnormality 
that would place the subject at increased risk for study participation according to the 
judgment of the investigator at screening and/or prior to surgery. 
5. Have a history of myocardial infarction within the preceding 12 months  
6. Have history of HIV, or hepatitis B or C at screening. 
7. 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 in the study. 
8. Have active or recent (within 6 months) gastrointestinal ulceration or bleeding. 
9. Have a known bleeding disorder which may be worsened with the administration of a 
NSAID. 
10. Have evidence of a clinically significant 12 lead ECG abnormality according to the 
judgment of the investigator. 
11. Have a history of alcohol abuse (regularly drinks > 4 units of alcohol per day; 8 oz. beer, 
3 oz. wine, 1 oz. spirits) or a history of prescription/illicit drug abuse within the previous 
5 years. 
12. Have positive results on the urine drug screen for cocaine or PCP, or alcohol breath test 
at screening, and/or prior to surgery.  
13. Unable to discontinue medications, that have not been at a stable dose for at least 14 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 
14. Be unable to discontinue herbal medications 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 
15. Be receiving lithium or a combination of furosemide with either an angiotensin 
converting enzyme inhibitor or an angiotensin receptor blocker. 


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16. Be currently receiving treatment with oral meloxicam (Mobic®) or another NSAID 
within 7 days prior to surgery. 
17. Have received any investigational product within 30 days before dosing with study 
medication. 
18. Have previously received N1539 in clinical trials, or had 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 within 60 days prior to screening, through the LSD+28 visit 
4.3. 
Postoperative Randomization Criteria 
Administration of Dose 1 should be completed within six hours of the end of surgery in subjects 
who meet the following criteria: 
1. Be able to achieve hemostasis and surgical incision closure, prior to Operating Room 
discharge.  
2. The surgical procedure did not require use of > 2 units of packed red blood cells or 
platelets. 
3. The surgical procedure from incision to closure was not longer than 12 hours. 
4. Subject is expected to have sufficient pain such that parenteral analgesia is clinically 
appropriate. 
5. The subject has had no evidence of respiratory insufficiency, clinically significant 
hypotension, bradycardia, coagulopathy, or any other abnormality, during or following 
surgery that, in the investigator’s opinion, significantly increases the risks of study 
participation.  
4.4. 
Discontinuation of Subjects 
4.4.1. 
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 the 
LSD+7 visit and to agree to be followed through 28 days after receiving study medication.   The 
date the subject is withdrawn and the primary reason for discontinuation will be recorded in the 
subject’s electronic case report form (eCRF). 
4.4.2. 
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 700 subjects in the safety population for 
evaluation. 


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4.5. 
Lifestyle Guidelines 
4.5.1. 
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.  Following the 
surgical procedure, qualifying subjects will be randomized and should initiate dosing with study 
drug on the day of surgery (Day 1) within six hours after surgery.  Subjects may continue to 
receive study drug every 24 hours so long as IV analgesia is clinically appropriate or until they 
receive a maximum of 7 study doses.  When inpatient care is no longer required, subjects may receive 
additional study doses under continued supervision of the investigator in an appropriate setting.  Subjects 
may be discharged from the study center when appropriate based on clinical status.    
Subjects will follow standard postoperative care instructions after discharge. 
4.5.2. 
Diet 
Subjects must not consume any poppy seeds within 48 hours prior to confinement, or any alcohol 
within 24 hours before or during the inpatient period.  


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5. 
TREATMENTS 
5.1. 
Surgical Procedure and Perioperative Care 
On Day 1, day of surgery, subjects will undergo major elective surgery, which may include, but 
is not limited to, open or laparoscopic abdominal or gynecological surgeries, or total hip or knee 
replacement.   
Disallowed surgical procedures for inclusion in this study include cranial surgeries, open heart 
procedures, any type of coronary artery bypass, organ transplant, and/or any other surgical 
procedure in which NSAIDs are contraindicated. 
Surgeries should be completed using an appropriate anesthesia and analgesic regimen according 
to the clinical practice of the surgeon based on the surgery type.  Disallowed medications are 
described in Section 5.12. 
Venous thromboembolism prophylaxis before and after surgery will be administered according 
to standard practice for the surgical procedure based on the patients individual needs, and at the 
discretion of the investigator and surgeon, taking into consideration known drug interactions and 
contraindications with NSAIDs. 
5.2. 
Administration of Study Medication 
Unblinded study personnel will prepare and administer all doses of study drug according to the 
treatment schedule.  All study doses will be administered as an IV bolus over 15-30 seconds.  If 
infusion over 15-30 seconds is not tolerated, the bolus may be administered over up to 2 minutes; 
stop and start time of IV push should be recorded in the subject’s eCRF.  Because the appearance 
of N1539 does not match the appearance of placebo, drug administration will be done in an 
appropriately blinded fashion so that the subjects, and other blinded study staff, will not be aware 
of the treatment administered. 
Each subject is expected to receive at least two study doses during the treatment phase of the 
study, with additional doses administered every 24±1 hours from Hour 0 until discharge, until IV 
analgesia is no longer clinically appropriate, or until they have received 7 study doses.  A final 
study dose may be administered up to 4 hours early in subjects who are scheduled to be 
discharged.  When inpatient care is no longer required, subjects may receive additional study 
doses under continued supervision of the investigator in an appropriate setting.   
The time of first administered study dose will be considered Hour 0. 
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 include:  dextrose and water for injection.  


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5.4. 
Method of Assigning Subjects to Treatment Groups 
A computer generated block randomization scheme will be prepared prior to study initiation.  
Subjects will be randomly assigned to treatment with N1539 30 mg or placebo in a 3:1 
assignment ratio according to the randomization scheme.  Randomization will be stratified by 
risk status (high risk [age > 65 years with GFR 60-89 mL/min/1.73 m2] vs. other) and surgery 
type (orthopedic vs. other surgeries), non-high risk subjects will further be stratified by study 
center.  All study doses 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 five previous clinical studies.  Clinical studies have evaluated doses of N1539 ranging 
from 5 to 60 mg.  Study N1539-02 demonstrated the analgesic efficacy of a single dose of N1539 
at 15, 30 and 60 mg administered following third molar extraction.  All three dose levels of 
N1539 resulted in a SPID24 value that was statistically superior to placebo.  The SPID24 value for 
the 60 mg dose of N1539 was also statistically significantly greater than that of the 15 or 30 mg 
doses of N1539.  In a subsequent study of 460 female subjects undergoing open abdominal 
hysterectomy (Study N1539-04), subjects were randomized to N1539 doses of 5, 7.5, 15, 30, or 
60 mg, as well as an active control arm (morphine) or placebo.  All N1539 dose levels showed 
statistically significant improvement compared to placebo in SPID24 results.  However, in this 
study, the LS mean SPID24 value for the 30 mg N1539 was numerically greater than that of the 
60 mg dose.  A third study of N1539 was conducted in subject undergoing laparoscopic 
abdominal surgery with doses of 7.5 or 15 mg every 12 hours, or 30 mg once daily, compared to 
placebo (Study N1539-05).  This study was discontinued early and efficacy analyses were not 
completed.  All study doses were well tolerated in these studies, and there was no evidence of 
any dose related safety concerns.   
The current study has been planned to evaluate the safety of the 30 mg dose level of N1539 in a 
range of postoperative subjects.     
5.6. 
Selection of Timing of Dose 
Qualified subjects will be administered study doses every 24 hours for a minimum of 2 study 
doses, and up to a maximum of 7 doses.  This interval has been evaluated to maintain consistent 
levels of analgesia.  The 24-hour dosing interval has been selected based on the pain relief and 
pharmacokinetic profile of N1539 established in previous clinical studies.  The exact start and 
stop time each dose is administered will be recorded in the subject’s eCRF.   
5.7. 
Blinding and Unblinding of Study Medications 
All doses administered in this study will be administered by an unblinded staff member.  Study 
doses will be prepared by the designated unblinded and appropriately qualified member(s) of the 
healthcare team at the research center, for administration according to the subject’s 
randomization sequence.   
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 


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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 
Unblinded 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.   
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 non-blinded, study labeled packaging for preparation by an 
unblinded study pharmacist for use in this study.   
N1539 will be provided in 1 mL, single use vials containing 30 mg meloxicam per vial.   
Placebo will be provided in 1 mL, 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 dosing 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 
surgical 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. 
5.12. 
Prohibited Medications 
The following medications or drug classes will be prohibited during the treatment phase of the 
study: 


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• Any NSAIDs (ketorolac, ibuprofen) 
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 treatment phase, pain symptoms that are not adequately controlled by dosing with 
study drug, may be treated according to the standard practice of the investigator except for use of 
NSAIDs.  All doses of analgesic medications should be recorded in the subject’s eCRF. 
Once discharged, subjects may utilize analgesics according to the standard practice of the 
investigator. 


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6. 
STUDY PROCEDURES 
A schedule of study procedures for overall study assessments and day-of-dosing assessments is 
provided in Appendix A. 
Study procedures should be completed within a window of ±15 minutes unless otherwise stated.  
6.1. 
Demographic Assessments 
6.1.1. 
Demographics  
Demographics information will be collected during screening visit including age, sex, ethnicity, 
race, weight, height, and BMI.  The type of surgery required will also be collected. 
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 LSD+1/prior to discharge, and at the follow-up visit (LSD+7 days).  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. 
6.2. 
Safety Assessments Description  
6.2.1. 
Clinical Laboratory Tests 
During the screening visit, on Day 1 during check-in (if greater than 14 days since screening labs 
or if screening labs were not performed at the central laboratory), Hour 48 ± 4 hours, at 
LSD+1/prior to discharge (if prior to Hour 48, or to be repeated in subjects who receive ≥ 4 
doses), and at the follow-up visit (LSD+7 days), subjects will have blood and urine samples 
collected for routine clinical laboratory testing as follows: 
• hematology:  complete blood count consisting of white blood cell (WBC) and red blood 
cell count, platelet count, hemoglobin, hematocrit, and differential counts (total 
neutrophils, eosinophils, basophils, lymphocytes, and monocytes) 
• clinical chemistry tests:  urea, glucose, creatinine, sodium, potassium, chloride, 
bicarbonate, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total bilirubin, direct bilirubin, gamma-glutamyltransferase, lactate dehydrogenase, 


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calcium, total protein, magnesium, phosphate, albumin, cholesterol, triglycerides, and 
uric acid 
• urinalysis:  pH, protein, specific gravity, glucose, ketones, blood, white blood cell 
esterase, nitrites, and urobilinogen; microscopic examination will be performed only if 
dip stick is positive for blood or leukocytes unless otherwise specified  
• coagulation tests:  prothrombin time, activated partial thromboplastin time, international 
normalized ratio  
Additional urine or blood samples will be collected and tested as follows: 
• urine drug screen (UDS) and alcohol breath test at the screening visit, and during 
admission to the study center on Day 1.  Urine drug screen will include screening of (at 
minimum): cocaine and phencyclidine (PCP). 
• serum pregnancy testing at the screening visit, and urine pregnancy testing at check-in on 
Day 1 for FOCBP.  
Screening laboratory results, and Day 1 urine drug and urine pregnancy results, will be used for 
assessing eligibility for randomization.  Clinical laboratory tests done on Day 1 prior to surgery 
will be used as baseline reference and not for assessing study randomization eligibility. 
6.2.2. 
Vital Sign Measurements 
Resting vital signs will include resting blood pressure, resting pulse, and peripheral oxygen 
saturation (SpO2).  Resting tests must be obtained after resting (seated/supine) for ≥ 5 minutes.    
At screening and on Day 1 prior to surgery, resting vital signs will be collected.  Vital signs will 
also be collected prior to the first two study doses, at LSD+1/prior to discharge, and at the 
follow-up visit (LSD+7 days).  Predose vital signs will be collected within 15 minutes prior to 
dosing.   
Actual times will be recorded for all events, and any deviation outside the specified ranges must 
be clearly documented in the subject’s study records.   
6.2.3. 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be completed for all subjects at screening, at check-in on Day 1 (if screening 
ECG was done >14 days prior to Day 1), at LSD+1/prior to discharge, at the follow-up visit 
(LSD+7 days), and at time of early discontinuation.  At the Screening Visit, 12-lead ECG will be 
used to exclude subjects with a clinically significant abnormal ECG. 
The findings (i.e., classification as “normal”, “abnormal not clinically significant” or “abnormal 
clinically significant”) will be recorded in the subject’s eCRF.  No interval measurements will be 
collected, and the ECG tracings will not be collected for Data Management. 
6.2.4. 
Wound Evaluation 
Surgical wound healing will be evaluated by the investigator at LSD+1/prior to discharge, and at 
the follow-up visit (LSD+7 days).   


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Wound evaluation will be performed at LSD+1/prior to discharge and at the follow-up visit 
(LSD+7 days) 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”.   
At the LSD+7 visit, the surgical wound healing status, and incidence of hematoma formation, 
will be evaluated according to the criteria defined in Appendix C.1. 
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 6.1.2) 
• Physical examination including height, weight and BMI (Section 6.1.3) 
• Measurement of resting vital signs (Section 6.2.2) 
• 12-lead ECG (Section 6.2.3) 
• Clinical laboratory tests (Section 6.2.1) 
• Drug and alcohol screen (Section 6.2.1) 
• Serum pregnancy test (FOCBP only; Section 6.2.1) 
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) 
• Measurement of resting vital signs (Section 6.2.2) 
• 12-lead ECG (if screening ECG was >14 days prior to Day 1) (Section 6.2.3) 
• Clinical laboratory tests  (required if greater than 14 days since screening labs or if 
screening labs were not performed at the central laboratory; Section 6.2.1) 
• Drug and alcohol screen (Section 6.2.1) 
• Urine pregnancy test (FOCBP only; Section 6.2.1) 
Subjects who continue to meet eligibility criteria will undergo surgical procedure per 
Section 5.1. 


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6.3.3. 
Day 1 (Randomization) 
The following assessments will be conducted on Day 1 following surgery, prior to administration 
of Dose 1 (Hour 0) for all subjects while confined at the study clinic: 
• Qualification, if subject meets eligibility criteria (Section 4.3) 
• Measurement of resting vital signs before Dose 1 (Section 6.2.2)  
6.3.4. 
Treatment Phase - Day 1 to Discharge (Up to Day 7) 
The following assessments/procedures will be conducted during the treatment phase on Day 1 
through discharge beginning with administration of the first study dose (Dose 1; Hour 0) for all 
subjects while confined at the study clinic: 
• Study drug administration  
• Clinical laboratory tests (Hour 48 ± 4 hours; Section 6.2.1) 
• Measurement of resting vital signs (Section 6.2.2)  
• Monitoring of AEs and concomitant medication (Section 7) 
6.3.5. 
LSD+1 Day / Discharge  
The following assessments will be conducted for all subjects at the earlier of LSD+1 day, or 
prior to discharge from the study center (including early termination): 
• Physical examination (Section 6.1.3) 
• Clinical laboratory tests (to be repeated in subjects who receive ≥ 4 doses; Section 6.2.1) 
• Measurement of resting vital signs (Section 6.2.2) 
• 12-lead ECG (Section 6.2.3) 
• Wound evaluation (Section 6.2.4) 
• Monitoring of AEs and concomitant medication (Section 7) 
6.3.6. 
Follow-Up Visit (LSD+7 Days ± 2)  
The following procedures will be conducted for all subjects during the follow-up visit. 
• Physical examination (Section 6.1.3) 
• Clinical laboratory tests (Section 6.2.1) 
• 12-lead ECG (Section 6.2.3) 
• Measurement of vital signs (Section 6.2.2) 
• Wound evaluation (Section 6.2.4) 
• Monitoring of AEs and concomitant medications (Section 7) 


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6.3.7. 
Follow-Up Telephone Contact (LSD+28 Days ± 4) 
The following procedures will be conducted during the follow-up telephone contact: 
• Monitoring of AEs and concomitant medications (Section 7) 
6.4. 
Appropriateness of Assessments 
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, SERIOUS ADVERSE EVENTS, AND 
SERIOUS SUSPECTED ADVERSE REACTIONS 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE, SAE, or Serious Suspected Adverse Reaction (SSAR) 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 medication, whether or not 
considered causally associated with the use of the study medication.  Any abnormal laboratory 
value deemed clinically significant by the investigator, regardless of causal relationship, must be 
reported as an AE beginning after administration of study medication. 
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 (e.g., 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 medication 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 (e.g., 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 or seriousness, will be assessed and recorded in the eCRF beginning after 
administration of study medication through 28 days after the last study dose.  SAEs will be 
assessed and recorded after administration of study medication through 28 days after the last 
study dose (see Sections 7.2 and 7.3).   


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7.2. 
Definition of a Serious Adverse Event 
An SAE is defined as any event that meets the following criteria: 
• It results in death or is life-threatening (i.e., presents an immediate risk of death from the 
event as it occurred).  (This criterion is not intended to include an AE that, had it 
occurred in a more severe form, might have caused death.) 
• It results in persistent or substantial disability or incapacitation.  (This criterion is not 
intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, diarrhea, or sprained ankle.) 
• It results in hospitalization. 
• It results in prolongation of an existing hospitalization. 
• It is a congenital anomaly or birth defect. 
• It requires medical or surgical intervention to prevent any of the above outcomes. 
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 intervention to 
prevent any of the other outcomes listed.  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 an 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 
an SAE. 
7.2.1. 
Serious Adverse Events That Occur After Study Completion 
If an investigator becomes aware of an SAE or death that occurs in a subject more than 30 days 
after the subject receives study medication and that investigator considers the event to be related 
to the study medication, the investigator is obligated to report the SAE to the sponsor. 
7.3. 
Definition of a Suspected Adverse Reaction (SAR) 
A SAR is defined as any adverse event for which there is a reasonable possibility that the 
adverse event was caused by the study drug.  For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug 
and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug. 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR) 
A SSAR is any Suspected Adverse Reaction (SAR) that is determined to be serious, based on the 
outcomes of a SAE described in Section 7.2; i.e. death, life-threatening, causes or prolongs 


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inpatient hospitalization, causes a persistent of significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital abnormality/birth defect. 
7.5. 
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. 
7.5.1. 
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 
• 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 an 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). 
7.5.2. 
Assessment of Causality 
The investigator is obligated to use his or her clinical judgment to assess the relationship 
between the study medication and the occurrence of each AE or SAE.  The investigator will 
assess the relationship to the study medication by using the following criteria: 
• Definitely Related:  An AE has a strong temporal relationship to the study drug.  The AE 
is most likely explained by study drug.  Dechallenge and rechallenge (if possible) are 
positive.  The AE is consistent with a known response to the study drug.  Another 
etiology is unlikely or significantly less likely. 
• Probably Related:  An AE has a strong temporal relationship to the study drug.  The AE 
is more likely explained by study drug than by another cause.  Dechallenge (if 
performed) is positive. 
• Possibly Related:  An AE has a reasonable temporal relationship to study drug.  The AE 
could have been due to another equally likely cause.  Dechallenge is positive. 
• Not Related:  The subject did not receive the study drug OR the AE has no temporal 
relationship to study drug OR the AE has a much more likely alternate etiology OR the 
AE is due to an underlying or concurrent illness or effect of another drug. 


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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. 
7.5.3. 
Assessment of Outcome 
All 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 by using the following terms: 
• Resolved:  The event resolved or the subject recovered without sequelae.  An event 
(either serious or nonserious) occurred and had an endpoint, and the subject experienced 
no restrictions.  Examples include stent placement for coronary artery disease (a device 
implanted is not a sequela), an appendectomy (a scar is not a sequela), a postoperative 
wound infection, or an upper respiratory tract infection. 
• Resolved with sequelae:  The event has at least one secondary outcome that may result 
in permanent disability, functional limitation, or both.  Such sequelae are usually limited 
to SAEs.  Examples include hip replacement resulting in foot drop (foot drop is not the 
intended outcome but is a risk of surgery), stroke resulting in paralysis, or emboli 
formation after a bacterial infection resulting in a renal infarct and loss of renal function. 
• Not resolved:  At the end of the study, a nonserious event either has not changed in 
intensity or may not have recovered to baseline values, and the outcome is unknown.  
Examples include headache, low-grade fever, or nausea. 
• Unknown:  The subject has withdrawn from the study prematurely or is lost to follow-
up, and the status of the event is unknown. 
• Death 
7.5.4. 
Assessment of Expectedness 
For the purposes of IND safety reporting, adverse events and suspected adverse events should be 
assessed as being expected or unexpected.  An AE or SAR 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. 
7.6. 
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 are designated as ongoing and will be reviewed at 
subsequent visits or contacts. 


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SAEs will be followed until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up.  The investigator will ensure that follow-up 
information provided to the sponsor 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 7.7. 
7.7. 
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 MEDICATION, MUST BE REPORTED TO THE SPONSOR IMMEDIATELY 
(within 24 hours). 
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY E-MAIL 
TO THE FOLLOWING SPONSOR CONTACT: 
Medical Safety 
Recro Pharma, Inc. 
 
Telephone:  484-395-2470 
Fax:  484-395-2471 
E-mail:  AE@recropharma.com 
In the initial e-mail, 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 
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 


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must be forwarded to the sponsor by using the same procedure and timelines as for an initial 
report. 
7.8. 
Regulatory Reporting Requirements  
The investigator must promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 7.7, “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 SSARs 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. 
Investigator letters are prepared according to sponsor policy and are forwarded to the 
investigators as necessary.  An investigator letter is prepared for any SAR that is attributable to 
study medication, 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. 
7.9. 
Precautions 
Any subject who becomes pregnant during the study must be discontinued immediately, but 
should be followed through delivery or termination of the pregnancy.  A subject should also 
notify the investigator if she becomes pregnant within 30 days after receiving study medication.  
The sponsor must be notified of all pregnancies reported to the investigator (see Section 7.7 for 
contact information). 


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8. 
STATISTICAL METHODOLOGY 
8.1. 
Determination of Sample Size 
The sample size for this study was selected to support the total exposure population for N1539.   
8.2. 
Study Endpoints 
8.2.1. 
Safety Endpoints 
The safety endpoints will include the following: 
1) incidence of AEs and SAEs 
2) change from baseline in laboratory tests; incidence of abnormal clinical laboratory tests, 
including routine blood chemistry, hematology, urinalysis, and coagulation tests 
3) change from baseline in vital signs; incidence of clinically significant changes in vital 
signs 
4) incidence of clinically significant abnormal ECG findings 
5) incidence of abnormal wound healing 
6) total opioid consumption during 0-24, 24-48, and 0-48 hours post first dose of study drug 
8.3. 
General Considerations for Statistical Analysis 
8.3.1. 
Analysis Datasets  
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include all randomized subjects.  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.   
8.3.2. 
Test Hypothesis and P Value Justification 
No formal hypothesis will be evaluated in this safety study; all safety endpoints will be tabulated 
by treatment groups with descriptive statistics.  Inferential statistics may be provided when 
appropriate. 
8.3.3. 
Procedures for Handling Missing Data  
Unless indicated otherwise, 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 period will be the last 
measurements taken before the subject receives the study medication.  End of Study Visit will be 
the last follow-up telephone call to be conducted on LSD+28 Days ± 4. 
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) will 
also be provided by randomization strata (surgery type and risk category) and study overall. 
8.4.2. 
Demographics and Surgery Characteristics 
The demographic summary will include descriptive statistics for age, sex, race, risk status, 
weight, height, and BMI by treatment group and by surgery type.  
Surgery characteristics include surgery type, surgery duration, time from end of surgery to first 
dose of study drug. 
8.4.3. 
Protocol Violations 
All protocol violations and deviations will be identified.  Tabulation may provide if data warrant. 
8.4.4. 
Treatment Compliance 
Doses of study medication will be administered by designated unblinded study personnel to 
study subjects while subjects are 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. 
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 
names using the World Health Organization (WHO) Drug classifications version 1Q2016 or 
higher.  
Total opioids contained in each analgesic will be determined based on total IV morphine 
equivalent dose for each medication.  Total opioid consumption during 0-24, 24-48, and 0-48 
hours post first dose of study drug will be determined for each subject and will be tabulated by 
treatment group. 


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8.5. 
Safety and Tolerability Evaluations 
8.5.1. 
Extent of Exposure 
A subject may receive up to 7 doses of N1539.  For N1539 treatment assigned subjects, the 
maximum exposure to meloxicam over the treatment period would be 210 mg (30 mg/dose * 
7 doses). 
Evaluation of the extent of exposure for the treatment period will be assessed via number of 
doses taken. 
8.5.2. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 18 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.    
8.5.3. 
Clinical Laboratory Tests 
Laboratory values will be collected at screening, Day 1 during check-in (baseline; centrally 
performed screening labs may act as baseline labs if collected within 14 days of Day 1), Hour 48, 
LSD+1/discharge (if prior to Hour 48, or to be repeated in subjects who receive ≥ 4 doses), and 
LSD+7 days follow-up visit.  Observed values at each time point, and change from baseline will 
be summarized for the 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. 
8.5.4. 
Vital Sign Measurements 
Resting vital sign values at each time point collected will be summarized by treatment group 
including change from baseline (predose), without formal statistical testing.  Number (%) 
subjects with clinically significant changes in vital signs post dosing will also be tabulated. 
8.5.5. 
Electrocardiograms 
The number and proportion of subjects with clinically significant abnormal ECG findings at each 
time point collected will be tabulated by treatment group.  A data listing will be provided for 
subjects with changes from normal at baseline to abnormal and clinically significant after 
baseline. 


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8.5.6. 
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 
hematoma formation will be summarized by treatment group. 
8.5.7. 
Subgroup Analyses for Safety Endpoints 
Subgroups to be analyzed for safety may include: race, gender, age, surgery type, surgery 
duration, and/or risk status (high risk vs others). 


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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 Health Canada 
and 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 review board (IRB, REB, HREC, or IEC).  
The investigator agrees to allow the review board direct access to all relevant documents.  The 
review board must be constituted in accordance with all applicable regulatory requirements.  The 
sponsor will provide the investigator with relevant documents or data needed for review board 
review and approval of the study.  Before investigational products can be shipped to the site, the 
sponsor must receive copies of the review board approval, the approved informed consent form, 
and any other information that the review board has approved for presentation to potential 
subjects. 
If the protocol, the informed consent form, or any other information that the review board has 
approved for presentation to potential subjects is amended during the study, the investigator is 
responsible for ensuring that the review board 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 review board 
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 
review board approval of the amended informed consent form or other information and the 
approved amended informed consent form or other information.  Review board 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 review board approval 
can be sought. 


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9.1.2.2. 
General Considerations 
The ethical standards defined within GCP are intended to ensure the following: 
• 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-15-017.  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. 


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13 July 2016 
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 
representative.  However, the witness shall sign both the short form and a copy of the summary, 
and the person actually 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: 


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13 July 2016 
• discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 
• 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) and where 
applicable in Canada the Privacy Act, Personal Information and Protection and Electronic 
Documents ACT (PIPEDA) and provincial privacy regulations.  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 


PROTOCOL REC-15-017 Amendment 003 
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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. 
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 


PROTOCOL REC-15-017 Amendment 003 
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13 July 2016 
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. 
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 
missing 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 will be used to track subject participation in the study. 


PROTOCOL REC-15-017 Amendment 003 
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13 July 2016 
10. 
REFERENCES 
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 March 2012. 
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 
Procedure; Dose/Hour 
Screening 
Inpatient (Day 1 – Discharge) 
Follow-Up Visit 
(LSD+7 days ± 2) 
Follow-Up 
Telephone 
(LSD+28 days ± 4) 
Prior to 
Surgery 
Surgery 
Dose 1 / 
Hour 0 
Dose 2 / 
Hour 24 
Dose 3 / 
Hour 48 
LSD+1 / 
Discharge 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Confinement 
 
X 
 
 
Eligibility Assessment 
X 
X 
 Xd 
 
 
 
  
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
 
Physical Examinatione 
X 
 X 
 
 
 
 
 X 
 X 
 
Pregnancy Test (FOCBP only) 
Xserum 
Xurine 
 
 
 
 
 
 
 
Alcohol Breath Test and UDS 
X 
X 
 
 
 
 
 
 
 
Clinical Laboratory Testsa 
X 
Xg 
 
 
 
X 
X 
X 
 
Vital Signsb 
X 
X 
 
X 
X 
 
X 
X 
 
12 Lead ECG 
X 
Xc 
 
 
 
 
X 
X 
 
Surgical Procedure 
 
 
X 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
X 
X 
X 
Xf 
 
 
Wound Evaluation 
 
 
 
 
 
 
X 
X 
 
Prior and Concomitant Medication 
X  
Adverse Event Monitoring 
 
 
 
X  
a Laboratory tests will include hematology, chemistry, urinalysis and coagulation tests.  
b Vital signs (VS) include: resting blood pressure, resting pulse, and SpO2. Tests must be obtained after resting (seated/reclined) for ≥ 5 minutes.   
c 12-lead ECG will be done prior to surgery only if screening ECG was done >14 days before Day 1 
d Postoperative randomization criteria will be assessed on the day of surgery (Day 1), prior to treatment.  
e BMI, height, and weight will be assessed at the screening visit only. 
f Doses may be administered every 24±1 hours for up to 7 days while continued use of IV analgesia is clinically appropriate. 
g Day 1 clinical laboratory tests will be required if greater than 14 days have elapsed since screening labs were performed or if screening labs were not performed at the central lab


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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 initials and subject numbers.  
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 (i.e., 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: 
Surgical Wound Status Assessment  
 
Parameter 
Grade 
Description 
Erythema 
0 
None 
1 
Very slight (barely perceptible) 
2 
Slight (well defined) 
3 
Moderate  
4 
Severe (beet redness) to slight eschar formation (injuries in depth) 
Drainage 
0 
None 
1 
Serous 
2 
Serosanguinous 
3 
Bloody 
4 
Purulent 
Edema 
0 
None 
1 
Very slight (barely perceptible) 
2 
Slight (edges well defined) 
3 
Moderate (raised approximately 1 mm) 
4 
Severe (raised >1 mm and beyond area of exposure) 
Induration 
0 
None 
1 
Minimal 
2 
Mild (spongy tissue) 
3 
Moderate (firm, warm) 
4 
Severe (hard, red, hot, crepitus) 
Hematoma 
0 
None 
1 
Minimal 
2 
Mild 
3 
Moderate 
4 
Severe 
 


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APPENDIX D. BMI CALCULATION 
Body Mass Index Calculations 
 
Body Mass Index = Weight in kilograms / (height in meters)2 
Meters = inches × 0.0254 
Kilograms = pounds × 0.45 
 
Example: 
For a man who weighs 165 pounds and is 71 inches tall: 
165 lbs × 0.45 = 74.25 kg 
71 in. × 0.0254 = 1.8 m 
74.25 / (1.8 × 1.8) = 22.92 kg/m2 
 
 
 
 
 
 


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APPENDIX E. MDRD CALCULATION 
The Modification of Diet in Renal Disease (MDRD) equation is to be used to calculate the 
estimated GFR, according to the following equation: 
 
GFR (mL/min/1.73 m2) = 175 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African 
American) 
 
SCr = serum creatinine measured with a standardized assay. 
 
Reference: FDA Guidance for Industry (Draft Guidance): Pharmacokinetics in Patients with Impaired Renal 
Function - Study Design, Data Analysis, and Impact on Dosing and Labeling; Revision 1, March 2010. 
 
 

SAP_001.pdf: 
 
 
 
REC-15-017 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Evaluation of the Safety of N1539 Following Major Surgery 
 
NCT02720692 
 
Statistical Analysis Plan 
 
17 February 2017 
 


 
 
 
 
Statistical Analysis plan 
 
 
Protocol Number: 
REC-15-017 
Protocol Title:  
 A Phase 3, Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Evaluation of the Safety of 
N1539 Following Major Surgery  
Date of Protocol:  
Amendment 003, 13 July 2016 


 
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REVISION HISTORY 
Version No. 
Version Date 
Author 
Description of Modification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
REVISION HISTORY ............................................................................................ 2 
SIGNATURES .......................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................ 4 
LIST OF IN-TEXT TABLES ................................................................................. 7 
LIST OF IN-TEXT FIGURES ............................................................................... 8 
LIST OF ABBREVIATIONS ................................................................................. 9 
1. INTRODUCTION ...........................................................................................11 
2. STUDY OVERVIEW ......................................................................................12 
2.1. 
Study Design and Objectives.......................................................................................... 12 
2.2. 
Study Assessment Schedule ............................................................................................ 14 
2.3. 
Study Endpoints .............................................................................................................. 16 
2.3.1. 
Efficacy Endpoints .................................................................................................... 16 
2.3.2. 
Safety Endpoints ....................................................................................................... 16 
2.4. 
Sample Size Consideration ............................................................................................. 16 
3. GENERAL CONSIDERATIONS ..................................................................17 
3.1. 
Analysis Population ........................................................................................................ 17 
3.2. 
Test Hypothesis and P Value Justification ................................................................... 17 
3.3. 
Procedures for Handling Missing Data......................................................................... 17 
3.4. 
Definitions for Analysis Visit ......................................................................................... 18 
3.5. 
Derived Variables for Analysis ...................................................................................... 18 


 
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3.5.1. 
Subject Group ........................................................................................................... 18 
3.5.2. 
Treatment Group ....................................................................................................... 19 
3.5.3. 
Analysis Center ......................................................................................................... 20 
3.5.4. 
Total Opioid Consumption ....................................................................................... 20 
3.5.5. 
Potentially Clinically Significant Changes in Vital Signs ........................................ 23 
4. STUDY POPULATION SUMMARIES ........................................................25 
4.1. 
Disposition ....................................................................................................................... 25 
4.2. 
Demographics and Baseline Characteristics ................................................................ 25 
4.3. 
Protocol Deviations ......................................................................................................... 26 
4.4. 
Treatment Compliance ................................................................................................... 27 
4.5. 
Prior and Concomitant Medications ............................................................................. 27 
4.5.1. 
Total Opioid Consumption for Pain Management During Treatment ...................... 27 
5. EFFICACY ANALYSIS .................................................................................28 
6. SAFETY AND TOLERABILITY EVALUATIONS ...................................29 
6.1. 
Extent of Exposure .......................................................................................................... 29 
6.2. 
Adverse Events ................................................................................................................ 29 
6.2.1. 
Adverse Event Summary .......................................................................................... 29 
6.2.2. 
Adverse Event Analysis ............................................................................................ 30 
6.3. 
Clinical Laboratory Tests............................................................................................... 30 
6.3.1. 
Analysis of Laboratory Tests of Special Interest ...................................................... 32 
6.4. 
Vital Sign Measurements ............................................................................................... 32 
6.5. 
Electrocardiograms......................................................................................................... 36 
6.6. 
Wound Healing................................................................................................................ 36 


 
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6.7. 
Subgroup Analyses for Safety Endpoints ..................................................................... 38 
7. REFERENCES ................................................................................................39 
 
 


 
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LIST OF IN-TEXT TABLES 
 
Table 1:  Overview of Study Schedule ......................................................................................... 15 
Table 2:  Surgeries Included in Each Surgery Type ..................................................................... 19 
Table 3:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics ......................... 21 
Table 4:  Blood Pressure Results and Change from Baseline Category ....................................... 23 
Table 5:  Protocol Deviation Category ......................................................................................... 26 
Table 6:  Abnormal Results in Selected Laboratory Tests of Special Interest ............................. 32 
Table 7:  Surgical Wound Status Assessment............................................................................... 37 
 
 
 
 


 
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LIST OF IN-TEXT FIGURES 
 
Figure 1:  Example of Hemoglobin Distribution Population Shift Analysis ................................ 31 
Figure 2:  Example of SBP Results Distribution Analysis ........................................................... 33 
Figure 3:  Example of SBP Change from Baseline Distribution Analysis ................................... 33 
Figure 4:  Example of DBP Results Distribution Analysis........................................................... 34 
Figure 5:  Example of DBP Change from Baseline Distribution Analysis................................... 34 
Figure 6:  Example of SBP Percent Change from Baseline Distribution Curves ......................... 35 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
abs 
absolute value 
AE 
adverse event 
AEOI 
Adverse event of interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BPM 
Beats per minute 
CFB 
Change from baseline 
ºC 
degrees Centigrade 
CV 
Cardiovascular 
CS 
Clinically Significant  
eCRF 
Electronic case report form 
eGRF 
estimated glomerular filtration rate 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
EOT 
End of Treatment  
EOS 
End of Study  
ºF 
degrees Fahrenheit 
GFR 
Glomerular filtration rate 
GGT 
gamma-glutamyltransferase 
GI 
Gastrointestinal 
H 
Hour 
HCT 
hematocrit 
Hg 
hemoglobin 
ICH 
International Conference on Harmonization 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVMED 
IV Morphine Equivalent Dose 


 
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Abbreviation 
Definition 
Kg 
Kilogram 
L 
Liter 
LFT 
Liver Function Test 
LSD 
Last Dose Date 
m2 
square meters 
MDRD 
Modification of Diet in Renal Disease 
Mg 
Milligram 
mL 
Milliliter 
mm Hg 
millimeters of mercury 
NCS 
Not Clinically Significant  
NRSDV 
Normal range standardized value 
NSAIDs 
nonsteroidal anti-inflammatory drugs  
pH 
negative log of hydrogen ion concentration 
PO 
by mouth 
PCFB 
Percent change from baseline 
PCSC 
Potentially Clinically Significant Change 
PLT 
Platelet counts 
PT 
prothrombin time 
PTT 
activated partial thromboplastin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SJS 
Stevens-Johnson Syndrome 
SOC 
System Organ Class 
SpO2 
Peripheral oxygen saturation 
TEAE 
treatment emergent adverse event 
TEN 
toxic epidermal necrolysis 
µg 
Microgram 
WBC 
white blood cell 


 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is prepared to provide a more technical and detailed 
elaboration of the principal statistical features stated in the protocol.  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-15-017 - Amendment 003, 13 July 2016 
• eCRF, version 4, 9 January 2017  
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 
protocols and this document, the description in this document supersedes the descriptions in the 
statistical section of the protocols. 


 
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2. 
STUDY OVERVIEW 
2.1. 
Study Design and Objectives 
Protocol REC-15-017 is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, 
evaluation of the safety of N1539 in adult subjects undergoing major surgery.  The study will 
enroll approximately 700 subjects. 
The primary objective of this study is to evaluate the safety and tolerability of N1539 compared 
with placebo, as evaluated with physical examination, vital signs, clinical laboratory tests, ECGs, 
wound evaluation, postoperative opioid consumption, and incidence of Adverse Events (AEs) 
and Serious AEs (SAEs). 
Adult subjects, age 18 to 80 years inclusive, requiring major surgery that is expected to result in 
inpatient hospitalization for at least 24-48 hours, will be screened for participation at 30-40 study 
sites in North America, Australia, and New Zealand.  Study enrollment will include a cohort of 
approximately 30-40 subjects meeting criteria as high risk subjects, defined as age >65 years 
with a glomerular filtration rate (GFR) of 60-89 mL/min/1.73m2, as calculated using the 
Modification of Diet in Renal Disease (MDRD) equation.  The study has three phases:  1) Pre 
Treatment Phase, 2) Treatment Phase, and 3) Follow-up.  The following describes key activities 
in each phase in the study. 
1. 
Pre Treatment Phase: 
a. Screening Period (Day -28 to Day -1):  Subject will be consented and screened for 
eligibility for the study.   
b. Day of Surgery (Day 1):    
1) Pre surgery:  Subject will be admitted to the clinic and reassessed for 
eligibility for the study.  Pre surgery activities will be conducted. 
2) Surgery:  Eligible subjects will undergo surgery using an appropriate 
anesthetic regimen according to the type of surgery (see Protocol Section 5.1) 
3) Postoperative Period:  Following surgery, subjects will be evaluated for 
eligibility for treatment   
c. Randomization Qualification (Day 1):  Subjects will be eligible for randomization 
and study dosing if/when they meet all of the postoperative randomization criteria 
within six hours after the end of surgery: 
1) Be able to achieve hemostasis and surgical incision closure, prior to Operating 
Room discharge.  
2) The surgical procedure did not require use of > 2 units of packed red blood 
cells or platelets. 
3) The surgical procedure from incision to closure was not longer than 12 hours. 
4) Subject is expected to have sufficient pain such that parenteral analgesia is 
clinically appropriate. 


 
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5) The subject has had no evidence of respiratory insufficiency, clinically 
significant hypotension, bradycardia, coagulopathy, or any other abnormality, 
during or following surgery that, in the investigator’s opinion, significantly 
increases the risks of study participation. 
2. 
Treatment Phase (Time 0 through Discharge/LSD+1): 
Once the subject meets postoperative randomization eligibility criteria, subjects will be randomly 
assigned to treatment with N1539 30 mg or placebo in a 3:1 assignment ratio according to the 
randomization scheme.  Randomization will be stratified by risk status (high risk [age > 65 years 
with GFR 60-89 mL/min/1.73 m2] vs. other, referenced to as Not high risk) and surgery type 
(orthopedic vs. other surgeries), not high risk subjects will further be stratified by study center.   
The time of first dose of study drug (Dose 1) will be recorded as Hour 0.  Subjects will be 
administered a study dose according to their randomization every 24 hours so long as IV 
analgesia is clinically appropriate or until they receive a maximum of 7 study doses.  A final study 
dose may be administered up to 4 hours early in subjects who are scheduled to be discharged.  When 
inpatient care is no longer required, subjects may receive additional study doses under continued 
supervision of the investigator in an appropriate setting.  Subjects who do not receive a study 
dose for >28 hours following their previous study dose should be considered off treatment, 
and should not receive further study dosing.  Subjects may continue to receive standard of 
care analgesics per the discretion of the investigator, except for medications which may interact 
with meloxicam or interfere with the objectives of the study, as defined in Protocol Section 5.12. 
During the treatment phase, pain symptoms that are not adequately controlled by dosing with 
study drug, may be treated with opioid analgesics according to the standard practice of the 
investigator.  Once discharged, subjects may utilize oral analgesics according to the standard 
practice of the investigator.  All doses of analgesic medications should be recorded in the 
subject’s eCRF. 
Subjects will undergo safety assessments at the earlier of LSD+1 day or at the time of discharge 
prior to leaving the study center.  Study safety assessments during treatment period will include 
monitoring adverse events, vital signs, physical examination, ECG, clinical laboratory test, and 
wound healing assessment.     
 
 


 
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3. 
Follow-up: 
Subjects will be provided routine standard of care for pain management after discharge from the 
study center.  All subjects will be asked to return to the study center at LSD+7 days to complete 
end of study assessments.  Subjects will complete a final safety assessment by telephone at 
LSD+28 days. 
Safety assessments at the LSD+7 days follow-up visit include AE, clinical Laboratory tests, PE, 
vital signs, ECG, and wound healing assessments. 
2.2. 
Study Assessment Schedule 
The following is an overview of study schedule activities (Table 1). 
 
 


 
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Table 1:  Overview of Study Schedule  
Procedure; Dose/Hour 
Screening 
Inpatient (Day 1 – Discharge) 
Follow-Up Visit 
(LSD+7 days ± 2) 
Follow-Up 
Telephone 
(LSD+28 days ± 4) 
Prior to 
Surgery 
Surgery 
Dose 1 / 
Hour 0 
Dose 2 / 
Hour 24 
Dose 3 / 
Hour 48 
LSD+1 / 
Discharge 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Confinement 
 
X 
 
 
Eligibility Assessment 
X 
X 
 Xd 
 
 
 
  
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
 
Physical Examinatione 
X 
 X 
 
 
 
 
 X 
 X 
 
Pregnancy Test (FOCBP only) 
Xserum 
Xurine 
 
 
 
 
 
 
 
Alcohol Breath Test and UDS 
X 
X 
 
 
 
 
 
 
 
Clinical Laboratory Testsa 
X 
Xg 
 
 
 
X 
X 
X 
 
Vital Signsb 
X 
X 
 
X 
X 
 
X 
X 
 
12 Lead ECG 
X 
Xc 
 
 
 
 
X 
X 
 
Surgical Procedure 
 
 
X 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
X 
X 
X 
Xf 
 
 
Wound Evaluation 
 
 
 
 
 
 
X 
X 
 
Prior and Concomitant Medication 
X  
Adverse Event Monitoring 
 
 
 
X  
a Laboratory tests will include hematology, chemistry, urinalysis and coagulation tests.  
b Vital signs (VS) include: resting blood pressure, resting pulse, and SpO2. Tests must be obtained after resting (seated/reclined) for ≥ 5 minutes.   
c 12-lead ECG will be done prior to surgery only if screening ECG was done >14 days before Day 1 
d Postoperative randomization criteria will be assessed on the day of surgery (Day 1), prior to treatment.  
e BMI, height, and weight will be assessed at the screening visit only. 
f Doses may be administered every 24±1 hours for up to 7 days while continued use of IV analgesia is clinically appropriate. 
g Day 1 clinical laboratory tests will be required if greater than 14 days have elapsed since screening labs were performed or if screening labs were not performed at the central  
 


 
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2.3. 
Study Endpoints 
2.3.1. 
Efficacy Endpoints 
There is no efficacy endpoint in this safety study. 
2.3.2. 
Safety Endpoints  
The safety endpoints will include the following: 
1. 
Incidence of AEs and SAEs 
2. 
Change from baseline in laboratory tests; incidence of abnormal clinical laboratory 
tests, including routine blood chemistry, hematology, coagulation tests, and urinalysis 
3. 
Change from baseline in vital signs; incidence of clinically significant changes in 
vital signs 
4. 
Incidence of clinically significant abnormal ECG findings  
5. 
Incidence of abnormal wound healing 
6. 
Total opioid consumption during 0-24, 24-48, 48-72, and 0-48, 0-72 hours, and 
During Treatment post first dose of study drug 
2.4. 
Sample Size Consideration  
The sample size for this study was selected to support the required total exposure population for 
N1539.  However, for a sample size of 525 subjects to be treated with N1539, this study will 
have 95% probability to observe at least one event if the event’s occurrence rate is 0.57% or 
higher in the N1539 treatment group. 
 


 
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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 all subjects randomized.  This 
dataset could 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.   
3.2. 
Test Hypothesis and P Value Justification 
There is no formal null hypothesis to be examined in this safety study.  Differences between 
N1539 30 mg and placebo group will be evaluated primarily using descriptive summary 
statistics.  If appropriate inferential statistics may be provided at the 0.05 level of significance 
using 2-sided test for null hypothesis of no difference between the two treatment groups. In this 
case nominal p-values will be reported as is.     
3.3. 
Procedures for Handling Missing Data  
Unless indicated otherwise, missing data imputation will not 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. 
 
 


 
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3.4. 
Definitions for Analysis Visit 
The following analysis visits will be identified based on the date of first dose, date of last dose, 
and date of (LSD+1/discharge): 
Baseline:  Baseline will be the last non-missing measurement taken before the subject receives 
the first dose of study medication. Unscheduled visits before the date of first dose could be 
assigned as the Baseline visit if it is the last non-missing record prior to the First Dose Date.     
Treatment Period:  Treatment period will include all records with date ≥ date of first dose and 
≤ date of last dose + 1 (ie, LSD+1).  Each record will be identified by their nominal time (hour 
XX) post Dose 1.  Unscheduled visits within this period will also be included and they will be 
labeled as is. 
For example,  
1) Hour 24 vital signs will be labeled as Hour 24. 
2) The first unscheduled record within treatment period will be label as Unscheduled 1 
End of Treatment (EOT):  End of treatment record should be the last record post baseline up to 
and include (LSD+1/Discharge) visit.  This record will be taken from the LSD+1/Discharge visit 
for the majority parameters.  However, for clinical laboratory analysis not all subjects will have 
this LSD+1/Discharge Lab.  It is anticipated that 
• A Subject will have LSD+1/Discharge lab and not an Hour 48 Lab if the subject has 1 
or 2 doses of study drug and is discharged prior to hour 48. 
• A subject will not have a LSD+1/Discharge lab but will have an Hour 48 lab if the 
subject has 3 doses of study drug and the Hour 48 lab is completed. 
• A subject will have an Hour 48 Lab and a LSD+1/discharge Lab if the subject has 4 
or more doses of the study drug. 
Hence, the EOT record will be LSD+1/Discharge record if performed; otherwise (see Scenario 2 
above) the Hour 48 lab will be the EOT lab. 
 the Hour 48 lab record in Scenario 2 above will have an analysis visit of End of 
Treatment whereas the Hour 48 lab in Scenario 3 will have an analysis visit of Hour 
48 (that is, it is a visit within the treatment period). 
End of Study (EOS):  The expected End of Study record is the measures taken after the date of 
(LSD+1/Discharge). It is typically taken from the (LSD+7) follow-up visit, however, the End of 
Study record could be an unscheduled visit if this UNSCHEDULED VISIT is after the LSD+7 
visit.  
3.5. 
Derived Variables for Analysis 
3.5.1. 
Subject Group 
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1) High Risk Subject Receiving Orthopedic Surgery 
2) High Risk Subject Receiving Other Surgery 
3) Not High Risk Subject Receiving Orthopedic Surgery 
4) Not High Risk Subject Receiving Other Surgery 
The following table shows some of the specific surgeries included in each surgery type. 
Table 2:  Surgeries Included in Each Surgery Type   
Surgery Type 
Specific Surgery 
Other Surgery 
Hernia Repair  
 
Hysterectomy 
 
Gynecological/Genitourinary 
Orthopedic Surgery 
Ankle Arthroplasty 
 
Bunionectomy 
  
Hip Arthroplasty 
 
Knee Arthroplasty 
 
Shoulder Arthroplasty 
 
Spinal 
 
Total Hip Replacement 
 
Total Knee Replacement 
 
Other 
Risk status is to be determined at the screening visit based on the eGFR and age at Screening 
Visit.  Screening lab for eGFR computation could be performed either at the central lab or at a 
local lab.  eGFR determined at a local lab will be available in the source document at the site and 
will not be entered to eCRF.  The randomization stratus is entered to eCRF.   
3.5.2. 
Treatment Group 
All subjects will be included in their randomized treatment group for analysis.  However if a 
treatment error (a subject was randomized to N1539 group but received placebo treatment or vice 
versa), the following rules will apply: 
1) All planned analysis will be based on the randomized (planned) treatment group. 
2) Sensitivity analysis will be conducted, such as  


 
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a. An analysis that includes the subject in the actual treatment group 
b. An analysis that excludes the subject from both treatment groups. 
Treatment error is a major protocol deviation; hence, this incidence will also be documented in 
the protocol deviation analysis (see Section 4.3).  
3.5.3. 
Analysis Center 
This study is planned to enroll subjects from 30-40 investigator sites in North American, 
Australia, and New Zealand.  An analysis center is an investigational site if the site has 
randomized more than 5 subjects; it could also be a unit of 2 or more small investigational sites.  
In the event that 2 or more investigator sites are combined to form an analysis center the 
following rules may apply.  
a. Pooled sites are in same geographic area 
b. Pooled sites are similar in medical practice / focus  
The analysis site will be used as a covariate for total opioids consumption analysis.  If data 
pooling is required to form analysis site, the pooling will be determined and documented prior to 
database hard lock.  
3.5.4. 
Total Opioid Consumption  
All concomitant medications will be mapped to WHO Drug (version 2015).  Opioid medication 
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.  Table 3 shows some 
examples of IVMED of some commonly used analgesics. 
All analgesic medications will be mapped to four time periods: (0-24, 24-48, 48-72, 0-48, 0-72, 
and During Treatment) hours after Dose 1 based on the start date/time and stop date/time.  
‘During Treatment’ period starts with Dose 1 date/time and ends with the LSD+1; that is, this 
period will equal to the study drug treatment duration.  This period is created to assess potential 
relationship of total opioid consumption and duration of study drug treatment since the duration 
of study drug treatment is expected to vary from subject to subject. 
 
 


 
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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 
AlFentanyl 
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 
For example, one tablet of 5 mg Oxycodone will equal to 2.5 mg IVMED (5*0.5=2.5).   
All opioid medication used for pain management during treatment will be clearly marked as 
‘Pain Management’ when entering the medications in the eCRF.  Although all efforts are made 
to have a date/time entered for all analgesics in the study, the following rules will be used to 
handle missing date/time if situation is present.  The rules should be executed in the same order 
as follows. 
1. All records without start date will be excluded. 
2. All records that the start date is before Date 1 or after LSD+1 will be excluded regardless 
if time is present or missing. 
3. If start date is present but stop date is missing, the stop date will be set to be equal to the 
start date. 
4. If the analgesic start date = date of first study dose, the stop time of study drug dose 1 
will be assigned to the missing start time.  


 
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5. If the start date is after the date of first study dose, the missing start time will be the first 
minute of the date (i.e., missing time =00:01:00). 
6. If stop time is missing, the start time of this analgesic will be used as the stop time as well 
(ie, start time = stop time) if the medication start date = stop date. 
7. If the start date is not equal to end date, and stop time is missing the end time will be set 
to last minutes of the day (ie, missing time = 00:59:00). 
8. If a pain medication started prior to study but the subject was on a stable dose through the 
treatment period (signaled by ONGOING=Yes) then start and stop date/time will be set 
to the first dose start date/time and (last dose stop date/time) +1 (ie, LSD+1).   
9. If a medication is started prior to Hour 0 but stopped during the treatment period, the 
duration of the medication will be interpolated for the time period of interest. 
The start date/time of first dose of study drug (=Hour 0) and stop date/time of the last dose 
(=Hour L) will be used to define the period as follows 
Period 
Criteria  
0-24 Hour 
Begin = Hour 0 and End  = Hour 0 + 24:00:00 
24-48 Hour 
Begin = Hour 0+24:01:00 and End = Hour 0+ 48:00:00  
48-72 Hour 
Begin = Hour 0+48:01:00 and End = Hour 0+ 72:00:00  
During Treatment 
Begin = Hour 0 and End = Hour L + 24:00:00 
 
Hour 0 = Start time of first dose 
Hour L = Stop time of last dose 
After IVMED is determined for each record, the total opioid consumption will be determined for 
each subject per time interval by sum of all records within a period.  If the duration of a record 
covered 2 periods (e.g., started during 0-24 period but stopped after Hour 24), linear 
interpolation method will be used to split the IVMED into 2 intervals based on the start and stop 
time.          
Opioids consumption during treatment is an ‘At-risk’ analysis. The following rules will be used 
to derive this parameter. 
1. If a subject did not use any opioids for pain management during a period and this subject 
is in the study during this period a zero (‘0’) will be assigned to this subject for this 
period.   
2. If a subject discontinues from the study drug treatment during 0-24 hours, this subject 
will be included in the analysis for period 0-24 and period 0-48 hours (rule No.1 above 
will apply to this subject for periods of 0-24 and 0-48 hours if this subject did not use any 
opioids for pain management prior to discontinuation); but this subject will be excluded 
from the analysis of 24-48 hours, 48-72 hours (opioids consumption is set to missing in 
those periods).    


 
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3. If a subject discontinues study drug treatment from the study during 24-48 hours, this 
subject will be included in the analysis of 0-24, 24-48, and 0-48 hours; rule No. 1 above 
will apply to this subject for a period if this subject did not use any rescue medications 
during this period. 
Since the study drug treatment is once daily regimen the following table summarizes the At-Risk 
period based on number of study drug treatment received.   
Number of Doses 
At Risk Period 
Subjects with 1 dose of study drug 
0-24, 0-48, 0-72, During Treatment 
Subjects with 2 doses of study drug 
0-24, 24-48, 0-48, 0-72, During Treatment 
Subjects with 3+ doses of study drug 
0-24, 24-48, 48-72, 0-48, 0-72, During Treatment 
3.5.5. 
Potentially Clinically Significant Changes in Vital Signs 
Vital signs will be taken at Screening, Day 1 (prior to surgery), Hour 0 on Day 1 (prior to first 
dose), Hour 24 (prior to Dose #2), LSD+1, and LSD+7.  Baseline vital signs will be the last non-
missing value prior to Dose 1; this typically would be the Hour 0 vital signs.  Change from 
baseline (CFB) and percent change from baseline (PCFB) in vital signs will be calculated for 
each post dosing vital signs. 
CFB = Post Baseline - Baseline 
PCFB = 100*(CFB/Baseline) 
Blood pressure results and change from baseline will be grouped into the following categories 
(Table 4).   
Table 4:  Blood Pressure Results and Change from Baseline Category 
Parameter 
Observation 
Change from Baseline (Post baseline – Baseline) 
SBP (mmHg) 
≤90  
91-120 
121-150 
151-179 
≥180 
≥ +20 (increased 20 or more mmHg) 
+19 to -19 (changed within 19 mmHg)  
≤ -20 (decreased 20 or more mmHg) 
 
DBP (mmHg) 
≤50   
51-80 
81-90 
91-104 
≥105  
≥ +15 (Increased 15 or more mmHg) 
+14 to -14 (changed within 14 mmHg)  
≤ -15 (decreased 14 or more mmHg) 
 
 


 
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Subjects are considered having a potentially clinically significant change (PCSC) in blood 
pressure if SBP change is 20 or more mmHg or DBP change is 15 or more mmHg, or Percent 
change is 25% or more.  Mathematically, the PCSC could be expressed as 
• PCSC=Y if abs(CFB_SBP) ≥20 mmHg or 
• PCSC=Y if abs(CFB_DBP) ≥15 mmHg or 
• PCSC=Y if abs(PCFB) ≥25%  
Where abs = absolute value 
Vital sign analysis will focus on blood pressure; other vital signs (heart rate and SpO2) will be 
available in data listings 
 


 
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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 
• Number (%) subjects randomized 
• Number (%) subjects treated with >=1 dose of study drug 
• Number (%) subjects completed study drug treatment 
o Number (%) subjects by reason for discontinuation of study drug treatment 
• Number (%) subjects completed study 
o Number (%) subjects by reason for discontinuation of study 
Subjects who did not complete study will include all subjects who discontinued from the 
study before the second follow-up (LSD+28) visit.  
Disposition information will be provided by treatment group for overall, and by surgery 
type and risk status 
A table (Table 14.1.1.2) will provide enrollment summary by site, including number of 
subjects screened, number of subjects randomized, number of subjects treated, number of 
subjects completed treatment, and number of subjects completed study. 
4.2. 
Demographics and Baseline Characteristics 
The demographic summary will include descriptive statistics for age, age group (<65, ≥65, ≥75), 
sex, race, ethnicity, weight, height, BMI, and BMI group (BMI < 35, BMI ≥ 35) overall and by 
treatment group.  
Baseline characteristics will include  
1. Child bearing potential among females 
2. Surgery duration (hr), surgery type, incision type, surgery site, and risk status.  Based on 
the detail information provided on the surgery page, specific surgeries will be grouped for 
the purpose of summary.   
3. Time (hr) from end of surgery to first dose of study drug 
Demographics and baseline characteristics will be tabulated for safety population by treatment 
group for overall, by risk status, and by surgery type (Tables 14.1.2.1.1).  Demographics table 
will also be provided by randomization strata and subgroups (Tables 14.1.2.2 - 14.1.2.2.5).     
Medical and surgical (Table 14.1.3) history will be tabulated by treatment group for the overall, 
by surgery type, and by risk status in safety analysis set.  No formal inferential tests will be 
performed. 
 


 
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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 the expected conduct of an approved study that is not consistent with the current 
research protocol, consent document or study agenda. 
All protocol deviations will be tabulated by protocol category, type, and treatment group for the 
overall and by surgery type and risk status in safety analysis set (Table 14.1.4).   
Table 5:  Protocol Deviation Category 
Protocol Deviation Category 
Informed Consent 
Eligibility Criteria not met 
Study procedure  
Exclusionary medication taken 
Other 
 
 
 


 
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4.4. 
Treatment Compliance 
Doses of study medication will be administered to the study subjects by study personnel.  The 
exact start and stop time of administration of study medication will be documented within each 
subject’s eCRF.  No formal summary of treatment compliance will be produced. 
4.5. 
Prior and Concomitant Medications 
All prior and concomitant medications will be tabulated for the overall study population and by 
treatment group (Table 14.1.5.1).  Prior and concomitant medications will be coded to the 
therapeutic drug classes and generic drug names using the World Health Organization (WHO) 
Drug classifications version 2015.  The table will also provide number of subjects in each 
medication grouped by ATC class (defined as ATC Level 2 or Level 3 if Level 2 is not defined).  
4.5.1. 
Total Opioid Consumption for Pain Management During Treatment 
Total opioid consumptions in IV morphine equivalent dose (mg) per subject will be determined 
for each period.  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; sites with less than 5 subjects in total will be pooled 
to form an analysis site for this purpose (See Section 3.5.3).  Nominal p-values will be reported 
as is.  This analysis will be prepared for treatment groups overall, and by surgery type, risk 
status, randomization strata and subgroups (Tables 14.1.5.2.1 - 14.1.5.2.5).       
 


 
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5. 
EFFICACY ANALYSIS 
Not applicable. 


 
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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 of study drug taken.  The summary 
will provide number of subjects (%) who had 1, 2, 3… or 7 doses of study drug in the study by 
treatment overall, by surgery type, risk status and randomization strata.  Percentage will be 
calculated based on total number of treated subjects in the group (Tables 14.3.1.1 and 14.3.1.2).  
The table will also provide cumulative statistics for each group. 
6.2. 
Adverse Events 
6.2.1. 
Adverse Event Summary 
Adverse events reported after Dose 1through the final follow-up (LSD+28) will be considered as 
treatment emergent adverse events (TEAEs).  The Medical Dictionary for Regulatory Activities 
(Version 18.1) will be used to classify all AEs with respect to system organ class (SOC) and 
preferred term. 
The following 7 summaries will be prepared for the TEAEs. All data summaries will provide 
event rate (number (%) subjects) as well as total number of events in each category.  A subject 
who had same event more than once will be counted only once in the event rate [n (%)] but all 
events will be included in the total ‘Events’ column. TEAE summaries are planned for all 
subjects, by risk status, and by surgery category.  If data warrants additional summary by 
subgroup (combination of risk status and surgery type) may be produced.  
1. a topline summary of TEAEs for overall, by risk status, and surgery type, and subgroups 
(Tables 14.3.2.1.1 – 14.3.2.1.5). 
2. a summary table by preferred term displayed in descending order of total events across 
treatment group in the study for overall, by risk status, and surgery type, randomization 
strata, and subgroups (Tables 14.3.2.2.1 – 14.3.2.2.5). 
3. a summary table by SOC and preferred term in the study for overall, by risk status, 
surgery type, randomization strata, and subgroups (Tables 14.3.2.3.1 – 14.3.2.3.5). 
4. a detailed summary table by system organ class, preferred term and intensity level for 
overall, by risk status, surgery type, randomization strata and subgroups 
(Tables 14.3.2.4.1 – 14.3.2.4.5). 
5. a detailed summary table by system organ class, preferred term and relationship to study 
drug for overall, by risk status, surgery type, randomization strata, and subgroups 
(Tables 14.3.2.5.1 – 14.3.2.5.5). 
6. a table of serious TEAEs by system organ class and preferred term for overall, by risk 
status, and surgery type and randomization strata (Tables 14.3.2.6.1 – 14.3.2.6.2). 


 
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7. a table of TEAEs leading to discontinuation of study drug treatment / study by system 
organ class and preferred term for overall, by risk status, and surgery type  (Tables 
14.3.2.7). 
6.2.2. 
Adverse Event Analysis 
6.2.2.1. 
Adverse Event of Special Interest 
A subset of TEAEs will be marked as Adverse Event of Special Interest (AEOSI) for adverse 
event analysis.  The AEOSI may include but are not limited to the following categories: 
1) Cardiovascular events 
2) Thrombotic events 
3) Bleeding-related events 
4) Renal events 
5) Hepatobiliary events 
6) Infusion site related events 
7) Wound healing related events 
AEOSI will be tabulated by category and AE preferred term for treatment overall, by risk status, 
surgery type, randomization strata, and subgroup (Tables 14.3.2.8.1 - 14.3.2.8.5). 
6.2.2.2. 
Acute Reactions  
Acute Reactions will include all AEs that occurred within 60 minutes (inclusive) of study drug 
administration.  This analysis will require complete onset data/time for AE.  Hence, if an AE’s 
onset time is absent this AE will be excluded from this analysis.   
To identify these events all TEAEs will be mapped to associated infusion number based on the 
onset date and time; the elapsed time (minutes) will be calculated between the onset date/time 
and the corresponding infusion end date/time. If the elapsed time is within 0-60 minutes 
(inclusive), the event would be flagged as an Acute Reaction.  Acute reactions will be identified 
in the TEAEs from all studies.  
Acute Reactions will be tabulated by treatment group for overall, by risk status, surgery type, 
randomization strata, and subgroups (Tables 14.3.2.9.1 - 14.3.2.9.5). 
6.3. 
Clinical Laboratory Tests 
Laboratory values, including chemistry, hematology, urinalysis, and coagulation tests, will be 
collected at screening, 24 hours, Day 1 prior to surgery, at Hour 48 , LSD+1/discharge (if prior 
to Hour 48, or to be repeated in subjects who receive ≥ 4 doses), and LSD+7.  
A central lab will be used for this study.  To evaluate change in lab test results, the observed 
value at each time point will be compared to the normal range, expressed as normal range 
standardized value (NRSDV).  


 
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NRSDV = (Observed – NRLO)/(NRHI – NRLO)   
Where NRLO = normal range lower limit, NRHI = normal range upper limit, when NRSDV is 
less than 0, the lab result is lower than the lower limit, whereas when NRSDV is greater than 1 
the lab result is greater than the upper limit.   
Each lab test result at each time point will be displayed using a cumulative distribution curve. 
Figure 1 is an example showing the cumulative distribution curves of hemoglobin at baseline and 
Day 7. 
Figure 1:  Example of Hemoglobin Distribution Population Shift Analysis 
 
 
When a post baseline NRSDV cumulative distribution curve is on the left of the baseline curve, 
one concludes that the lab test result is shifted downward in the population.  On another hand, if 
the post baseline curve is on the right of the baseline curve, one concludes that the lab test result 
is shifted upward in the population. 
The significance of the shift will be evaluated based on the degree of shift comparing to the 
baseline and shift pattern observed in the placebo group.  This approach is referred to as the 
population shift analysis.  The population shift curves will be produced for Baseline, End of 
Treatment and End of Study.  Subjects who have 4 or more doses will also have an Hour 48 lab 
during treatment (see Section 3.4); this time point may be excluded from the analysis if there is 
not sufficient number of subjects with this data point (Figures 14.3.3.1 to 14.3.3.4). 
Unless an unscheduled Lab is served as the Baseline or End of Treatment or End of Study record 
(see Section3.4) the unscheduled laboratory tests will not be included in the shift analysis, but all 
lab results will be included in data listing.  


 
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6.3.1. 
Analysis of Laboratory Tests of Special Interest  
Proportion of subjects with clinically significant abnormal laboratory tests will be identified.   
The selected laboratory tests and the criteria for clinically significant abnormal results are 
provided in Table 6.  All lab tests, scheduled and un-scheduled will be included for this 
assessments.  This analysis will be an at risk analysis (Tables 14.3.3.5.1 - 14.3.3.5.4).   
Table 6:  Abnormal Results in Selected Laboratory Tests of Special Interest 
Category 
Test Name (s) 
Category for post baseline result [1] 
Hematology tests 
HGB, WBC, 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 
 
 
Albumin  
1) Shift from Normal to Abnormal, Low 
 
 
Total Bilirubin 
>1 to <1.5 times of ULN 
1.5 to <2 times of ULN 
2 to <2.5 times of ULN 
2.5 to <3 times of ULN 
≥ 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; ACM Global Central Laboratory was 
used in Phase 3 studies. 
[2] Subjects who had abnormal baseline will be tabulated separately if those subjects had post baseline lab tests that 
met the criteria in the renal and liver function tests. 
6.4. 
Vital Sign Measurements 
A vital sign listing will be prepared to display all vital signs measurements (blood pressure, heart 
rate, and SpO2).  Blood pressure will be analyzed visually (Figure 14.3.4.1) by showing the 
proportion of subjects in each result category and in each change from baseline category as 
demonstrated in example Figure 2 to Figure 5.  In addition, a cumulative distribution plot 
(Figure 14.3.4.2.1 - 14.3.4.2.2) showing blood pressure percent change from baseline will be 
produced for each post baseline time point as demonstrated in example Figure 6.  
If data warrant, a summary table may be produced to examine number of subjects meeting the 
PCSC criteria (SBP abs(CFB) ≥ 20 mmHg or DBP abs(CFB) ≥ 15 mmHg or abs(PCFB) ≥25%) 
at any time, during treatment and during follow-up (ie, post discharge) for treatment group 
overall, by risk status, and surgery type (Table 14.3.4.3). 


 
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Figure 2:  Example of SBP Results Distribution Analysis 
 
 
Figure 3:  Example of SBP Change from Baseline Distribution Analysis 
 
 


 
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Figure 4:  Example of DBP Results Distribution Analysis 
 
 
Figure 5:  Example of DBP Change from Baseline Distribution Analysis 
 
 


 
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Figure 6:  Example of SBP Percent Change from Baseline Distribution Curves 
 
 
 


 
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6.5. 
Electrocardiograms 
12-Lead ECG will be taken at screening, at Check-in, LSD+1 /discharge, LSD+7 and at time of 
early discontinuation.  Clinical interpretation of ECG results will be recorded as normal, 
abnormal and not clinically significant (NCS), or abnormal and clinically significant (CS).  ECG 
findings at each time point collected will be tabulated by treatment group at analysis visits of 
Baseline, End of Treatment, and End of Study for overall, by risk status, and by surgery type 
(Table 14.3.5). 
An ECG listing will be prepared and time point where the abnormal ECG is observed will be 
flagged. 
6.6. 
Wound Healing 
Wound healing progress will be assessed on LSD+1/ discharge, LSD+7 days, and at time of 
discontinuation.  Wound evaluation assessments will include investigator satisfaction score 
(0=completely unsatisfied and 10=completely satisfied) performed on LSD+1/discharge, and 
LSD+7days or discontinuation and surgical wound healing status performed on LSD+7 days or 
discontinuation only (see Table 7).   
Wound healing investigator satisfaction score will be tabulated with descriptive statistics of 
sample size, mean, standard deviation, minimum, median, and maximum.  Grading of erythema, 
drainage, edema, induration, and hematoma, severity of each symptom, and investigator’s 
judgement of clinical significance will be tabulated by treatment group with n (%) in each 
grade/category without inferential statistics.  A summary will be provided for overall, by risk 
status, and surgery type (Tables 14.3.6.1 – 14.3.6.6).   
A listing will be prepared for wound healing assessments. 
 
 


 
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Table 7:  Surgical Wound Status Assessment  
Parameter 
Grade 
Description 
Erythema 
0 
None 
1 
Very slight (barely perceptible) 
2 
Slight (well defined) 
3 
Moderate  
4 
Severe (beet redness) to slight eschar formation (injuries in depth) 
Drainage 
0 
None 
1 
Serous 
2 
Serosanguinous 
3 
Bloody 
4 
Purulent 
Edema 
0 
None 
1 
Very slight (barely perceptible) 
2 
Slight (edges well defined) 
3 
Moderate (raised approximately 1 mm) 
4 
Severe (raised >1 mm and beyond area of exposure) 
Induration 
0 
None 
1 
Minimal 
2 
Mild (spongy tissue) 
3 
Moderate (firm, warm) 
4 
Severe (hard, red, hot, crepitus) 
Hematoma 
0 
None 
1 
Minimal 
2 
Mild 
3 
Moderate 
4 
Severe 
 
 
 


 
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6.7. 
Subgroup Analyses for Safety Endpoints 
This study employs a stratified randomization based on surgery type and risk status.  Hence, 
study subjects are grouped into 4 subgroups based on their randomization strata. 
1) High Risk + Orthopedic Surgery 
2) Not High Risk + Orthopedic Surgery 
3) High Risk + Other Surgery 
4) Not High Risk + Other Surgery 
The following subgroups are planned in this study: 
A. Subgroup by surgery type (Orthopedic vs Other) 
B. Subgroup by risk status (High Risk vs Not High Risk) 
C. Subgroup by randomization strata (see above) 
D. Subgroup by age (age <65 vs age ≥65 at baseline)  
E. Subgroup by sex (male vs female) 
F. Subgroup by race (white vs non-white) 
Subgroup analyses are already planned for risk status, surgery type and randomization strata for 
all key safety parameters in this study.   The following parameters will also have a table for 
subgroups of (D) to (F): 
 Demographics and baseline characteristics 
 Total opioid consumption for pain management 
 TEAE, AEOSI, and Acute Reactions 


 
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7. 
REFERENCES 
None