Clinical trial NCT03434275
Conditions: Pain, Postoperative
Keywords: Total Knee Arthroplasty Pain Analgesia N1539 Phase 3b Knee Replacement
Sponsor: Baudax Bio
Start date: 2018-02-19; Completion date: 2019-05-21
Enrollment: 194 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to assess the effect of preoperative administration of N1539 on opioid consumption in subjects undergoing open unilateral total knee arthroplasty compared to placebo.

Detailed description:

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

Protocol documents:
Prot_000.pdf: 
 
 
 
REC-17-025 
 
A Phase 3b, Randomized, Double-Blind, Placebo-Control, Multicenter, Evaluation 
of the Safety and Efficacy of N1539 Administered Preoperatively in Open 
Unilateral Total Knee Arthroplasty 
 
NCT03434275 
 
Study Protocol – Amendment 002 
 
24 January 2018 
 


Page 1 of 65 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Compound Name: 
N1539 (meloxicam) Injection, for intravenous use 
Protocol Number: 
REC-17-025 
Protocol Title: 
A Phase 3b, Randomized, Double-Blind, Placebo-Control, 
Multicenter, Evaluation of the Safety and Efficacy of N1539 
Administered Preoperatively in Open Unilateral Total Knee 
Arthroplasty  
Date of Protocol: 
Amendment 001: 
Amendment 002: 
29 September 2017 
17 November 2017 
24 January 2018 
Study Designated 
Physician: 
Stewart McCallum, MD 
490 Lapp Rd 
Malvern, PA 19355 
Mobile: 610-888-3984 
Fax: 484-395-2471 
Email: smccallum@recropharma.com 
Contact: 
Erin Coyle 
Clinical Trial Manager 
490 Lapp Rd 
Malvern, PA 19355 
Mobile: 609-221-6498 
Email: ecoyle@recropharma.com 
 
Unauthorized copying or use of this information is prohibited. 


Protocol REC-17-025 with Amendment 002 
24JAN2018 
Page 2 of 65 
 
INVESTIGATOR’S AGREEMENT 
By signing below, I confirm that I have read this protocol (REC-17-025) 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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol REC-17-025 with Amendment 002 
24JAN2018 
Page 3 of 65 
 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Objectives:  The primary objective of this study is to assess the effect of preoperative administration 
of N1539 on opioid consumption in subjects undergoing open unilateral total knee arthroplasty 
compared to placebo. 
Secondary objectives are to assess: 
• 
The safety and tolerability of preoperative administration of N1539 compared to placebo 
• 
The effect of preoperative administration of N1539 on postoperative pain compared to 
placebo 
• 
The effect of preoperative administration of N1539 on healthcare utilization costs 
compared to placebo. 
Methodology:  This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study in 
adult subjects undergoing elective open unilateral total knee arthroplasty.  The surgical procedure will 
be conducted in an inpatient hospital setting that is expected to result in a hospital stay of ≥24 hours.  
Each subject will be screened for eligibility within 28 days before undergoing surgery on Day 1.   
Before surgery, approximately 200 eligible subjects will be randomized in a 1:1 ratio to receive either 
N1539 30 mg or placebo administered as an intravenous (IV) bolus injection in ≤15 seconds.   
As part of multimodal pain management, subjects will receive oral acetaminophen 650 mg and oral 
gabapentin 600 mg 30 to 90 minutes before the scheduled surgical procedure.  Subjects will continue 
to receive acetaminophen 650 mg PO Q8H through last study dose + 1 day (LSD+1).  Subjects will 
also receive an appropriate prophylactic IV antibiotic and tranexamic acid 1 gram IV 30 to 90 minutes 
before surgery (Appendix B). 
Following administration of spinal anesthesia and before the start of surgery (ie, time of first incision), 
subjects will receive the first dose of study drug according to randomization.  All subjects will then 
undergo the surgical procedure according to the investigator’s clinical practice and in accordance with 
institutional standards. 
Just prior to wound closure, bupivacaine HCl 0.5% 30 mL with epinephrine 0.5 mg expanded in a 
volume of 90 mL normal saline will be injected locally into various areas of the surgical site as 
described in Section 5.2.3.   
At the end of the surgical procedure (Hour 0, defined as the time of last suture, staple, or steri-strip 
placement) and through hospital discharge, postoperative pain management will be according to the 
protocol (Section 5.13).  Other standard of care procedures associated with the surgical procedure will 
be carried out according to the investigator’s clinical practice and in accordance with institutional 
standards.  Subjects may also receive IV ondansetron 4 mg as needed for postoperative nausea and 
vomiting (PONV) according to FDA prescribing information. 


Protocol REC-17-025 with Amendment 002 
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Page 4 of 65 
 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Additional doses of study drug will be administered every 24 hours (±1 hour) after the first dose.  
Dosing will continue until the subject is either discharged from the hospital or until IV study drug 
analgesia is no longer clinically appropriate. 
In addition to study drug, all subjects will have access to IV and/or oral (PO) opioid medication as 
needed for the management of breakthrough pain starting at Hour 0 and continuing through hospital 
discharge. 
Subjects will remain as inpatients for at least 24 hours or until inpatient care is no longer clinically 
indicated.  Upon discharge, subjects will be provided a standard of care regimen for pain management 
and for physical therapy as determined by the investigator. 
Twenty-four hours and 48 hours after hospital discharge qualified study staff will conduct telephone 
interviews to assess opioid medication use, pain intensity, physical therapy visits, and utilization of 
healthcare resources (ie, hospital readmission, use of skilled nursing facilities, unscheduled phone 
calls and/or office visits related to pain, and emergency room [ER] visits related to pain and/or other 
medical issues).   
Subjects will visit the clinical site between Postoperative Days (PODs) 10 and 14 to be assessed for 
adverse events, wound healing, and utilization of healthcare resources.    
A final telephone interview will be conducted on POD 30 to assess for AEs, opioid use, and utilization 
of healthcare resources.  After the POD 30 telephone interview, subjects will be discharged from the 
study.  
Number of subjects to be enrolled:  Approximately 200 subjects will be enrolled (N1539: 100; 
placebo, 100). 
Number of study sites:  Up to 20 sites 
Study country location:  United States 
Inclusion criteria:  No subject should be assigned to treatment until all eligibility criteria have 
been satisfied.  To qualify for the study a subject must: 
1. Voluntarily provide written informed consent. 
2. Be able to understand and comply with all study procedures and agree to participate in the 
study program as outlined in the protocol. 
3. Be male or female 35 to 80 years of age, inclusive at the time of consent. 
4. Have plans to undergo an elective, primary (no repeat arthroplasties) open unilateral total knee 
arthroplasty, and be expected to require IV analgesia, remain in an inpatient setting for ≥24 
hours, and receive at least two doses of study drug. 
5. Be classified as American Society of Anesthesiology (ASA) physical status category 1, 2, or 3 
(Appendix D). 


Protocol REC-17-025 with Amendment 002 
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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Inclusion criteria (continued): 
6. Have a negative pregnancy test at screening and before surgery and be using a highly effective 
contraception method (ie, abstinence, intrauterine device [IUD], hormonal 
[estrogen/progestin] contraceptives, or double barrier method) for at least one menstrual cycle 
prior to screening and for the duration of the study, if female of childbearing potential; or be 
menopausal defined as 12 months of amenorrhea in the absence of other biological or 
physiological causes; or post-menopausal for at least 1 year; or be surgically sterile 
(documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy). 
7. Be surgically sterile (biologically or surgically) or commit to the use of a highly effective 
contraception method (eg, abstinence or double barrier method) with female partner(s) of 
childbearing potential from screening through the end of the study, if male. 
8. Have a body mass index <40 kg/m2, inclusive at screening. 
Exclusion criteria: A subject will be excluded from study participation if he/she: 
1. Has a known allergy or hypersensitivity to eggs, meloxicam, aspirin, other non-steroidal 
anti-inflammatory drugs (NSAIDs), or any excipient of N1539 or placebo. 
2. Has plans for the open unilateral total knee arthroplasty procedure to be performed under 
general anesthesia (requiring intubation or laryngeal mask airway). 
3. Is female and presently nursing a baby or providing breast milk for a baby. 
4. Is female and intends to become pregnant during the study. 
5. Has a diagnosis of rheumatoid or inflammatory arthritis or systemic disease. 
6. Has a history of previous total knee arthroplasty (TKA). 
7. Has plans for a concurrent surgical procedure (eg, bilateral TKA). 
8. Is undergoing unicompartmental knee replacement or revision TKA.    
9. Has a history of myocardial infarction within the 12 months before screening. 


Protocol REC-17-025 with Amendment 002 
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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Exclusion criteria (continued): 
10. Has, as determined by the investigator or the sponsor’s medical monitor, a history or clinical 
manifestations of significant renal (glomerular filtration rate [GFR]<60 mL/min/1.73 m2), 
hepatic, cardiovascular, metabolic, neurologic, psychiatric, respiratory, or other condition that 
would preclude participation. 
11. Has a clinically significant abnormal clinical laboratory test value as determined by the 
investigator. 
12. Has active or recent (within 6 months) gastrointestinal ulceration or bleeding, with exception 
of events related to an ulcerative colitis diagnosis. 
13. Has a known bleeding disorder that may be worsened with the administration of an NSAID. 
14. Has evidence of a clinically significant 12-lead ECG abnormality as determined by the 
investigator. 
15. Has a confirmed allergy to opioid medications. 
16. Has received chronic opioid therapy (daily use of opioids for 30 days or longer) or > 5 days of 
opioid use, within 30 days prior to screening. 
17. Has used long acting opioid medication within 3 days before the surgical procedure.    
18. Is unable to discontinue medications, that have not been at a stable dose for at least 7 days 
prior to the scheduled surgical procedure, within 5 half-lives of the specific medication (or, if 
half-life is not known, within 48 hours) before dosing with study drug, with exception of 
medications utilized for surgical preparation.   
19. Is unable to discontinue herbal medications/supplements associated with an increased 
bleeding risk at least 7 days prior to surgery through hospital discharge, including but not 
limited to:  gingko biloba, garlic, ginger, ginseng, hawthorn, fish oil (omega-3-fatty acid), 
dong quai, feverfew, vitamin E.    
20. Is receiving lithium or a combination of furosemide with either an angiotensin converting 
enzyme inhibitor or an angiotensin receptor blocker.   
21. Is currently receiving treatment with oral meloxicam (Mobic®) or another NSAID within 
48 hours prior to surgery.   
22. Has received any investigational product within 30 days before dosing with study drug.   
23. Has undergone major surgery in the last 3 months that could interfere with study assessments. 
24. Has undergone or is expected to undergo radiation therapy, chemotherapy, or other biological 
therapy for cancer treatment, within 60 days prior to screening through POD 30. 
Investigational product:  N1539 (meloxicam) Injection 30 mg, for intravenous use  
Reference product: Placebo injection for intravenous use 


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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Duration of treatment:  Each subject is expected to receive at least two doses of study drug during 
their participation in the study.  Randomized subjects will receive their first dose of study drug (Dose 
1) after administration of spinal anesthesia and prior to the start of surgery (defined as time of first 
incision).   Additional doses of study drug will be administered every 24 hours ± 1 hour from Dose 1 
(ie, 24 hours and 48 hours) until hospital discharge or until IV study drug analgesia is no longer 
clinically appropriate, whichever is first.   
A final dose of study drug may be administered up to 4 hours early in subjects who are scheduled to 
be discharged, at the discretion of the investigator.  Subjects who do not receive a dose of study drug 
for >28 hours following their previous dose should be considered off treatment, and should not receive 
further study drug. 
Efficacy assessments:  Efficacy assessments include: 
• 
Pain intensity assessments using an 11-point numeric pain rating scale (NPRS; 0 - 10) 
where 0=no pain, and 10=the worst pain imaginable, as follows:  upon arrival at the 
PACU, at various scheduled timepoints relative to first dose of study drug, before 
administration of opioid medication, before and during ambulation, before hospital 
discharge, 24 hours and 48 hours after discharge, POD 10 to 14, and POD 30  
• 
Patient Global Assessment (PGA) of pain control starting at POD 1 and continuing each 
day through hospital discharge or last study dose (LSD) +1 day, whichever occurs first. 
• 
Overall Benefit of Analgesia Score Questionnaire (OBAS) starting at POD 1 and 
continuing each day through hospital discharge or LSD +1, whichever occurs first 
Efficacy endpoints: The primary efficacy endpoint is total use of opioid analgesia from Hour 0 
through 24 hours. 
Secondary endpoints include: 
• 
Sum of pain intensity from the time of first dose of study drug through 24 hours (SPI24) 
• 
Percentage of subjects who are opioid free from Hour 0 through 24 hours 
• 
Time to first use of IV or oral opioid analgesia 
Other efficacy endpoints include: 
• 
Total use of opioid analgesia from first dose of study drug through 24 hours (before 2nd 
dose of study drug) 
• 
Total use of opioid analgesia from Hour 0 through 48 hours 
• 
Total use of opioid analgesia from Hour 0 through hospital discharge 
• 
Total use of opioid analgesia from hospital discharge through 24-hour telephone interview 


Protocol REC-17-025 with Amendment 002 
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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Efficacy endpoints (continued): 
• 
Total use of opioid analgesia from the 24-hour telephone interview through the 48-hour 
telephone interview 
• 
Percentage of subjects that are opioid free from Hour 0 through 48 hours 
• 
Percentage of subjects that are opioid free from Hour 0 through hospital discharge 
• 
Percentage of subjects who used any opioid medication after hospital discharge through 
POD 30.   
• 
Time to first IV opioid medication defined as the time from Hour 0 until time of first use 
of IV opioid medication 
• 
Time to first oral opioid rescue medication defined as the time from Hour 0 until time of 
first use of oral opioid medication  
• 
Pain intensity during first assisted ambulation  
• 
Pain intensity during first unassisted ambulation 
• 
SPI from time of first dose of study drug through first assisted ambulation 
• 
SPI from time of first dose of study drug through first unassisted ambulation 
• 
SPI from time of first dose of study drug through 48 hours 
• 
SPI from time of first dose of study drug through hospital discharge or LSD+1, whichever 
comes first  
• 
Time to first assisted ambulation defined as the time from Hour 0 until time when first 
assisted ambulation occurs 
• 
Time to first unassisted ambulation defined as the time from Hour 0 until time when first 
unassisted ambulation occurs 
• 
Subject overall evaluation of pain control on 5-point categorical scale on each 
postoperative day, starting on POD 1 and continuing through hospital discharge or 
LSD+1, whichever occurs first.   
• 
The OBAS total score and opioid distress dimension subscore on each postoperative day, 
starting on POD 1 and continuing through hospital discharge or LSD+1, whichever occurs 
first 
• 
Pain intensity at the following follow-up time points: 24 hours and 48 hours post 
discharge, and POD 10-14, and POD 30 


Protocol REC-17-025 with Amendment 002 
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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Safety Assessments:  Safety will be assessed throughout the study through the recording of adverse 
events, vital signs, clinical laboratory testing, and the evaluation of wound healing.  
Safety endpoints include: 
• 
Incidence of treatment-emergent adverse events (TEAEs) 
• 
Incidence of potentially clinically significant abnormal clinical laboratory values 
• 
Investigator satisfaction with wound healing before hospital discharge and during the 
follow-up visit (POD 10 to 14). 
Healthcare Utilization Assessments: 
Health economic outcomes assessments include: 
• 
Hospital length of stay  
• 
Total cost of hospitalization 
• 
Incidence of hospital readmissions 
• 
Postsurgical physical therapy visits  
• 
Use of skilled nursing facility 
• 
Use of other health services following hospital discharge (ie, unscheduled phone calls 
related to pain, unscheduled visits related to pain, and visits to the emergency department 
related to pain). 


Protocol REC-17-025 with Amendment 002 
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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Healthcare Utilization endpoints include: 
• 
Length of hospital stay defined as days from hospital admission until the hospital 
discharge order is written. 
• 
Total cost of hospitalization (taken from the UB-04/hospital claims form) 
• 
Duration of time in the PACU (time in through time out of PACU) 
• 
Percentage of subjects with hospital readmission through POD 30 
• 
Total number of postsurgical physical therapy visits through POD 30 
• 
Percentage of subjects who required a skilled nursing facility from hospital discharge 
through POD 30 
• 
Total time spent in skilled nursing facility from hospital discharge through POD 30 
• 
Percentage of subjects who made a phone call related to postsurgical pain from hospital 
discharge through POD 30 
• 
Total number of phone calls per subject related to postsurgical pain from hospital 
discharge through POD 30 
• 
Percentage of subjects who had an unscheduled visit related to postsurgical pain from 
hospital discharge through POD 30 
• 
Total number of unscheduled visits per subject related to postsurgical pain from hospital 
discharge through POD 30 
• 
Percentage of subjects who had an emergency room visit for postsurgical pain from 
hospital discharge through POD 30 
• 
Total number of visits to the emergency room per subject for postsurgical pain from 
hospital discharge through POD 30 


Protocol REC-17-025 with Amendment 002 
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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Sample Size:  The sample size for this study (100 subjects per group) will have at least 90% power to 
detect the difference between N1539 30 mg versus placebo in total opioid consumption based on the 
results observed in a Phase 3 safety study that evaluated all major surgeries.  The study results 
suggested that the total opioid consumption was lower in subjects treated with N1539 30 mg 
compared to placebo, and that the observed effect size in total opioids consumption measured by IV 
morphine equivalent dose (IVMED, mg) ranged from 0.5 to 0.7 in this subgroup.   
Study populations:   
Intent-to-Treat Population (ITT):  The ITT population will include all subjects who qualify for the 
study and are randomized for treatment prior to surgery.  ITT subjects may or may not receive 
randomized treatment.  
Safety population: The safety population will consist of all subjects who receive at least one injection 
of study drug.  All safety evaluations will be based on the safety population. 
The efficacy population (ie, modified intent-to-treat [mITT]):  The efficacy population will consist of 
all subjects who receive at least one injection of study drug and have the scheduled surgery.  All 
efficacy evaluations will be based on the efficacy population. 


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Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-025 
Name of Study Drugs:   
N1539 (meloxicam) Injection, for 
intravenous use 
Protocol Title:  A Phase 3b, Randomized, Double-Blind, 
Placebo-Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered Preoperatively in 
Open Unilateral Total Knee Arthroplasty  
Name of Active Ingredient:  
Meloxicam 
Phase of Development:  3b 
Statistical Methods: 
Efficacy analysis:  Efficacy endpoints will be tabulated by treatment groups and time points as 
appropriate; descriptive statistics will be provided, including sample size, mean, standard deviation, 
median, minimum and maximum for continuous variables, or frequency (number of subjects and 
percentage) distribution of each category for categorical variables.   
Treatment effect will be evaluated using Analysis of Covariance (ANCOVA) for opioid consumption 
related endpoints, pain intensity related endpoints, and OBAS related endpoints; the ANCOVA model 
will include treatment effect and investigational sites as a covariate.  Difference in LS means will be 
compared between the treatment groups. 
Kaplan-Meier survival analysis will be carried out for time to event endpoints, including survival 
curves, 25%, 50% and 75% tiles estimates and corresponding 95% confidence intervals (CI), and log-
rank test.  Cox proportional hazards analysis will also be performed for time to event endpoints; the 
model will include the treatment effect and the investigational sites; hazards ratio and corresponding 
95% CI will be presented. 
Treatment effect on PGA scores will be evaluated based on proportion of subjects rated their pain 
control as good, very good, or excellent using CMH test controlling for analysis center.  CMH test 
will apply to other category variables, such as proportion of subjects who took any opioids or who 
were opioid free at various time periods.   
Safety analysis:  The Medical Dictionary for Regulatory Activities (Version 20 or higher) will be 
used to classify all AEs with respect to system organ class and preferred term.  AEs will be 
summarized by treatment group.  Clinical laboratory parameters collected after the first dose of study 
drug will be evaluated by comparing to baseline; subjects with potentially clinically significant 
changes from baseline in clinical laboratory parameters will be identified and tabulated by treatment 
group.   The number and proportion of subjects with abnormal wound healing observations will be 
summarized by treatment group. 
Healthcare Utilization analysis: A separate SAP will be constructed for analysis of Health Care 
Utilization and total costs as recorded on the UB 04.  This SAP will detail the objectives, methods for 
conducting the relevant analyses, and the format for presentation of the findings.  Subject cohorts of 
interest will be defined and the variables to be measured as well as the steps in data processing and 
analyses will also be presented. 
 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ...................................................................................... 3 
TABLE OF CONTENTS ..................................................................................... 13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 17 
1. 
INTRODUCTION ............................................................................ 20 
1.1. 
N1539 (meloxicam) Injection, for Intravenous Use ......................... 20 
1.2. 
Total Knee Arthroplasty ................................................................... 21 
2. 
STUDY OBJECTIVE ....................................................................... 21 
3. 
INVESTIGATIONAL PLAN ........................................................... 22 
3.1. 
Overall Study Design ........................................................................ 22 
3.2. 
Rationale for Study Design and Control Groups .............................. 23 
4. 
STUDY POPULATION ................................................................... 24 
4.1. 
Inclusion Criteria .............................................................................. 24 
4.2. 
Exclusion Criteria ............................................................................. 24 
4.3. 
Discontinuation of Subjects .............................................................. 26 
4.3.1. 
Procedures for Withdrawal ............................................................... 26 
4.3.2. 
Replacement of Subjects ................................................................... 26 
4.4. 
Lifestyle Guidelines .......................................................................... 26 
4.4.1. 
Confinement ..................................................................................... 26 
4.4.2. 
Diet ................................................................................................... 26 
5. 
TREATMENTS ................................................................................ 27 
5.1. 
Venous Thromboembolism Prophylaxis .......................................... 27 
5.2. 
Perioperative Drug Administration ................................................... 27 
5.2.1. 
Intrathecal Anesthesia ....................................................................... 27 
5.2.2. 
Intraoperative Medications ............................................................... 28 
5.2.3. 
Local Infiltrate .................................................................................. 28 
5.2.4. 
Study Drug Administration............................................................... 29 
5.3. 
Identity of Study Drug ...................................................................... 29 
5.4. 
Method of Assigning Subjects to Treatment Groups ....................... 29 
5.5. 
Selection of Doses ............................................................................ 29 
5.6. 
Selection of Timing of Dose ............................................................. 30 


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5.7. 
Blinding and Unbinding of Study Drug ............................................ 30 
5.8. 
Treatment Compliance ...................................................................... 30 
5.9. 
Drug Accountability ......................................................................... 30 
5.10. 
Packaging, Labeling, and Storage .................................................... 30 
5.11. 
Prior and Concomitant Medications ................................................. 31 
5.12. 
Concomitant Interventions and Procedures ...................................... 31 
5.13. 
Opioid Medication ............................................................................ 31 
5.13.1. 
Intraoperative .................................................................................... 31 
5.13.2. 
Inpatient ............................................................................................ 31 
5.13.3. 
Follow-up .......................................................................................... 32 
5.14. 
Non-Opioid Analgesics .................................................................... 32 
5.15. 
Prohibited Medications/Procedures .................................................. 32 
6. 
STUDY PROCEDURES .................................................................. 33 
6.1. 
Total Knee Arthroplasty ................................................................... 33 
6.2. 
Demographic and Efficacy Assessments .......................................... 33 
6.2.1. 
Demographics ................................................................................... 33 
6.2.2. 
Medical History ................................................................................ 33 
6.2.3. 
Physical Examination ....................................................................... 34 
6.2.4. 
Physical Therapy Assessments ......................................................... 34 
6.2.5. 
Ambulation ....................................................................................... 34 
6.2.6. 
Pain Intensity (PI) ............................................................................. 34 
6.2.7. 
Patient Global Assessment (PGA) of Pain Control .......................... 35 
6.2.8. 
Overall Benefit of Analgesia Score Questionnaire (OBAS) ............ 36 
6.3. 
Safety Assessments ........................................................................... 36 
6.3.1. 
12-Lead Electrocardiogram (ECG) ................................................... 36 
6.3.2. 
Clinical Laboratory Tests ................................................................. 36 
6.3.3. 
Vital Sign Measurements .................................................................. 37 
6.3.4. 
Wound Healing Assessment ............................................................. 37 
6.3.5. 
Post Discharge Telephone Interviews for Healthcare Utilization .... 37 
6.3.6. 
Cost of Hospitalization ..................................................................... 38 
6.3.7. 
End of Study ..................................................................................... 38 
6.4. 
Assessments by Visit ........................................................................ 38 


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6.4.1. 
Screening Period (Day -28 to Day -1) .............................................. 38 
6.4.2. 
Inpatient Period ................................................................................. 39 
6.4.3. 
Hospital Discharge ............................................................................ 40 
6.4.4. 
24-Hour and 48-Hour Post Discharge Telephone Interviews ........... 40 
6.4.5. 
Follow-up Visit (POD 10 to 14) ....................................................... 41 
6.4.6. 
Postoperative Day 30 Telephone Interview (End of Study) ............. 41 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........ 42 
7.1. 
Definition of an Adverse Event ........................................................ 42 
7.2. 
Definition of a Serious Adverse Event ............................................. 43 
7.3. 
Recording and Evaluating Adverse Events and Serious Adverse 
Events ............................................................................................... 43 
7.3.1. 
Assessment of Intensity .................................................................... 44 
7.3.2. 
Assessment of Causality ................................................................... 44 
7.3.3. 
Assessment of Outcome ................................................................... 44 
7.4. 
Follow-up of Adverse Events and Serious Adverse Events ............. 45 
7.5. 
Prompt Reporting of Serious Adverse Events to the Sponsor .......... 45 
7.6. 
Regulatory Reporting Requirements ................................................ 46 
7.7. 
Special Reporting Situations: Pregnancy .......................................... 47 
8. 
STATISTICAL METHODOLOGY AND DETERMINATION OF 
SAMPLE SIZE ................................................................................. 48 
8.1. 
Determination of Sample Size .......................................................... 48 
8.2. 
Study Endpoints ................................................................................ 48 
8.2.1. 
Efficacy Endpoints ............................................................................ 48 
8.2.2. 
Safety Endpoints ............................................................................... 49 
8.2.3. 
Healthcare Utilization Endpoints ...................................................... 50 
8.1.1. 
Analysis Populations ........................................................................ 50 
8.1.2. 
Test Hypothesis and P Value Justification ....................................... 51 
8.1.3. 
Procedures for Handling Missing Data ............................................. 51 
8.1.4. 
Definitions for Assessment Windows .............................................. 51 
8.1.5. 
Derived Variables ............................................................................. 51 
8.2. 
Study Population Summaries ............................................................ 51 
8.2.1. 
Disposition ........................................................................................ 51 
8.2.2. 
Demographics and Baseline Characteristics ..................................... 52 


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8.2.3. 
Protocol Violations ........................................................................... 52 
8.2.4. 
Treatment Compliance ...................................................................... 52 
8.2.5. 
Prior and Concomitant Medications ................................................. 52 
8.3. 
Efficacy Summaries and Analysis .................................................... 52 
8.4. 
Safety Summaries ............................................................................. 53 
8.4.1. 
Extent of Exposure ........................................................................... 53 
8.4.2. 
Adverse Events ................................................................................. 53 
8.4.3. 
Subjects with Clinically Significant Laboratory Values .................. 53 
8.4.4. 
Wound Healing ................................................................................. 53 
8.5. 
Healthcare Utilization Summaries .................................................... 53 
9. 
STUDY ADMINISTRATION ......................................................... 54 
9.1. 
Regulatory and Ethical Considerations ............................................ 54 
9.1.1. 
Ethical Conduct of the Study ............................................................ 54 
9.2. 
Quality Assurance ............................................................................. 55 
9.3. 
Study and Site Closure...................................................................... 56 
9.4. 
Records Retention ............................................................................. 56 
9.4.1. 
Archiving of Study-Related Documents ........................................... 56 
9.5. 
Information Disclosure ..................................................................... 57 
9.5.1. 
Publication ........................................................................................ 57 
10. 
LIST OF REFERENCES .................................................................. 58 
APPENDIX A: STUDY ASSESSMENTS: PROTOCOL REC-17-025 .......... 59 
APPENDIX B:  CLINICAL CARE PROTOCOL MEDICATIONS ............... 60 
APPENDIX C: NUMBERIC PAIN RATING SCALE (NPRS) ...................... 63 
APPENDIX D: AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM ........... 65 
 
LIST OF TABLES 
Table 1: 
Perioperative Medications ................................................................ 27 
Table 2: 
Overall Benefit of Analgesia Score Questionnairea ......................... 36 
Table 3: 
Clinical Laboratory Testing .............................................................. 37 
Table 4: 
Local Infiltrate Administration ......................................................... 61 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition of Term 
AE 
Adverse event 
ASA 
American Society of Anesthesiology 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BP 
Blood Pressure 
BPM 
Beats per minute 
CFR 
(United States) Code of Federal Regulations 
ºC 
degrees Centigrade 
CL 
Clearance 
Cmax 
Maximum observed drug concentration 
eCRF 
Electronic case report form 
ER 
Emergency room 
DBP 
Diastolic Blood Pressure 
DOS 
Day of surgery 
Dose 1 
Start time of first dose of study drug via IV bolus injection 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
H 
Hour 
HCl 
Hydrochloride 
Hour 0 
Time of end of surgery (ie, time of last suture, staple, or 
steri-strip placement) 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IP 
Investigational Product 
IR 
Immediate release 
ITT 
Intend-to-treat 
IUD 
Intrauterine device 
IV 
Intravenous 
Kg 
Kilogram 


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Abbreviation 
Definition of Term 
L 
Liter 
LSD 
Last study dose 
LSD +1 
Last study dose plus 1 day 
m2 
Square meters 
Mg 
Milligram 
Min 
Minute 
mITT 
Modified intent-to-treat 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
N1539 
N1539 (meloxicam) Injection, for intravenous use 
NCD 
NanoCrystal Colloidal Dispersion 
NF 
National Formulary 
NPRS 
Numeric Pain Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall Benefit of Analgesia Score Questionnaire 
PGA 
Patient Global Assessment 
pH 
Negative log of hydrogen ion concentration 
PI 
Pain Intensity 
PK 
Pharmacokinetic 
POD (PODx) 
Postoperative Day (Postoperative day x) 
PONV 
Postoperative nausea and vomiting 
Q2H 
Every 2 hours 
Q4H 
Every 4 hours 
Q24H 
Every 24 hours 
SAR 
Suspected adverse reaction 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SPI 
Sum of pain intensity 
SSAR 
Serious suspected adverse reaction 
SUSAR 
Serious unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
Tmax 
Time to maximum observed drug concentration 


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Abbreviation 
Definition of Term 
µL 
Microliter 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
 


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1. 
INTRODUCTION 
1.1. 
N1539 (meloxicam) Injection, for Intravenous Use 
Meloxicam, a non-steroidal anti-inflammatory (NSAID) of the enolic acid class, was first 
approved for oral use in the United States in 2000 and has a well-established safety 
profile in commercial use as an effective treatment for osteoarthritis and rheumatoid 
arthritis. 
Meloxicam administered orally 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) 
approximately 5-6 hours following oral administration (Degner 1997; Turck 1997a), 
which is consistent with its poor aqueous solubility.  By increasing the dissolution rate of 
the active meloxicam moiety using the proprietary NanoCrystal technology, N1539 
administered by (intravenous) IV bolus injection has been shown to have a rapid onset of 
action. 
In the N1539 clinical studies, meloxicam exposure was consistently greater after 
administration of N1539 via IV bolus injection compared to oral administration of Mobic 
at equivalent doses.  As expected, N1539 administered as an IV bolus injection resulted 
in substantially higher maximum observed concentration (Cmax) and earlier time to 
maximum concentration (Tmax) compared with oral administration of Mobic at equivalent 
doses over a range of 15 to 60 mg.  Eight to 12 hours after administration of equivalent 
doses of IV and oral meloxicam, plasma concentration-time curves were similar.  The 
Cmax and area under the concentration-time curve (AUC) for N1539 administered IV 
were similar across studies.   
Ad hoc analyses from the Phase 1 studies demonstrated that a single dose of N1539 
30 mg administered by IV bolus injection resulted in a slightly more than 2-fold higher 
AUC∞ and 4.65-fold higher Cmax relative to a single dose of Mobic 15 mg, the highest 
FDA approved dose, administered orally.  Importantly meloxicam plasma concentrations 
were sustained for 24 hours after N1539 IV administration making N1539 suitable for 
once a day dosing. 
In the clinical program for N1539 for the management of moderate to severe acute pain, a 
total of 2075 subjects were evaluated for safety in 11 clinical studies: 109 subjects were 
healthy volunteers who were enrolled in the four Phase 1 studies and 1966 were 
postoperative subjects who were enrolled in the seven Phase 2/3 efficacy and safety 
studies. 
In clinical studies, subjects who received N1539 by IV bolus injection had a rapid onset 
of pain relief.  Improvement in pain intensity scores was observed as early has 10 minutes 
after N1539 dosing and the treatment effect was sustained over the 24-hour dosing 
interval.  The reduction in pain intensity after treatment with N1539 30 mg was 
associated with less opioid rescue medication utilization.   
The safety data from the 1045 subjects who received two or more doses of N1539 
postoperatively including the 743 who received two or more doses at the commercial 


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dose of 30 mg support N1539 administered IV once daily as a safe treatment for the 
management of moderate to severe pain in adults.  The safety data demonstrate that 
N1539 30 mg has a safety profile similar to approved drugs in this NSAID class. 
1.2. 
Total Knee Arthroplasty 
Total knee arthroplasty, also known as total knee replacement, is one of the most 
commonly performed orthopedic procedures. As of 2010, total knee replacements were 
becoming increasingly common with over 600,000 performed annually in the United 
States (UpToDate®). Among older patients in the United States, the per capita number of 
primary total knee replacements doubled from 1991 to 2010 (from 31 to 62 per 10,000 
Medicare enrollees annually) (Cram 2012) and this number is expected to grow by 673 
percent to 3.48 million procedures by 2030 (Kurtz 2007). A variety of pathologic 
conditions affecting the knee can be treated with total knee replacement, leading to pain 
relief, to restoration of function, and to mobility.   
Severe postoperative pain, which remains one of the main problems after total knee 
arthroplasty, can negatively affect postoperative recovery.  Over the last 10 years, 
surgeons have prescribed IV patient-controlled analgesia, femoral nerve block, and 
continuous epidural infusions for 24 and 48 hours with and without a femoral block 
(Maheshwari 2009). Unfortunately, these techniques have been found to have 
shortcomings, not the least of which has been suboptimal pain control and unwanted side 
effects (Maheshwari 2009).  
Improvements in pain management techniques in the last decade have had a major impact 
on the practice of total hip and knee arthroplasty; however, a gold standard has not been 
established.  Although there are a number of treatment options for postoperative pain, 
there appears to be a shift towards multimodal approaches using systemic, local, and 
regional analgesia to minimize opioid consumption and to avoid opioid-related side 
effects (Maheshwari 2009). 
In a double-blind, randomized study by Motififard et al, (2017) a multimodal pain 
management regimen that included injections of bupivacaine, morphine, and the NSAID 
ketorolac was shown to provide postoperative pain relief and resulted in less opioid 
consumption and better early rehabilitation 48 hours after total knee arthroplasty 
compared to a control group that received epinephrine only.   
This study is designed to evaluate the effect of N1539 administered preoperatively and 
postoperatively as part of a multimodal pain management plan.  It is expected that N1539 
administered as an IV bolus injection before and after surgery will reduce the 
requirement for opioid analgesia and will improve the rehabilitation course in subjects 
undergoing total knee arthroplasty. 
2. 
STUDY OBJECTIVE 
The primary objective of this study is to assess the effect of preoperative administration 
of N1539 on opioid consumption in subjects undergoing open unilateral total knee 
arthroplasty compared to placebo. 


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Secondary objectives are to assess: 
• The safety and tolerability of preoperative administration of N1539 compared 
to placebo 
• The effect of preoperative administration of N1539 on postoperative pain 
compared to placebo 
• The effect of preoperative administration of N1539 on healthcare utilization 
costs compared to placebo. 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study in 
adult subjects undergoing elective open unilateral total knee arthroplasty.  The surgical 
procedure will be conducted in an inpatient hospital setting that is expected to result in a 
hospital stay of ≥24 hours.  Each subject will be screened for eligibility within 28 days 
before undergoing surgery on Day 1.   
Before surgery, approximately 200 eligible subjects will be randomized in a 1:1 ratio to 
receive either N1539 30 mg or placebo administered as an intravenous (IV) bolus 
injection in ≤15 seconds.   
As part of multimodal pain management, subjects will receive oral acetaminophen 650 
mg and oral gabapentin 600 mg 30 to 90 minutes before the scheduled surgical 
procedure.  Subjects will continue to receive acetaminophen 650 mg PO Q8H through 
last study dose + 1 day (LSD+1).  Subjects will also receive an appropriate prophylactic 
IV antibiotic and tranexamic acid 1 gram IV 30 to 90 minutes before surgery (Appendix 
B). 
Following administration of spinal anesthesia and before the start of surgery (ie, time of 
first incision), subjects will receive the first dose of study drug according to 
randomization.  All subjects will then undergo the surgical procedure according to the 
investigator’s clinical practice and in accordance with institutional standards. 
Just prior to wound closure, bupivacaine HCl 0.5% 30 mL with epinephrine 0.5 mg 
expanded in a volume of 90 mL normal saline will be injected locally into various areas 
of the surgical site as described in Section 5.2.3.   
At the end of the surgical procedure (Hour 0, defined as the time of last suture, staple, or 
steri-strip placement) and through hospital discharge, postoperative pain management 
will be according to the protocol (Section 5.13).  Other standard of care procedures 
associated with the surgical procedure will be carried out according to the investigator’s 
clinical practice and in accordance with institutional standards.  Subjects may also 
receive IV ondansetron 4 mg as needed for PONV according to FDA prescribing 
information. 


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Additional doses of study drug will be administered every 24 hours (±1 hour) after the 
first dose.  Dosing will continue until the subject is either discharged from the hospital or 
until IV study drug analgesia is no longer clinically appropriate. 
In addition to study drug, all subjects will have access to IV and/or oral (PO) opioid 
medication as needed for the management of breakthrough pain starting at Hour 0 and 
continuing through hospital discharge. 
Subjects will remain as inpatients for at least 24 hours or until inpatient care is no longer 
clinically indicated.  Upon discharge, subjects will be provided a standard of care 
regimen for pain management and for physical therapy as determined by the investigator. 
Twenty-four hours and 48 hours after hospital discharge qualified study staff will conduct 
telephone interviews to assess opioid medication use, pain intensity, physical therapy 
visits, and utilization of healthcare resources (ie, hospital readmission, use of skilled 
nursing facilities, unscheduled phone calls and/or office visits related to pain, and 
emergency room [ER] visits related to pain and/or other medical issues).   
Subjects will visit the clinical site between Postoperative Days (PODs) 10 and 14 to be 
assessed for adverse events, wound healing, and utilization of healthcare resources.    
A final telephone interview will be conducted on POD 30 to assess for AEs, opioid use, 
and utilization of healthcare resources.  After the POD 30 telephone interview, subjects 
will be discharged from the study. 
3.2. 
Rationale for Study Design and Control Groups 
The double-blind, placebo-controlled study design for N1539 30 mg administered 
preoperatively and followed by once daily dosing in a population of subjects undergoing 
open unilateral total knee arthroplasty is intended to avoid potential bias from subject or 
investigator knowledge of assigned treatment that could confound the interpretation of 
the efficacy and safety findings.   
 
   
 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
No subject should be assigned to treatment until all eligibility criteria have been satisfied.  
To qualify for the study a subject must: 
1. Voluntarily provide written informed consent. 
2. Be able to understand and comply with all study procedures and agree to 
participate in the study program as outlined in the protocol. 
3. Be male or female 35 to 80 years of age, inclusive at the time of consent. 
4. Have plans to undergo an elective, primary (no repeat arthroplasties) open 
unilateral total knee arthroplasty, and be expected to require IV analgesia, remain 
in an inpatient setting for ≥24 hours, and receive at least two doses of study drug. 
5. Be classified as American Society of Anesthesiology (ASA) physical status 
category 1, 2, or 3 (Appendix D). 
6. Have a negative pregnancy test at screening and before surgery and be using a 
highly effective contraception method (ie, abstinence, intrauterine device [IUD], 
hormonal [estrogen/progestin] contraceptives, or double barrier method) for at 
least one menstrual cycle prior to screening and for the duration of the study, if 
female of childbearing potential; or be menopausal defined as 12 months of 
amenorrhea in the absence of other biological or physiological causes; or post-
menopausal for at least 1 year; or be surgically sterile (documented hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). 
7. Be surgically sterile (biologically or surgically) or commit to the use of a highly 
effective contraception method (eg, abstinence or double barrier method) with 
female partner(s) of childbearing potential from screening through the end of the 
study, if male. 
8. Have a body mass index <40 kg/m2, inclusive at screening. 
4.2. 
Exclusion Criteria  
A subject will be excluded from study participation if he/she: 
1. Has a known allergy or hypersensitivity to eggs, meloxicam, aspirin, other non-
steroidal anti-inflammatory drugs (NSAIDs), or any excipient of N1539 or 
placebo. 
2. Has plans for the open unilateral total knee arthroplasty procedure to be 
performed under general anesthesia (requiring intubation or laryngeal mask 
airway). 
3. Is female and presently nursing a baby or providing breast milk for a baby. 
4. Is female and intends to become pregnant during the study. 
5. Has a diagnosis of rheumatoid or inflammatory arthritis or systemic disease. 


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6. Has a history of previous total knee arthroplasty (TKA). 
7. Has plans for a concurrent surgical procedure (eg, bilateral TKA). 
8. Is undergoing unicompartmental knee replacement or revision TKA 
9. Has a history of myocardial infarction within the 12 months before screening. 
10. Has, as determined by the investigator or the sponsor’s medical monitor, a history 
or clinical manifestations of significant renal (glomerular filtration rate 
[GFR]<60 mL/min/1.73 m2), hepatic, cardiovascular, metabolic, neurologic, 
psychiatric, respiratory, or other condition that would preclude participation. 
11. Has a clinically significant abnormal clinical laboratory test value as determined 
by the investigator. 
12. Has active or recent (within 6 months) gastrointestinal ulceration or bleeding, 
with exception of events related to an ulcerative colitis diagnosis. 
13. Has a known bleeding disorder that may be worsened with the administration of 
an NSAID.   
14. Has evidence of a clinically significant 12-lead ECG abnormality as determined 
by the investigator. 
15. Has a confirmed allergy to opioid medications. 
16. Has received chronic opioid therapy (daily use of opioids for 30 days or longer) or 
> 5 days of opioid use, within 30 days prior to screening. 
17. Has used long acting opioid medication within 3 days before the surgical 
procedure.    
18. Is unable to discontinue medications, that have not been at a stable dose for at 
least 7 days prior to the scheduled surgical procedure, within 5 half-lives of the 
specific medication (or, if half-life is not known, within 48 hours) before dosing 
with study drug, with exception of medications utilized for surgical preparation.   
19. Is unable to discontinue herbal medications/supplements associated with an 
increased bleeding risk at least 7 days prior to surgery through hospital discharge, 
including but not limited to: gingko biloba, garlic, ginger, ginseng, hawthorn, fish 
oil (omega-3-fatty acid), dong quai, feverfew, vitamin E.    
20. Is receiving lithium or a combination of furosemide with either an angiotensin 
converting enzyme inhibitor or an angiotensin receptor blocker.   
21. Is currently receiving treatment with oral meloxicam (Mobic®) or another 
NSAID within 48 hours prior to surgery.   
22. Has received any investigational product within 30 days before dosing with study 
drug.   
23. Has undergone major surgery in the last 3 months that could interfere with study 
assessments.     


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24. Has undergone or is expected to undergo radiation therapy, chemotherapy, or 
other biological therapy for cancer treatment, within 60 days prior to screening 
through POD 30. 
4.3. 
Discontinuation of Subjects 
4.3.1. 
Procedures for Withdrawal 
A subject may be discontinued from the study by the investigator or the sponsor at any 
time if either determines that it is not in the subject’s best interest to continue 
participation.  Subjects who receive at least one dose of study drug and are subsequently 
withdrawn from the study should be encouraged to complete the discharge assessments 
prior to leaving the study.  Subjects will be encouraged to return for the POD 10 to 14 
follow-up visit and to be followed through POD 30 telephone interview.  The date the 
subject is withdrawn and the primary reason for discontinuation will be recorded. 
4.3.2. 
Replacement of Subjects 
Discontinued subjects will not be replaced in this study.  However, the study will enroll 
an adequate number of subjects to meet the target size of approximately 200 subjects for 
evaluation in the safety population. 
4.4. 
Lifestyle Guidelines 
4.4.1. 
Confinement 
Each subject will arrive at the study site on Day 1 with sufficient time to be prepared for 
the surgical procedure and for the investigator or qualified designee to confirm continued 
eligibility to participate in the study.   
Subjects are expected to remain in the hospital for a minimum of 24 hours and will be 
discharged when appropriate based on clinical status.   Subjects may be discharged to 
home or to a skilled nursing facility as determined by the investigator or qualified 
designee. 
4.4.2. 
Diet 
Prior to the surgical procedure, subjects will be allowed nothing by mouth starting at a 
time designated by the investigator.  Following surgery, subjects will be encouraged to 
progress to a regular diet as tolerated and as determined by the investigator.   


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5. 
TREATMENTS 
5.1. 
Venous Thromboembolism Prophylaxis 
 Venous thromboembolism prophylaxis before and after surgery will be administered 
according to standard practice, based on the subject’s individual needs, at the discretion 
of the investigator and surgeon, and taking into consideration the American College of 
Chest Physicians (ACCP) (http://journal.chestnet.org/article/S0012-3692(12)60114-
7/fulltext#cesec390) and American Academy of Orthopaedic Surgeons (AAOS) 
https://www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdfguidelines for 
orthopedic  surgery. 
5.2. 
Perioperative Drug Administration 
On the day of surgery (Day 1), eligible subjects will receive perioperative medications as 
shown in Table 1.  All subjects will undergo open unilateral total knee arthroplasty 
according to institutional standards.   Surgery start (first incision) and surgery end (last 
suture, staple, or steri-strip placement [Hour 0]) times will be recorded. 
Table 1: 
Perioperative Medications 
30 to 90 Minutes  
Prior to Start of  
Surgical Procedure 
 
Prior to Start of  
Surgical Procedure 
 
Prior to 
Wound Closure 
End of Surgical 
Procedure 
(ie, Hour 0) 
Administer: 
Acetaminophen 650 mg PO 
Gabapentin 600 mg PO 
Tranexamic acid 1gram IVa 
Prophylactic IV antibiotic 
Following administration of 
intrathecal anesthesia (ie, 7.5 to 
15 mg bupivacaine HCl 
(Section 5.2.1) and before the 
start of surgery;  
Administer 1st dose of study drug 
by IV bolus injection in ≤15 
seconds according to 
randomization (Section 5.2.4) 
Administer local 
infiltration of 
bupivacaine HCl 0.5% 
30 mL with epinephrine 
0.5 mg expanded in a 
volume of 90 mL 
normal saline 
(Section 5.2.3) 
Follow a standardized 
care regime based on 
the surgeon’s clinical 
practice and according 
to institutional 
standards 
Acetaminophen 650 mg 
Q8H PO through 
LSD+1 
Subjects may receive 
IV ondansetron 4 mg as 
needed for 
postoperative nausea 
and vomiting (PONV) 
according to FDA 
prescribing information. 
Surgery start (first incision) 
Surgery end (last suture, staple, or steri-strip placement [Hour 0]) 
a 
A second dose of tranexamic acid may be given approximately 3 hours after the first at the discretion of the surgeon. 
5.2.1. 
Intrathecal Anesthesia 
Before the start of surgery, 7.5 mg to 15 mg of bupivacaine HCl will be administered 
intrathecally.  The time intrathecal anesthesia is administered will be recorded. 


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The following are prohibited: 
• Femoral and adductor canal blocks 
• Other regional neuraxial blocks not specified by protocol 
• Recent or planned cryoneurolysis   
5.2.2. 
Intraoperative Medications 
Fentanyl and morphine or other morphine derivatives may be administered 
intraoperatively (during the course of the surgical procedure); however, dosing with 
fentanyl (and morphine or other morphine derivatives) is to be avoided within the 
30 minutes prior to the anticipated conclusion of the surgical procedure (Section 5.12.1). 
Anxiolytics, sedatives, and other medications (except for analgesic agents) that are used 
for subject well-being during the intraoperative period may be administered according to 
the investigator’s clinical practice and in accordance with institutional standards.   
The time and dose of any medication administered during the intraoperative period will 
be recorded. 
5.2.3. 
Local Infiltrate  
Expand 30 mL of bupivacaine HCl 0.5% + epinephrine (0.5 mg) in a volume of 90 mL 
normal saline.  Draw up the expanded bupivacaine into six 20 mL syringes each with a 
22-gauge needle.   
Just prior to wound closure, inject approximately 1 mL of the local infiltrate per needle 
stick into each of the following areas.  The tissue in each area should visibly expand with 
minimal leakage.  
• Prior to final implant placement:  
− Posterior capsule (8-10 sticks medial and 8-10 sticks lateral) 
− Femur (medial and lateral periosteum, posterior periosteum 
suprapatellar/quadriceps tendon—20 sticks) 
− Tibia—fat pad (5 sticks); pes anserinus, medial collateral ligament, and 
gutter (15 sticks) 
− Circumferential periosteum (15-20 sticks) 
• After final implant placement: 
− Midline quadriceps tendon (10 sticks)  
− Retinaculum, medial gutter, femoral to tibia (10 sticks)  
− Lateral gutter, femoral to tibial (10 sticks) 
− Subcutaneous/closure (10 sticks) 


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5.2.4. 
Study Drug Administration 
Appropriately qualified study personnel will prepare all doses of study drug according to 
subject randomization.  All doses of study drug will be administered as an IV bolus 
injection in ≤15 seconds.  Start time of IV push should be recorded.  Additional details on 
study drug preparation and administration will be provided in the study specific 
pharmacy manual. 
Each subject is expected to receive at least two doses of study drug during their 
participation in the study.  Randomized subjects will receive their first dose of study drug 
(Dose 1) after administration of spinal anesthesia and prior to the start of surgery (defined 
as time of first incision).  Additional doses of study drug will be administered every 24 
hours ± 1 hour from Dose 1 (ie, 24 hours and 48 hours) until hospital discharge or until 
IV study drug analgesia is no longer clinically appropriate, whichever is first.   
The investigator may administer a final dose of study drug up to 4 hours ahead of 
schedule in subjects who are to be discharged. Subjects who do not receive a dose of 
study drug for more than 28 hours following their previous dose will be considered off 
treatment, and will not receive further doses of study drug.    
5.3. 
Identity of Study Drug 
N1539 (meloxicam) Injection for intravenous use 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 injection for intravenous use will contain:  soybean oil, egg yolk phospholipids, 
glycerin, fluorescein sodium, sodium folate, edetate disodium, benzyl alcohol, 
polysorbate 80, dextrose and water for injection.  Hydrochloric acid and/or sodium 
hydroxide may be used for pH adjustment. 
5.4. 
Method of Assigning Subjects to Treatment Groups 
A computer-generated randomization scheme will be prepared prior to study initiation.  
Eligible subjects will be randomized in a 1:1 ratio to IV treatment with N1539 30 mg or 
placebo according to the randomization scheme.  A block randomization will be 
generated stratified by center.  Investigators and site staff will not be aware of the size of 
the block.  All doses of study drug administered will be according to the original 
assignment. 
5.5. 
Selection of Doses 
The proposed commercial dose of N1539 30 mg administered once daily by IV bolus 
injection and matching placebo have been chosen for this study.   
Based on the findings from multiple adequate and well-controlled Phase 2 and 3 studies, 
along with supportive PK/PD modeling, N1539 30 mg administered once daily by IV 
bolus injection has been shown to be safe and effective in the management of moderate to 
severe pain.    


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5.6. 
Selection of Timing of Dose 
In the Phase 2 and 3 registration studies, N1539 was administered once daily by IV bolus 
injection in the postoperative period to manage (reduce) moderate to severe pain. 
This study is designed to explore the efficacy and safety of N1539 30 mg administered 
preoperatively and followed by once daily dosing in a population of subjects undergoing 
open unilateral total knee arthroplasty.  It is expected that preoperative administration of 
N1539 30 mg followed by once daily dosing will reduce the need for postoperative 
opioid analgesics and will result in an improved postoperative recovery course, a shorter 
length of hospital stay, and higher degree of subject satisfaction with pain control.   
5.7. 
Blinding and Unbinding of Study Drug 
All doses of study drug will be prepared by an appropriately qualified member(s) of the 
healthcare team at the research center according to the subject’s randomization.   
Doses of study drug will be administered by staff members who will be blinded to the 
treatment assignment. 
The study blind may be broken only if the safety of a subject is at risk and the treatment 
plan for that subject depends on which study drug he or she received.  Unless the subject 
is at immediate risk, the investigator must make diligent attempts to contact the sponsor 
before unblinding the subject’s data.   
If a subject’s data are unblinded without the prior knowledge of the sponsor, the 
investigator must notify the sponsor as soon as possible and no later than the next 
business morning.  All circumstances surrounding a premature unblinding must be clearly 
documented. 
5.8. 
Treatment Compliance 
Blinded study personnel will administer each dose of study drug.  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 drugs when they are received.  The 
study drug 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 drug 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 drug will be provided in study labeled packaging for preparation for use in this 
study. 
N1539 will be provided in single use vials containing 30 mg per mL.   


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Placebo will be provided in single use vials. 
Directions for preparation of study drug will be provided as pharmacy instructions prior 
to initiation of the study. 
Study drug 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 drug should be protected 
from light. 
All study drug 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 
administration of the first dose of study drug and during the study through POD 30 will 
be recorded in the eCRF. 
All medications that have not been at a stable dose for at least 7 days prior to the 
scheduled surgical procedure on Day 1 will be prohibited within five half-lives of the 
specific medication (or, if half-life is unknown, within 48 hours) before the surgical 
procedure, with exception of medications utilized in the preparation of the subject for 
surgery. 
5.12. 
Concomitant Interventions and Procedures 
All interventions or procedures, whether diagnostic or therapeutic, will be recorded 
through POD 30, 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. 
5.13. 
Opioid Medication 
5.13.1. 
Intraoperative 
Fentanyl and morphine or other morphine derivatives may be administered 
intraoperatively (during the course of the surgical procedure); however, dosing with 
fentanyl (and morphine or other morphine derivatives) is to be avoided within the 30 
minutes prior to the anticipated conclusion of the surgical procedure.  The time and dose 
of fentanyl (and morphine or other morphine derivatives) administered will be recorded. 
Other opioid analgesics are not to be administered pre- or intraoperatively, as this may 
confound or influence the subjects’ demand for opioid analgesia during the postoperative 
period (Hour 0 through hospital discharge). 
5.13.2. 
Inpatient 
Starting at Hour 0 and continuing through hospital discharge, pain intensity that is not 
adequately controlled with study drug may be treated with IV and/or PO opioids as 


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follows.  Conversion from IV to oral analgesia should be made once subjects are 
tolerating liquid intake. 
• Morphine 1 to 4 mg IV every 10 minutes for the first hour and then 1 to 8 mg 
IV Q1H PRN 
• oxycodone immediate release (IR) 5 mg PO Q4H (maximum of 10 mg Q4H 
PRN) 
No other analgesic agents except for study drug, the opioids designated above, 
acetaminophen, and aspirin for venous thromboembolism prophylaxis at the discretion of 
the investigator and according to institutional standards are permitted (Section 5.14). 
5.13.3. 
Follow-up 
Opioid medication usage for the management of postsurgical pain will be assessed at the 
following time points during the follow-up period: 
• Telephone interview 24 hours after hospital discharge (Section 6.3.5) 
• Telephone interview 48 hours after hospital discharge (Section 6.3.5) 
• Postoperative clinical visit (POD 10 to 14) (Section 6.4.5)  
• Telephone interview on POD 30 (Section 6.3.5) 
5.14. 
Non-Opioid Analgesics  
All subjects will receive 650 mg of acetaminophen Q8H PO as tolerated until LSD+1.   
Aspirin is also allowed for venous thromboembolism prophylaxis at the discretion of the 
investigator and according to institutional standards (Section 5.1). 
5.15. 
Prohibited Medications/Procedures 
The following medications/drug classes or procedures are prohibited: 
• All NSAIDs (eg, ketorolac, ibuprofen, diclofenac), other than study drug, 
starting 48 hours prior to surgery and continuing through last study dose 
(LSD) +1 day.   
• Non-opioid analgesics through LSD+1 except for: 
− acetaminophen (Section 5.14) 
− aspirin if needed for thromboembolism prophylaxis according to the 
investigator and institutional standards (Section 5.1)   
• Femoral and adductor canal blocks and other regional neuraxial blocks not 
specified by protocol 
• Recent or planned cryoneurolysis 
Please contact the medical monitor for any questions regarding prohibited medications. 


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6. 
STUDY PROCEDURES 
The timing of postoperative study procedures will be relative to the end of surgery (ie, 
Hour 0, defined as placement of the last suture, staple, or steri-strip) except for pain 
intensity assessments at designated time points, which will be relative to the first dose of 
study drug.  A schedule of study procedures is provided in Appendix A. 
6.1. 
Total Knee Arthroplasty 
On Day 1 eligible subjects will undergo unilateral total knee arthroplasty under spinal 
anesthesia according to the investigator’s standard surgical practice.   During the surgical 
procedure, the investigator or qualified designee will record the following: 
• Start of surgery (ie, first incision) and end of surgery (ie, placement of the last 
suture, staple, or steri-strip) 
• Was the quadriceps tendon spared during surgery? (yes/no) 
• Estimated blood loss (mL)  
• Times in and out of the post anesthesia care unit (PACU) 
• Post PACU disposition 
• Transfusions  
• Surgical complications   
Preoperative, intraoperative, and postoperative standard of care procedures associated 
with the surgical procedure and not specifically mentioned in this protocol will be carried 
out according to the investigator’s clinical practice and in accordance with institutional 
standards.   
6.2. 
Demographic and Efficacy Assessments 
6.2.1. 
Demographics 
Demographics information including age, gender, ethnicity, and race will be collected 
during the screening visit. 
6.2.2. 
Medical History 
During the screening period, the investigator or qualified designee will obtain a medical 
history from each subject that includes relevant diagnoses and/or procedures/therapies 
with onset/resolutions dates.  Medical histories should also include history of tobacco and 
alcohol use (never, current, former).  Medical history will be updated with any relevant 
information before the surgical procedure on Day 1 to determine the subject’s continued 
eligibility for inclusion in the study. 


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6.2.3. 
Physical Examination 
The investigator or designee will perform a physical examination by body system during 
the screening visit, before surgery on Day 1, and during the follow-up visit (POD 10 to 
14).   
Body weight and height will be measured and body mass index (BMI) will be calculated 
during the screening visit only.    
Physical examination results collected within 7 days prior to the screening visit may be 
utilized to evaluate subject eligibility at screening. 
6.2.4. 
Physical Therapy Assessments 
Within 2 to 4 hours after discharge from the PACU a physical therapy consult will be 
initiated.  Each subject will meet with the physical therapist and a physical therapy 
rehabilitation plan will be implemented.  Follow-up physical therapy assessments will be 
made at least once daily starting on POD 1 and continuing through hospital discharge. 
As part of discharge planning, subjects will meet with the physical therapist to determine 
an outpatient physical therapy rehabilitation plan.    
6.2.5. 
Ambulation 
Within 12 hours after Hour 0 on Day 1, each subject will be assisted out of bed to 
ambulate with assistance (ie, with the assistance of hospital staff and with or without a 
walking aid [eg, walker]).     
Starting on POD 1, subjects will be encouraged to continue to progress with assisted and 
unassisted ambulation at least three to four times each day through hospital discharge.  
Study staff will document the time of each postoperative ambulation through hospital 
discharge or LSD +1, whichever occurs first, including first assisted ambulation and first 
independent ambulation.   
First assisted ambulation is defined as first time walking with the assistance of hospital 
staff (with or without a walking aid).  First unassisted ambulation is defined as first time 
walking without the assistance of hospital staff (with or without a walking aid). 
Pain intensity will be recorded before and during ambulation as described in 
Section 6.2.6. 
6.2.6. 
Pain Intensity (PI)  
Subjects will be questioned regarding pain intensity using an 11-point numeric pain 
rating scale (NPRS; 0 - 10) where 0=no pain, and 10=the worst pain imaginable as 
follows: 
• Upon arrival at the PACU 
• Timepoints relative to first dose of study drug:  4 hours ± 15 minutes, 6 hours 
±15 minutes, 8 hours ± 30 minutes, 10 hours ± 1 hour, 12 hours ± 1 hour, 16 ± 
1 hour, 20 hours ± 1 hour, 24 hours ± 1 hour (before study drug 


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administration, if indicated), 30 hours ± 2 hours, 36 hours ± 2 hours, 42 hours 
± 2 hours, and 48 hours ± 2 hours (before study drug administration, if 
indicated), when the subject is awake 
• Immediately before each administration of opioid medication from Hour 0 
through hospital discharge or LSD +1, whichever occurs first 
• Before and during each ambulation through hospital discharge or LSD +1, 
whichever occurs first   
• Before hospital discharge      
Following hospital discharge, subjects will also be questioned regarding pain intensity 
using the NPRS during each follow-up telephone interview (24 hours and 48 hours after 
discharge and POD 30) and during the follow-up visit (POD 10 to 14) (Appendix C).   
6.2.7. 
Patient Global Assessment (PGA) of Pain Control  
Starting on POD 1 and continuing each day through hospital discharge or LSD+1, 
whichever occurs first, study staff will ask subjects to respond to the following question: 
“Overall, please rate how well your pain has been controlled during the last 24 hours?”  
Poor (0) 
Fair (1) 
Good (2) 
Very Good (3) 
Excellent (4) 


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6.2.8. 
Overall Benefit of Analgesia Score Questionnaire (OBAS)  
Starting on POD 1 and continuing each day through hospital discharge or LSD+1, 
whichever occurs first, study staff will ask subjects to respond to the seven questions 
contained in the OBAS questionnaire (Table 2). 
Table 2: 
Overall Benefit of Analgesia Score Questionnairea  
1. Please rate your current pain at rest on a scale between 0=minimal pain and 4=maximum 
imaginable pain 
2. Please grade any distress and bother from vomiting in the past 24 hours 
(0=not at all to 4=very much) 
3. Please grade any distress and bother from itching in the past 24 hours 
(0=not at all to 4=very much) 
4. Please grade any distress and bother from sweating in the past 24 hours 
(0=not at all to 4=very much) 
5. Please grade any distress and bother from freezing in the past 24 hours 
(0=not at all to 4=very much) 
6. Please grade any distress and bother from dizziness in the past 24 hours 
(0=not at all to 4=very much) 
7. How satisfied are you with your pain treatment during the past 24 hours 
(0=not at all to 4=very much) 
a 
Lehmann 2010 
6.3. 
Safety Assessments 
6.3.1. 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be completed for all subjects at screening.  Historic ECG results 
collected within 7 days prior to the screening visit may be utilized for evaluation of 
subject eligibility; 12-lead ECG will be used to exclude subjects with a clinically 
significant abnormal ECG. 
6.3.2. 
Clinical Laboratory Tests 
Routine clinical laboratory testing will be at the time points shown in Table 3.  Screening 
laboratory testing will be performed at a local laboratory.  Historic laboratory results 
collected within 7 days prior to the screening visit may be utilized for subject eligibility 
evaluation at screening visit.  Historical laboratory results must include the full panel for 
each laboratory test described in Table 3. 
Laboratory testing subsequent to screening will be analyzed at a central laboratory.  Urine 
pregnancy testing at screening and before surgery on Day 1 will be done at the clinical 
site using kits provided by the central laboratory. 
Additional clinical laboratory testing may be performed according to the investigator’s 
clinical practice and in accordance with institutional standards. 


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Table 3: 
Clinical Laboratory Testing 
Hematology 
Platelet count, hemoglobin, and hematocrit 
Screening  
Day 1: prior to dosing  
Before hospital discharge 
POD 10 to 14, if indicated 
Serum chemistry 
Urea, glucose, creatinine, sodium, 
potassium, chloride, bicarbonate, aspartate 
aminotransferase, alanine aminotransferase, 
alkaline phosphatase, total bilirubin, direct 
bilirubin, and gamma-glutamyltransferase 
Screening  
Day 1: prior to dosing  
Before hospital discharge 
POD 10 to 14, if indicated 
Coagulation 
prothrombin time, activated partial 
thromboplastin time, international 
normalized ratio 
Screening  
Day 1: prior to dosing  
Before hospital discharge 
POD 10 to 14, if indicated 
Urine pregnancya 
Women of childbearing potential. 
Screening  
Day 1: prior to dosing  
a 
Results must be available before the first dose of study drug on Day 1. 
Additional clinical laboratory testing may be performed according to the investigator’s clinical practice and 
in accordance with institutional standards. 
Any clinically significant changes in laboratory values after study drug administration on 
Day 1 should be captured as AEs at the discretion of the investigator. 
6.3.3. 
Vital Sign Measurements 
Vital signs including blood pressure, pulse, and respiratory rate will be collected after the 
subject has rested (seated/supine) for ≥5 minutes during the screening visit and before 
dosing on Day 1.  Vital sign results will be used to determine subject eligibility.  Historic 
vital signs results collected within 7 days prior to the screening visit may be utilized for 
subject eligibility evaluation at screening visit. 
Vital sign assessments during the surgical procedure, while the subject is in the PACU, 
and during the postoperative period will be at the discretion of the investigator and in 
accordance with institutional standards. 
6.3.4. 
Wound Healing Assessment 
Before hospital discharge and during the follow-up visit (POD 10 to 14), the investigator 
or qualified designee will rate his/her satisfaction with wound healing using an 11-point 
scale (0-10) where a score of 0 is “completely unsatisfied”, and a score of 10 is 
“completely satisfied”.   
6.3.5. 
Post Discharge Telephone Interviews for Healthcare Utilization 
6.3.5.1. 
24 Hours and 48 Hours Post Discharge and POD 30 
Qualified study staff will conduct telephone interviews 24-hours and 48-hours after 
hospital discharge and on POD 30.  During each phone interview, subjects will be asked 


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about opioid medication use, pain intensity, physical therapy visits, and utilization of 
healthcare resources (ie, hospital readmission, use of skilled nursing facilities, 
unscheduled phone calls and/or office visits related to pain, and emergency room [ER] 
visits related to pain). Please refer to the Operations Manual for details.   
6.3.6. 
Cost of Hospitalization 
Cost of the initial hospitalization will be determined using UB-04 and/or similar hospital 
claim forms used for billing purposes.  Total hospital charges, as recorded on the 
UB-04/hospital claims forms, will be recorded.  In addition, total hospital costs will be 
determined from the billing codes and/or procedure codes for all hospital care from the 
time of hospital admission until discharge as reported on the UB-04/hospital claims 
forms. 
6.3.7. 
End of Study 
The end of the study is when the last subject completes the POD 30 telephone interview. 
6.4. 
Assessments by Visit 
6.4.1. 
Screening Period (Day -28 to Day -1) 
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 the initial dose of study drug on Day 1.  
After informed consent is obtained, the following will be assessed and documented 
during the screening visit: 
1. Review of inclusion/exclusion criteria eligibility (Section 4.1 and Section 4.2) 
2. Demographics and medical history (Section 6.2.1 and Section 6.2.2) 
3. Review of prior/concomitant medications/procedures (Section 5.11) 
4. Physical examination including height, weight and calculation of BMI 
(Section 6.2.3) 
5. 12-lead ECG (Section 6.3.1) 
6. Vital sign measurements (Section 6.3.3) 
7. Clinical laboratory testing (Section 6.3.2): 
• Hematology, chemistry, and coagulation 
• Urine pregnancy test for women of childbearing potential 
8. Serious adverse events (Section 7.2) 


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6.4.2. 
Inpatient Period 
6.4.2.1. 
Open Total Knee Arthroplasty (Day 1) 
6.4.2.1.1. Preoperative 
The following will be assessed and documented preoperatively: 
1. Update medical history  
2. Concomitant medications/procedures (Section 5.11) 
3. Physical examination (Section 6.2.3) 
4. Vital sign measurements (Section 6.3.3)  
5. Clinical laboratory testing (Section 6.3.2): 
• Hematology, chemistry, and coagulation 
• Urine pregnancy test for women of childbearing potential 
6. Establish continued eligibility for treatment 
7. Randomization of eligible subjects to treatment (Section 5.4) 
8. Administer preoperative medications (Section 5.2) 
9. Administer intrathecal anesthesia (Section 5.2.1) 
10. Administer study drug according to randomization (Section 5.2.4) 
11. Adverse events (Section 7) 
6.4.2.1.2. Intraoperative 
The following will be assessed and documented intraoperatively: 
1. Open unilateral total knee arthroplasty according to the investigator’s clinical 
practice and in accordance with institutional standards (Section 6.1) 
2. Concomitant medications/procedures (Section 5.11) 
3. Administer local infiltrate prior to wound closure (Section 5.2.3) 
4. Adverse events (Section 7) 
Surgery start (first incision) and surgery end (last suture, staple, or steri-strip placement 
[Hour 0]) times, confirmation of quadriceps tendon sparing during surgery, estimated 
blood loss (mL), transfusions, and surgical complications will be recorded.  Upon 
completion of surgery, subjects may be transported to the post anesthesia care unit 
(PACU) until they are deemed ready for transport to their hospital room.  The times in 
and out of the PACU and post PACU disposition will be recorded. 


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6.4.2.2. 
Postoperative 
The following will be assessed during the postoperative period as follows: 
1. Concomitant medications/procedures through hospital discharge (Section 5.11) 
2. Administration of study drug as needed through hospital discharge (Section 5.2.4) 
3. Administration of opioid pain medication as needed through hospital discharge 
(Section 5.13)  
4. Pain intensity through hospital discharge (Section 6.2.6) 
5. Physical therapy through hospital discharge (Section 6.2.4) 
6. Ambulation through hospital discharge or LSD+1, whichever occurs first 
(Section 6.2.5) 
7. Patient Global Assessment of Pain Control starting on POD 1 through hospital 
discharge or LSD+1, whichever occurs first (Section 6.2.7) 
8. Overall Benefit of Analgesia Score Questionnaire starting on POD 1 through 
hospital discharge or LSD+1, whichever occurs first (Section 6.2.8) 
9. Adverse events through hospital discharge (Section 7) 
6.4.3. 
Hospital Discharge 
The following will be assessed before hospital discharge: 
1. Concomitant medications/procedures (Section 5.11) 
2. Clinical laboratory testing including hematology, chemistry, and coagulation 
(Section 6.3.2) 
3. Administration of study drug at the discretion of the investigator (Section 5.2.4)  
4. Administration of opioid pain medication as needed (Section 5.13)  
5. Pain intensity: 
• Before administration of opioid pain medication, if still receiving study drug 
(Section 6.2.6) 
• Before discharge 
6. Wound healing assessment (Section 6.3.4) 
7. Adverse events (Section 7) 
The time hospital discharge order is written and actual departure time from hospital will 
be recorded.  Discharge pain medication prescription(s) and discharge to home or to a 
skilled nursing facility will be documented. 
6.4.4. 
24-Hour and 48-Hour Post Discharge Telephone Interviews 
Qualified study staff will conduct telephone interviews 24-hours and 48-hours after 
hospital discharge (refer to Section 6.3.5 for details). 


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6.4.5. 
Follow-up Visit (POD 10 to 14)  
Subjects will visit the clinical site and the following will be assessed and documented 
during the follow-up visit: 
1. Concomitant medications/procedures (Section 5.11) 
2. Physical examination (Section 6.2.3) 
3. Clinical laboratory testing including hematology, chemistry, and coagulation, if 
indicated (Section 6.3.2) 
4. Opioid pain medication usage (Section 5.13.3) 
5. Pain intensity (Section 6.2.6) 
6. Wound healing assessment (Section 6.3.4) 
7. Healthcare utilization including physical therapy visits (Section 6.3.5) 
8. Adverse events (Section 7) 
6.4.6. 
Postoperative Day 30 Telephone Interview (End of Study) 
Qualified study staff will conduct telephone interviews POD 30 (refer to Section 6.3.5 for 
details).  Following this interview subjects will be discharged from the study. 


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


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7.2. 
Definition of a Serious Adverse Event 
A SAE is defined as any event that meets the following criteria: 
• Results in death 
• Is immediately life-threatening (ie, presents an immediate risk of death from the 
event as it occurred; this does not include an AE had it occurred in a more serious 
form may have caused death).   
• Results in persistent or significant incapacity or substantial disruption of the 
ability to perform normal life functions.   
• Results in hospitalization. 
•  Results in prolongation of an existing hospitalization. 
•  Is a congenital anomaly or birth defect (in the offspring of a subject using the 
study drug regardless of time to diagnosis). 
•  Is considered an important medical event. 
Medical and scientific judgment should be exercised in determining whether an AE is 
serious when considering important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may 
require medical or surgical intervention to prevent any of the outcomes listed that define 
a SAE. Examples of such medical events that may also be considered serious include, but 
are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of a SAE. 
Social or convenience admission to a hospital or prolongation of a hospitalization for 
social or convenience reasons not associated with the occurrence of an AE does not meet 
the definition of a SAE. 
SAEs will be assessed and recorded in the eCRF after the signing of informed consent 
through the end of the study (ie, Day 30). If an investigator becomes aware of a SAE or 
death that occurs more than 30 days after the subject receives study drug and the 
investigator considers the event to be related to the study drug, he/she is obligated to 
report the SAE to the sponsor. 
7.3. 
Recording and Evaluating Adverse Events and Serious 
Adverse Events 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, or other clinical information. In such cases, the diagnosis, not the individual 
signs or symptoms, should be documented as the AE or SAE. 


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7.3.1. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study, using his or her clinical judgment. The intensity of each AE and SAE 
recorded in the eCRF should be assigned to one of the following categories: 
• Mild: an event that is easily tolerated by the subject, causes minimal discomfort, 
and does not interfere with everyday activities 
• Moderate: an event that is sufficiently discomforting to interfere with normal 
everyday activities 
• Severe:  an event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with a SAE. Severity is a term 
used to describe the intensity of a specific event, and both AEs and SAEs can be assessed 
as severe. The event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as serious, which is based on the 
subject’s or event’s outcome or on action criteria usually associated with events that pose 
a threat to a subject’s life or functioning (see Section 7.2). 
7.3.2. 
Assessment of Causality 
The investigator must record the causal relationship of each event in the eCRF, and 
additionally for SAEs, on the SAE reporting form.  An investigator's causality assessment 
is the determination of whether there exists a reasonable possibility that the study drug 
caused or contributed to an AE.  
• Related: There is evidence to suggest a causal relationship between the study drug 
and the AE.   
• Not related: The AE is due to underlying or concurrent illness or effect of another 
drug or event and is not related to the study drug (eg, has a more likely alternate 
etiology and / or a temporal relationship does not suggest a causal relationship).   
Even in situations in which minimal information is available for the initial SAE report, it 
is important that the investigator always make an assessment of causality for every event 
before transmitting the SAE reporting form and completing the AE eCRF page(s). The 
causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change his or her opinion of causality in light of 
follow-up information and amend the SAE reporting form and AE eCRF page(s) 
accordingly. 
7.3.3. 
Assessment of Outcome 
All AEs and SAEs must be followed until they are resolved, the condition stabilizes, the 
events are otherwise explained, or the subject is lost to follow-up. The investigator will 
assess the outcome of the event(s) by using the following terms: 
• Resolved:  The event resolved and the subject returned to baseline.  
• Resolving:  At last observation, the event was improving. 


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• Resolved with sequelae:  The event resolved but the subject is left with residual 
problems (eg, functional deficits)  
• Not resolved: At the last observation, the event was unchanged.  
• Unknown:  There were no observations after the onset (initial observation or 
report) of the event, and the status of the event is unknown. 
• Death (Fatal):  To be selected for the one AE, which in the judgement of the 
investigator was the primary cause of death.  
7.4. 
Follow-up of Adverse Events and Serious Adverse Events 
After the occurrence of an AE or SAE, the investigator is required to follow each subject 
proactively and provide further information on the subject’s condition. All AEs and SAEs 
documented at a previous visit or contact that are designated as ongoing will be reviewed 
at subsequent visits or contacts until the event resolves, the condition stabilizes, the event 
is otherwise explained, or the subject is lost to follow-up. Any additional events that are 
relevant to the ongoing event will be documented. 
The investigator will ensure that follow-up information relevant to SAEs is provided to 
the sponsor and includes results of any additional laboratory tests or investigations, 
histopathologic examinations, or consultations with other healthcare professionals that 
serve to clarify the nature of the event, the cause of the event, or both. 
New or updated information will be recorded on the originally completed SAE reporting 
form and entered into the eCRF pages, with all changes signed and dated by the 
investigator. The updated SAE reporting form should be resubmitted to the sponsor 
within the time frames outlined in Section 7.5. 
7.5. 
Prompt Reporting of Serious Adverse Events to the Sponsor 
Once the investigator determines that an event meets the protocol definition of an SAE, 
he or she must notify the sponsor within 24 hours. 
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE, WHICH 
OCCURS DURING THE COURSE OF THIS STUDY, REGARDLESS OF 
RELATIONSHIP TO STUDY DRUG, MUST BE REPORTED TO THE 
SPONSOR IMMEDIATELY (within 24 hours). 
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY 
EMAIL TO THE FOLLOWING SPONSOR CONTACT: 
Medical Safety Recro Pharma, Inc. 
Telephone: 484-395-2470 
eFax: 484-395-2472 
email: AE@recropharma.com 
 


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In the initial email, the investigator must provide to the sponsor the following eCRF 
pages, completed to the greatest extent possible: 
• AE record 
• Medical history 
• Prior and concomitant medications 
Also, the following documents are to be forwarded: any laboratory results, diagnostic test 
results, or medical reports relevant to the SAE. 
E-mail transmission is the preferred method to transmit SAE information. In rare 
circumstances and in the absence of e-mail capacity, notification by fax or telephone is 
acceptable, with a copy of the SAE reporting form sent by overnight mail. Initial 
notification via telephone does not replace the need for the investigator to complete the 
SAE reporting form and eCRF pages within the time frames outlined. 
If the investigator does not have all information regarding an SAE, he or she must not 
wait to receive additional information before notifying the sponsor of the event. The form 
must be updated when additional information is received. Follow-up information 
received on all SAEs must be forwarded to the sponsor by using the same procedure and 
timelines as for an initial report. 
7.6. 
Regulatory Reporting Requirements 
The investigator must promptly report all SAEs to the sponsor in accordance with the 
procedures detailed in Section 7.5 “Prompt Reporting of Serious Adverse Events to the 
Sponsor.” The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation. Prompt notification of SAEs by the investigator to the appropriate 
project contact for SAE receipt is essential so that SAEs that are either unexpected or 
observed with increasing occurrence, be reported and legal obligations and ethical 
responsibilities regarding the safety of other subjects are met. 
For the purposes of IND safety reporting, expectedness of the SAE will be assessed by 
the sponsor.  A SAE is considered unexpected if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application. 
The sponsor will determine whether the SAE meets regulatory reporting criteria (ie, 7- or 
15-day report) in compliance with local and regional law. If so, the sponsor (or the 
sponsor’s representative) will report the event to the appropriate regulatory authorities. 
The sponsor will report SAEs to the central IRB/EC and the investigator will be report 
SAE to their local to institutional review board (IRB)/EC. Investigator letters are 
prepared according to sponsor policy and are forwarded to the investigators as necessary. 
An investigator letter is prepared for any SAE that is attributable to study drug, serious, 


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and unexpected. The purpose of the investigator letter is to fulfill specific regulatory and 
Good Clinical Practice (GCP) requirements regarding the product under investigation. 
The investigator, or responsible person according to local requirements, must comply 
with requirements related to the reporting of SAEs to the IRB or IEC. 
7.7. 
Special Reporting Situations: Pregnancy  
Any subject who becomes pregnant during the study must discontinue further study drug 
administration and should be followed through delivery or termination of the pregnancy.  
A subject should be instructed to also notify the investigator immediately if she becomes 
pregnant within 30 days after receiving study drug.  The sponsor must be notified of all 
pregnancies reported to the investigator (see Section 7.5 for contact information). 
Any uncomplicated pregnancy that occurs in a subject during this clinical study will be 
reported for tracking purposes only. All subject pregnancies that are identified during or 
after this study, where the estimated date of conception is determined to have occurred 
within 30 days of receiving study drug need to be reported, followed to conclusion 
(delivery or termination), and the outcome reported, even if the subject is discontinued 
from the study. The investigator should report all pregnancies within 24 hours using the 
Pregnancy Report/Outcome Form, according to the usual timelines and directions for 
SAE reporting provided in Section 7.5. Monitoring of the pregnancy should continue 
until conclusion of the pregnancy; and follow-up detailing the outcome of the pregnancy 
submitted using the Pregnancy Report/Outcome Form. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication. Likewise, elective abortions without complications are not considered AEs.  
Any SAEs associated with pregnancy (eg, congenital abnormalities/birth 
defects/spontaneous miscarriages or any other serious events) must additionally be 
reported as such using the SAE report form according to the usual timelines and 
directions for SAE reporting provided in Section 7.5. 


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8. 
STATISTICAL METHODOLOGY AND DETERMINATION 
OF SAMPLE SIZE 
The following outlines some of the key elements of the data analysis approach.  A formal 
statistical analysis plan (SAP) will be developed for this study in which statistical models, 
data derivation methods and rules will be described in detail.  A separate statistical 
analysis plan will be developed for the healthcare utilization endpoints detailed in this 
study (Section 8.5). 
8.1. 
Determination of Sample Size 
The sample size for this study (100 subjects per group) will have at least 90% power to 
detect the difference between N1539 30 mg versus placebo in total opioid consumption 
based on the results observed in a Phase 3 safety study that evaluated all major surgeries.  
The study results suggested that the total opioid consumption was lower in subjects 
treated with N1539 30 mg compared to placebo, and that the observed effect size in total 
opioids consumption measured by IV morphine equivalent dose (IVMED, mg) ranged 
from 0.5 to 0.7 in this subgroup. 
8.2. 
Study Endpoints 
8.2.1. 
Efficacy Endpoints 
8.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is total use of opioid analgesia from Hour 0 through 
24 hours. 
8.2.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• Sum of pain intensity from the time of first dose of study drug through 24 
hours (SPI24) 
• Percentage of subjects who are opioid free from Hour 0 through 24 hours 
• Time to first use of IV or oral opioid analgesia 
8.2.1.3. 
Other Efficacy Endpoints 
Other efficacy endpoints include: 
• Total use of opioid analgesia from first dose of study drug through 24 hours 
(before 2nd dose of study drug) 
• Total use of opioid analgesia from Hour 0 through 48 hours 
• Total use of opioid analgesia from Hour 0 through hospital discharge 
• Total use of opioid analgesia from hospital discharge through 24-hour 
telephone interview 


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• Total use of opioid analgesia from the 24-hour telephone interview through 
the 48-hour telephone interview 
• Percentage of subjects that are opioid free from Hour 0 through 48 hours 
• Percentage of subjects that are opioid free from Hour 0 through hospital 
discharge 
• Percentage of subjects who used any opioid medication after hospital 
discharge through POD 30.   
• Time to first IV opioid medication defined as the time from Hour 0 until time 
of first use of IV opioid medication 
• Time to first oral opioid rescue medication defined as the time from Hour 0 
until time of first use of oral opioid medication  
• Pain intensity during first assisted ambulation  
• Pain intensity during first unassisted ambulation 
• SPI from time of first dose of study drug through first assisted ambulation 
• SPI from time of first dose of study drug through first unassisted ambulation 
• SPI from time of first dose of study drug through 48 hours 
• SPI from time of first dose of study drug through hospital discharge or 
LSD+1, whichever comes first  
• Time to first assisted ambulation defined as the time from Hour 0 until time 
when first assisted ambulation occurs 
• Time to first unassisted ambulation defined as the time from Hour 0 until time 
when first unassisted ambulation occurs 
• Subject overall evaluation of pain control on 5-point categorical scale on each 
postoperative day, starting on POD 1 and continuing through hospital 
discharge or LSD+1, whichever occurs first.   
• The OBAS total score and opioid distress dimension subscore on each 
postoperative day, starting on POD 1 and continuing through hospital 
discharge or LSD+1, whichever occurs first 
• Pain intensity at the following follow-up time points: 24 hours and 48 hours 
post discharge, and POD 10-14, and POD 30 
8.2.2. 
Safety Endpoints 
Safety endpoints include: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of potentially clinically significant abnormal clinical laboratory 
values 


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• Investigator satisfaction with wound healing before hospital discharge and 
during the follow-up visit (POD 10 to 14). 
8.2.3. 
Healthcare Utilization Endpoints 
Healthcare utilization endpoints include: 
• Length of hospital stay defined as days from hospital admission until the 
hospital discharge order is written 
• Total cost of hospitalization (taken from the UB-04/hospital claims form) 
• Duration of time in the PACU (time in through time out of PACU) 
• Percentage of subjects with hospital readmission through POD 30 
• Total number of postsurgical physical therapy visits through POD 30 
• Percentage of subjects who required a skilled nursing facility from hospital 
discharge through POD 30 
• Total time spent in skilled nursing facility from hospital discharge through 
POD 30 
• Percentage of subjects who made a phone call related to postsurgical pain 
from hospital discharge through POD 30 
• Total number of unscheduled phone calls related to postsurgical pain from 
hospital discharge through POD 30 
• Percentage of subjects who had an unscheduled visit related to postsurgical 
pain from hospital discharge through POD 30 
• Total number of unscheduled visits related to postsurgical pain from hospital 
discharge through POD 30 
• Percentage of subject who had an emergency room visit for postsurgical pain 
from hospital discharge through POD 30 
• Total number of visits to the emergency room for postsurgical pain from 
hospital discharge through POD 30 
8.1. 
General Considerations for Statistical Analysis 
8.1.1. 
Analysis Populations 
8.1.1.1. 
Intent-to-Treat (ITT) Population 
The ITT population will include all subjects who qualify for the study and are 
randomized for treatment prior to surgery.  ITT subjects may or may not receive 
randomized treatment.  


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8.1.1.2. 
Safety Population 
The safety population will consist of all subjects who receive at least one injection of 
study drug.  All safety evaluations will be based on the safety population. 
8.1.1.3. 
Efficacy Population (Modified Intent-to-Treat) 
The efficacy population (ie, modified intent-to-treat [mITT]) will consist of all subjects 
who receive at least one injection of study drug and have the scheduled surgery.  All 
efficacy evaluations will be based on the efficacy population. 
8.1.2. 
Test Hypothesis and P Value Justification 
Each efficacy analysis will be performed to assess the differences between the 2 
treatment groups; N1539 30 mg vs Placebo.     
The null hypothesis is that there is not difference between the examined treatment groups.  
The alternative hypothesis is that the treatment groups are different.  Differences between 
the 2 groups will be evaluated via 2-sided 2-sample t-test at the 0.05 level of significance.  
Nominal p-value will be reported as is.   
8.1.3. 
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. 
8.1.4. 
Definitions for Assessment Windows 
For the purpose of data analysis, baseline measures will be the last measurements taken 
before the subject receives the first dose of study drug. 
8.1.5. 
Derived Variables 
The study SAP will provide detail description for each endpoint derivation methodology, 
including censoring rules for each time to events, mapping of opioid dose in IV morphine 
equivalence dose (mg) for each time period, missing data (time) imputation rules, total 
pain intensity for each period, OBAS total score and sub-score for opioid distress 
dimension.   
8.2. 
Study Population Summaries 
Population summaries will be provided for the safety analysis set included in this study. 
8.2.1. 
Disposition 
The summary tables will provide frequency counts for subject disposition (all treated 
subjects, subjects who completed the study, subjects who discontinued from the study, 
and reason for discontinuation) by treatment group and study overall.   


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Disposition in terms of number of subjects excluded from each analysis sets (ITT, safety, 
and mITT) will also be provided by treatment groups and study overall. 
8.2.2. 
Demographics and Baseline Characteristics 
The demographic summary will include descriptive statistics for age, sex, race, weight, 
height, and BMI for the overall and by treatment group.  
Baseline characteristics will include history of tobacco and alcohol use, surgery duration, 
time from first dose to start of surgery, duration in PACU, and additional surgery related 
variables (eg, estimated blood lost, number of transfusions). 
8.2.3. 
Protocol Violations 
All protocol violations and deviations will be identified.  Tabulation may be provided if 
data warrant. 
8.2.4. 
Treatment Compliance 
Doses of study drug will be administered by designated study personnel to study subjects 
while subjects are confined to the study site.  The exact time of administration of study 
drug will be documented within each subject’s eCRF.  No formal summary of treatment 
compliance will be produced. 
8.2.5. 
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 1Q2017 or higher. 
8.3. 
Efficacy Summaries and Analysis 
Efficacy endpoints will be tabulated by treatment groups and time points as appropriate; 
descriptive statistics will be provided, including sample size, mean, standard deviation, 
median, minimum and maximum for continuous variables, or frequency (number of 
subjects and percentage) distribution of each category for categorical variables.   
Treatment effect will be evaluated using Analysis of Covariance (ANCOVA) for opioid 
consumption related endpoints, pain intensity related endpoints, and OBAS related 
endpoints; the ANCOVA model will include treatment effect and investigational sites as 
a covariate.  Difference in LS means will be compared between the treatment groups. 
Kaplan-Meier survival analysis will be carried out for time to event endpoints, including 
survival curves, 25%, 50% and 75% tiles estimates and corresponding 95% confidence 
intervals (CI), and log-rank test.  Cox proportional hazards analysis will also be 
performed for time to event endpoints; the model will include the treatment effect and the 
investigational sites; hazards ratio and corresponding 95% CI will be presented. 
Treatment effect on PGA scores will be evaluated based on proportion of subjects rated 
their pain control as good, very good, or excellent using CMH test controlling for 


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analysis center.  CMH test will apply to other category variables, such as proportion of 
subjects who took any opioids or who were opioid free at various time periods.   
8.4. 
Safety Summaries 
8.4.1. 
Extent of Exposure 
The extent of exposure for the study drug treatment will be assessed via number of doses 
received. 
8.4.2. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 20 or higher) will be used to 
classify all AEs with respect to system organ class and preferred term.  An event is 
considered treatment emergent if the event onset date/time is on or after the first dose of 
study drug or if a prior condition is worsened after the first dose of study drug.  AEs will 
be summarized by treatment group.  AE summaries will be provided for all treatment 
emergent AEs, study drug related TEAEs, and serious TEAEs. 
AEs that lead to premature discontinuation from the study or to death will be listed 
separately via data listings.    
8.4.3. 
Subjects with Clinically Significant Laboratory Values 
Clinical laboratory parameters collected after the first dose of study drug will be 
evaluated by comparing to baseline.  Subjects with potentially clinically significant 
changes from baseline in clinical laboratory parameters will be identified and tabulated 
by treatment group.    
8.4.4. 
Wound Healing 
The number and proportion of subjects with abnormal wound healing observations will 
be summarized by treatment group. 
8.5. 
Healthcare Utilization Summaries 
A separate SAP will be constructed for analysis of Health Care Utilization and total costs 
as recorded on the UB-04.  This SAP will detail the objectives, methods for conducting 
the relevant analyses, and the format for presentation of the findings.  Subject cohorts of 
interest will be defined and the variables to be measured as well as the steps in data 
processing and analyses will also be presented.   
 


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9. 
STUDY ADMINISTRATION 
9.1. 
Regulatory and Ethical Considerations 
9.1.1. 
Ethical Conduct of the Study  
This study will be conducted according to the clinical research guidelines established by 
FDA Title 21 Code of Federal Regulations (CFR) Parts 50, 54, 56, and 312, ICH GCP 
and other regulations as applicable.  
9.1.1.1. 
Institutional Review Board/Independent Ethics Committee 
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 (eg, advertisements or information that supports or 
supplements the informed consent form) are reviewed and approved by the appropriate 
IRB or IEC.  If the protocol, the informed consent form, or any other information that the 
IRB or IEC has approved for presentation to potential subjects is amended during the 
study, the investigator is responsible for ensuring that the IRB or IEC reviews and 
approves, where applicable, these amended documents prior to implementation of any 
changes. The investigator must follow all applicable regulatory requirements pertaining 
to the use of an amended informed consent form, including obtaining IRB or IEC 
approval of the amended form, before new subjects consent to take part in the study using 
the new version of the form. 
For study sites with IECs that comply with ICH GCP, but not US FDA 21CFR Part 56, a 
waiver request will be submitted to the FDA.  If granted, the FDA’s letter documenting 
the waiver will be provided to the Investigator.   
In addition, the investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC safety procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC and all other applicable 
regulations 
9.1.1.2. 
Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation.  
Template informed consent forms will be provided by the sponsor but may be adapted to 
meet the needs of the institution.  Final consent forms will be IRB/IEC approved and 
accepted by the sponsor. The subject will be asked to read and review the consent 
document.  The investigator or designee will explain the study to the subject and answer 


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any questions that may arise.  A verbal explanation will be provided in terms suited to the 
subject’s comprehension of the purpose, procedures, and potential risks of the study and 
of their rights as research subjects.  Subjects will have the opportunity to carefully review 
the written consent form and ask questions prior to signing.  The subjects should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate.  The subject will sign the informed consent document prior to any 
procedures being done specifically for the study.  Subject must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice.  A copy of the informed consent document will be given to the subjects for 
their records.  The informed consent process will be conducted and documented in the 
source document and the form signed before the subject undergoes any study-specific 
procedures.  The rights and welfare of the subjects will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in the study.    
9.1.1.3. 
Subject Confidentiality 
 Subjects will be assigned a unique identifier by the sponsor.  Any subject records or data 
that are transferred to the sponsor will contain the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.  The 
investigator will keep a Master Subject List on which the identifier and full name, 
address, and telephone number of each subject are listed.  The Master Subject List will be 
stored in a secure location at the site and will not be shared with the sponsor.  It is the 
Investigator’s responsibility to inform subjects as part of the informed consent process 
that representatives of the sponsor, FDA, or other regulatory agencies may review all 
records that support their participation in the study.  The Investigator will comply with all 
privacy laws to which he/she is subject. 
9.1.1.4. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.  
9.2. 
Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (eg, 
laboratory data).  The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  


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• The investigator must permit study-related monitoring, audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to source 
data documents. 
• The sponsor or designee is responsible for the data management of this study 
including quality checks of the data. 
• Study monitors will perform ongoing source data verification to confirm that 
that data entered into the CRF by site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the 
current approved version of the protocol, ICH GCP, and all applicable 
regulatory requirements. 
9.3. 
Study and Site Closure 
If the sponsor, investigator, or officials from regulatory agencies discover conditions 
arising during the study that indicate that the study should be halted or that the study site 
should be closed, this action may be taken after appropriate consultation between the 
sponsor and investigator.  Conditions that may warrant termination of the study include, 
but are not limited to, the following: 
• discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study 
• 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 (eg, 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 
9.4. 
Records Retention 
9.4.1. 
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 


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elapsed since the formal discontinuation of clinical development of the investigational 
product.  The sponsor will notify the investigator as to when these documents no longer 
need to be retained for this use.  No records may be transferred to another location or 
party without written notification to and approval of the sponsor. 
9.5. 
Information Disclosure  
9.5.1. 
Publication 
For multicenter studies, the first publication or disclosure of study results shall be a 
complete, joint, multicenter publication or disclosure coordinated by Recro Pharma, Inc.  
Thereafter, any secondary publications will reference the original publication(s).  If no 
multicenter publication is submitted for publication within 18 months of study database 
hard lock, then the site shall be free to disclose its own results, subject to sponsor rights 
under the written contract executed for the conduct of the study.  Authorship will be 
determined by mutual agreement and in line with the International Committee of Medical 
Journal Editors authorship requirements. 
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 120 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. 
Where a written contract is executed for the conduct of the study, that contract’s 
publication provisions will supersede the language in this section. 


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10. 
LIST OF REFERENCES 
Cram P, Lu X, Kates SL, et al. Total knee arthroplasty volume, utilization, and outcomes 
among Medicare beneficiaries, 1991-2010. JAMA 2012; 308:1227. 
Degner F, Turck D, Pairet M. Pharmacological, pharmacokinetic and clinical profile of 
meloxicam. Drugs Today. 1997;33(10):739-58. 
Guidelines for the Management of Postoperative Pain after Total Knee Arthroplasty, 
Korean Knee Society. 2012. Knee Surg Relat Res. 2012 Dec; 24(4): 201–207. 
Kurtz S, Ong K, Lau E, et al. Projections of primary and revision hip and knee 
arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 2007; 89:780. 
Lehmann et al., Development and longitudinal validation of the overall benefit of 
analgesia score: A simple multi-dimensional quality assessment instrument: 
https://www.researchgate.net/publication/45537797.  Accessed September 2017. 
Maheshwari AV, Blum YC, Shekhar L, Ranawat AS, et al.  Multimodal pain 
management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. 
2009. Clin Orthop Relat Res. 467(6): 1418–1423. 
Motififard M, Omidian A, Badiei S. Pre-emptive injection of peri-articular-multimodal 
drug for post-operative pain management in total knee arthroplasty: a double-blind 
randomized clinical trial. 2017. International Orthopaedics (SICOT). 41:939–947. 
Turck D, Busch U, Henizel G, Narjes H. Clinical pharmacokinetics of meloxicam. 
Arzneim-Forsch/Drug Res. 1997;47(I):253-8. 
UpToDate®: https://www.uptodate.com/contents/total-knee-arthroplasty. Accessed 
September 2017. 
 
 
 


Protocol REC-17-025 with Amendment 002 
24JAN2018 
Page 59 of 65 
 
APPENDIX A: 
STUDY ASSESSMENTS: PROTOCOL REC-17-025 
 
Screening 
Surgery (Day 1) Through Hospital Discharge or LSD+1, 
whichever occurs first 
Hospital 
Discharge 
Telephone 
Interview 
Follow-up  
Visit 
Telephone 
Interview 
 
Day 28 to 
Day -1 
Preoperative 
Intraoperative 
(End of Surgery= 
Hour 0) 
Postoperative 
Hour 0 Through 
Hospital Discharge 
or LSD +1 
 
24 Hours and  
48 Hours  
Post-Discharge 
POD   
10 to Day 14 
POD  
30 ± 4 days 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
  
 
  
 
 
 
Demographics and medical history 
X 
X (update) 
 
 
 
 
 
 
Prior/concomitant 
medications/procedures 
X 
X 
X 
Xa 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
 X 
 
12-Lead electrocardiogram 
X 
 
 
 
 
 
 
 
Vital signs 
Xb 
Xb 
 
 
 
 
 
 
Clinical laboratory testing 
X (local lab) 
X 
 
 
X 
 
X, if indicated 
 
Urine pregnancy testing 
X 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Perioperative medications 
 
Xc 
Xd 
 
 
 
 
 
Intrathecal anesthesia (spinal) 
 
Xe 
 
 
 
 
 
 
Study drug administration 
 
Xf 
 
Q24H from Dose 1a,g 
Xg 
 
 
 
PI assessment 
 
 
 
Xh 
X 
X 
X 
X 
Opioid pain medication 
 
 
 
Xa 
X 
X 
X 
X 
Physical therapy  
 
 
 
Xa 
 
X 
X 
X 
Ambulation 
 
 
 
Xi 
 
 
 
 
PGA of pain control 
 
 
 
Each postop day 
starting with POD 1i 
 
 
 
 
OBAS 
 
 
 
Each postop day 
starting with POD 1i 
 
 
 
 
Wound healing assessment 
 
 
 
 
X 
 
X 
 
Serious adverse events only 
X 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
Xa 
X 
X 
X 
X 
Healthcare utilizationj 
 
 
 
 
 
X 
X 
X 
IV=intravenous; OBAS=Overall Benefit of Analgesia Score Questionnaire; PGA=Patient Global Assessment; PI=pain intensity; PO=by mouth; POD=postoperative day 
a Through hospital discharge. 
b Vital signs after the subject has rested (seated/supine) for ≥5 minutes.  Results will be used to determine subject eligibility. 
c Acetaminophen 650 PO, gabapentin 600 mg PO, tranexamic acid 1 g IV, and prophylactic IV antibiotic 30 to 90 minutes before start of surgical procedure.  Subjects will continue to receive 
acetaminophen 650 mg PO Q8H through LSD+1.  Venous thromboembolism prophylaxis before and after surgery according to standard practice, based on the subject’s individual needs, at the discretion of 
the investigator and surgeon, and taking into consideration the ACCP and AAOS guidelines for orthopedic surgery. 
d Local infiltrate prior to wound closure. 
e Prior to start of surgical procedure. 
f Dose 1 is to be administered after spinal anesthesia and before the start of the surgical procedure. Subsequent doses may be administered Q24±1 hours from Dose 1. 
g At the discretion of the investigator. 
h PI will be assessed upon arrival at the PACU, at various scheduled timepoints relative to first dose of study drug, before each administration of opioid medication (Time 0 through hospital discharge or 
 
LSD+1, whichever first), before and during each ambulation (Time 0 through hospital discharge or LSD+1, whichever first), before hospital discharge, 24 hours and 48 hours after discharge, POD 10 to 
 
14, and POD 30 (Section 6.2.6). 
i Through hospital discharge or LSD+1, whichever occurs first. 
j Hospital readmission, use of skilled nursing facilities, unscheduled phone calls or office visits related to pain, and ER visits related to pain. 
 


Protocol REC-17-025 with Amendment 002 
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APPENDIX B: 
CLINICAL CARE PROTOCOL MEDICATIONS  
 
Venous Thromboembolism Prophylaxis: 
Venous thromboembolism prophylaxis before and after surgery will be administered 
according to standard practice, based on the subject’s individual needs, at the discretion 
of the investigator and surgeon, and taking into consideration the American College of 
Chest Physicians (ACCP) and American Academy of Orthopaedic Surgeons (AAOS) 
guidelines for orthopedic surgery. 
Perioperative Concomitant Medications: 
• 30 to 90 minutes before surgical procedure administer: 
− Acetaminophen 650 mg by mouth (PO) (administered with sips of water) 
− Gabapentin 600 mg PO (administered with sips of water) 
− Tranexamic acid 1 gram IV (a second dose of tranexamic acid may be given 
approximately 3 hours after the first, at the discretion of the surgeon). 
− Prophylactic IV antibiotic 
• Before the start of the surgical procedure: 
Following administration of intrathecal anesthesia (ie, 7.5 mg to 15 mg bupivacaine HCl) 
and before the start of surgery, administer 1st dose of study drug by IV bolus injection in 
≤15 seconds according to randomization. 
• Intraoperative 
Fentanyl and morphine or other morphine derivatives may be administered 
intraoperatively (during the course of the surgical procedure); however, dosing with 
fentanyl (and morphine or other morphine derivatives) is to be avoided within the 30 
minutes prior to the anticipated conclusion of the surgical procedure.  The time and dose 
of fentanyl (and morphine or other morphine derivatives) administered will be recorded. 
Other opioid analgesics are not to be administered pre- or intraoperatively, as this may 
confound or influence the subjects’ demand for opioid analgesia during the postoperative 
period (Hour 0 through hospital discharge). 
Anxiolytics, sedatives, and other medications (except for analgesic agents) that are used 
for subject well-being during the intraoperative period may be administered according to 
the investigator’s clinical practice and in accordance with institutional standards.  The 
time and dose of any medication administered during the intraoperative period will be 
recorded. 
• Intraoperative:  Prior to wound closure administer: 
Local infiltration of bupivacaine HCl 0.5% 30 mL with epinephrine 0.5 mg expanded in a 
volume of 90 mL normal saline and drawn up into six 20 mL syringes each with a 
22-gauge needle. 


Protocol REC-17-025 with Amendment 002 
24JAN2018 
Page 61 of 65 
 
Local infiltrate should be administered so that each needle stick delivers approximately 
1 mL of the drug to the intended area.  The tissue should visibly expand with minimal 
leakage.  Infiltrate should be injected into the prescribed locations based on the areas of 
highest nerve density as shown in Table 4.   
Table 4: 
Local Infiltrate Administration 
Timing 
Infiltrate Administration Location 
Number of Needle 
Sticksa 
Prior to final implant 
placement 
Posterior capsule 
8-10 sticks medial  
8-10 sticks lateral 
Femur (medial and lateral periosteum, posterior 
periosteum suprapatellar/quadriceps tendon 
20 sticks 
Tibia—fat pad 
5 sticks 
Pes anserinus, medial collateral ligament, and gutter 
15 sticks 
Circumferential periosteum  
15-20 sticks 
After final implant 
placement 
Midline quadriceps tendon  
10 sticks 
Retinaculum, medial gutter, femoral to tibia  
10 sticks 
Lateral gutter, femoral to tibial  
10 sticks 
Subcutaneous/closure  
10 sticks 
a 
Each needle stick delivers approximately 1 mL of the bupivacaine infiltrate. 


Protocol REC-17-025 with Amendment 002 
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Page 62 of 65 
 
Postoperative Concomitant Medications: 
• Opioid pain medications: 
Starting at Hour 0 and continuing through hospital discharge, pain intensity that is not 
adequately controlled with study drug may be treated with IV and PO opioids as 
follows.  Conversion from IV to oral analgesia should be made once subjects are 
tolerating liquid intake. 
− Morphine 1 to 4 mg IV every 10 minutes for the first hour and then 1 to 8 
mg IV Q1H PRN 
− Oxycodone immediate release (IR) 5 mg PO Q4H (maximum of 10 mg 
Q4H PRN) 
• Acetaminophen: 
All subjects will receive 650 mg of acetaminophen Q8H PO as tolerated until 24 hours 
following the last dose of study drug (LSD+1). 
No other analgesic agents except for study drug, the opioids (described above), 
acetaminophen (through LSD+1), and aspirin for venous thromboembolism prophylaxis 
according to the investigator and institutional standards (Section 5.1) are permitted. 
• Treatment of postoperative nausea and vomiting: 
Subjects may receive IV ondansetron 4 mg as needed for postoperative nausea and 
vomiting (PONV) according to FDA prescribing information. 
Study Drug: 
Additional doses of study drug will be administered every 24 hours (±1 hour) after the 
first dose.  Dosing will continue until the subject is either discharged from the hospital or 
until IV study drug analgesia is no longer clinically appropriate.  The investigator may 
administer a final dose of study drug up to 4 hours ahead of schedule in subjects who are 
to be discharged. 
 


Protocol REC-17-025 with Amendment 002 
24JAN2018 
Page 63 of 65 
 
APPENDIX C: 
NUMBERIC PAIN RATING SCALE (NPRS) 
Protocol-Defined Time Points 
• Upon arrival at the PACU 
• At time points relative to first dose of study drug:  4 hours ± 15 minutes, 6 
hours ±15 minutes, 8 hours ± 30 minutes, 10 hours ± 1 hour, 12 hours ± 1 
hour, 16 ± 1 hour, 20 hours ± 1 hour, 24 hours ± 1 hour (before study drug 
administration, if indicated), 30 hours ± 2 hours, 36 hours ± 2 hours, 42 hours 
± 2 hours, and 48 hours ± 2 hours (before study drug administration, if 
indicated), when the subject is awake 
• Before hospital discharge 
Subjects will be asked:  On a scale of 0-10 where 0 is ‘no pain’ and 10 is the ‘worst 
imaginable pain’, please rate your pain NOW. 
0 
No 
pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
 
 
 
 
 
 
 
 
 
 
Opioid Medication Use (Hour 0 through hospital discharge or LSD +1, whichever 
occurs first) 
Immediately before each administration of opioid medication subjects will be asked:  On 
a scale of 0-10 where 0 is ‘no pain’ and 10 is the ‘worst imaginable pain’, please rate 
your pain NOW. 
0 
No 
pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
 
 
 
 
 
 
 
 
 
 
  


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Ambulation (Hour 0 through hospital discharge or LSD +1, whichever occurs first) 
Within 15 minutes before each ambulation subjects will be asked: 
On a scale of 0-10 where 0 is ‘no pain’ and 10 is the ‘worst imaginable pain’, please rate 
your pain NOW. 
0 
No 
pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
 
 
 
 
 
 
 
 
 
 
After each ambulation, subjects will be asked: 
On a scale of 0-10 where 0 is ‘no pain’ and 10 is the ‘worst imaginable pain’, please rate 
your WORST pain during ambulation. 
0 
No 
pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
 
 
 
 
 
 
 
 
 
 
24 Hours and 48 Hours After Discharge and POD 30 Telephone Interviews and 
During the POD 10 to 14 Visit 
At each time point, subjects will be asked:  
On a scale of 0-10 where 0 is ‘no pain’ and 10 is the ‘worst imaginable pain’, please rate 
your WORST pain during the past 24 hours. 
0 
No 
pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol REC-17-025 with Amendment 002 
24JAN2018 
Page 65 of 65 
 
APPENDIX D: 
AMERICAN SOCIETY OF 
ANESTHESIOLOGISTS PHYSICAL STATUS 
CLASSIFICATION SYSTEM 
Classification 
Description 
I 
Normal healthy patient. 
II 
Patient with mild systemic disease; no functional limitation (eg, 
smoker with well controlled hypertension). 
III 
Patient with severe systemic disease; definite functional impairment 
(eg, diabetes and angina with relatively stable disease, but requiring 
therapy). 
IV 
Patient with severe systemic disease that is constant threat to life (eg, 
diabetes and angina and congestive heart failure; patients with dyspnea 
on mild exertion and chest pain). 
V 
Unstable moribund patient who is not expected to survive 24 hours 
with or without operation. 
VI 
Brain dead patient whose organs are removed for donation to another. 
E 
Emergency operation of any type, which is added to any of the above 
six categories, an in ASA II E. 
 

SAP_001.pdf: 
 
 
 
REC-17-025 
 
A Phase 3b, Randomized, Double-Blind, Placebo-Control, Multicenter, Evaluation 
of the Safety and Efficacy of N1539 Administered Preoperatively in Open 
Unilateral Total Knee Arthroplasty 
 
NCT03434275 
 
Statistical Analysis Plan 
 
30 April 2019 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
  REC-17-025 
Protocol Title:  
 
  A Phase 3b, Randomized, Double-Blind, Placebo-
Control, Multicenter, Evaluation of the Safety 
and Efficacy of N1539 Administered 
Preoperatively in Open Unilateral Total Knee 
Arthroplasty 
Date of Original 
Protocol 
September 29, 2017     
Date of Protocol 
Amendment 001 
November 17, 2017     
Date of Protocol 
Amendment 002 
January 24, 2018     
 
 
 


Protocol REC-17-025 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 3 of 47 
 
TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS AND PHRASES .............................................................................6 
IN-TEXT TABLES ..........................................................................................................................8 
1. 
INTRODUCTION AND SCOPE .................................................................................9 
2. 
OVERVIEW OF STUDY OBJECTIVES AND ASSESSMENTS............................10 
2.1. 
Study Endpoints ..........................................................................................................13 
2.1.1. 
Efficacy Endpoints ......................................................................................................13 
2.1.2. 
Healthcare Utilization Endpoints ................................................................................14 
2.1.3. 
Safety Endpoints .........................................................................................................15 
3. 
GENERAL CONSIDERATIONS ..............................................................................16 
3.1. 
Analysis Population ....................................................................................................16 
3.2. 
Test Hypothesis and P Value Justification .................................................................16 
3.3. 
Procedures for Handling Missing Data .......................................................................16 
3.4. 
Analysis Center ...........................................................................................................16 
3.5. 
Definitions and Derived Variables .............................................................................17 
3.5.1. 
Definitions ..................................................................................................................17 
3.5.2. 
Analysis Visit..............................................................................................................18 
3.5.3. 
Subjects at Risk ...........................................................................................................19 
3.5.4. 
Total Opioid Consumption in IVMED (mg) ..............................................................21 
3.5.5. 
Missing Date/time Imputation for Opioid Records ....................................................22 
3.5.6. 
Opioid Free Subjects ...................................................................................................26 
3.5.7. 
Time to First Rescue ...................................................................................................26 
3.5.8. 
Missing Date/time Imputation for Ambulation Records ............................................28 
3.5.9. 
Time to First Ambulation ...........................................................................................28 
3.5.10. 
Sum of Pain Intensity (SPI) ........................................................................................29 
3.5.11. 
Overall Benefit of Analgesia Score (OBAS) ..............................................................31 
3.5.12. 
Patient Global Assessment of Pain Control (PGA) ....................................................33 
3.5.13. 
Physical Therapy ........................................................................................................33 


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3.5.14. 
Additional Health Care Utilization Endpoints ............................................................34 
4. 
STUDY POPULATION SUMMARIES ....................................................................35 
4.1. 
Disposition ..................................................................................................................35 
4.2. 
Demographics and Baseline Characteristics ...............................................................35 
4.2.1. 
Other Medical History ................................................................................................36 
4.3. 
Protocol Deviations ....................................................................................................36 
4.4. 
Treatment Compliance ................................................................................................36 
4.5. 
Prior and Concomitant Medications ...........................................................................37 
5. 
EFFICACY ANALYSIS ............................................................................................38 
5.1. 
Opioid Consumptions .................................................................................................38 
5.1.1. 
Number (%) Subjects Opioid Free .............................................................................38 
5.1.2. 
ANCOVA Analysis of Total Opioid Consumption ....................................................39 
5.1.3. 
Rank Analysis of Total Opioid Consumption ............................................................39 
5.1.4. 
Time to First Rescue ...................................................................................................39 
5.1.5. 
Number of Times Used Rescue Analgesia .................................................................40 
5.2. 
Scheduled Pain Intensity (PI) Assessment .................................................................40 
5.2.1. 
Sum of Pain Intensity by Intervals..............................................................................40 
5.2.2. 
Scheduled Pain Intensity by Time Points ...................................................................41 
5.3. 
Ambulation Assessments ............................................................................................41 
5.3.1. 
Time to First Ambulation Events ...............................................................................41 
5.3.2. 
Pain Before and the Worst Pain During Ambulation .................................................41 
5.3.3. 
Number of Times of Ambulation ...............................................................................42 
5.4. 
Patient Global Assessment (PGA) of Pain Control ....................................................42 
5.5. 
Overall Benefit of Analgesic Questionnaire ...............................................................42 
6. 
HEALTHCARE RESOURCE UTILIZATION .........................................................43 
6.1. 
Total Cost of Hospital Stay .........................................................................................43 
6.2. 
Hospital Readmission, ER Visits, Doctor Visits, and Phone Calls ............................43 
6.3. 
Physical Therapy Sessions from Post Surgery to POD 30 .........................................43 
6.4. 
Requiring a Skilled Nursing Facility from Post Discharge to POD 30 ......................44 
7. 
SAFETY AND TOLERABILITY EVALUATIONS ................................................45 
7.1. 
Extent of Exposure .....................................................................................................45 


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7.2. 
Adverse Events ...........................................................................................................45 
7.3. 
Change in Laboratory Tests ........................................................................................46 
7.4. 
Wound Healing ...........................................................................................................47 
 


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Statistical Analysis Plan 
 
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Page 6 of 47 
 
LIST OF ABBREVIATIONS AND PHRASES 
Abbreviation 
Definition 
N1539 
Injectable NanoCrystal® Colloidal Dispersion (NCD) Meloxicam 
AE 
adverse event 
ANCOVA 
Analysis of Covariance 
BMI 
body mass index 
CMH 
Cochran-Mantel-Haenszel  
eCRF 
Electronic case report form 
EOS 
End of Study (POD 30 ± 4 days) 
EOT 
End of Treatment Period (Discharge or LSD+1, whichever comes first) 
Hour 0 
Time of End of Surgery (H0) 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-treat  
IV 
Intravenous 
IVMED 
IV Morphine Equivalent Dose (mg) 
Kg 
Kilogram 
mITT 
Modified Intent-to-treat  
OBAS 
Overall Benefit of Analgesic Score 
ODDS 
Opioid Distress Dimension Score (a sub domain of OBAS) 
PDD 
Post discharge day (24-hour period starting time of actual hospital discharge) 
PGA 
Patient Global Assessment   
PI 
Pain Intensity Score  
POD 
Post-operative day (number of calendar day(s) after surgery date) 
PSD 
Post-surgery day (a 24-hour period starting end of surgery) 
LSD 
Last Study Drug Dose 
LSD+1 
24 hours after the last dose 
mL 
Milliliter 
NPRS 
Numeric Pain Rating Scale 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SPI 
Summed of time weighted pain intensity 


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Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 7 of 47 
 
Abbreviation 
Definition 
SPIAA 
Summed of time weighted pain intensity from Time 0 to first assisted 
ambulation 
SPIIA 
Summed of time weighted pain intensity from Time 0 to first independent 
ambulation 
SPIDC 
Summed of time weighted pain intensity from Time 0 to hospital discharge 
TEAE 
Treatment emergent adverse event 
Time 0 
Time of First Dose (T0) 
TTE 
Time to Event 
µg 
Microgram 
µL 
Microliter 
 
 
 
 
 


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Page 8 of 47 
 
 
IN-TEXT TABLES 
 
Table 1:  Analysis Visit Using Post-operative Day and Post-surgery Day....................................19 
Table 2:  Subjects at Risk for 16 Periods Defined for Opioid Summary .......................................20 
Table 3:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics ..........................21 
Table 4:  Definition of Opioid Consumption Period .....................................................................24 
Table 5:  Overall Benefit of Analgesia Questionnaire and Rating ................................................32 
Table 6:  Selected Laboratory Tests of Special Interest ................................................................46 
Table 7:  Definition of Potentially Clinically Significant Abnormal Results in Selected 
Laboratory Tests of Special Interest ...........................................................................47 
 


Protocol REC-17-025 
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Page 9 of 47 
 
1. 
INTRODUCTION AND SCOPE 
Protocol REC-17-025 is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter 
study evaluating the safety and efficacy of preoperative dosing with N1539 30 mg in adult 
subjects undergoing open unilateral total knee arthroplasty surgery. The study will enroll 
approximately 200 subjects randomized (1:1) to N1539 30 mg or placebo. 
This Statistical Analysis Plan (SAP) is intended to provide a more technical and detailed 
elaboration of the principal statistical features stated in the protocols.  The objective of the SAP 
is to reasonably assure that the statistical methodologies to be used for analysis are complete and 
accurate.   
In the development of this SAP, the following documents were used: 
• Protocol REC-17-025: Amendment 2, January 24, 2018  
• REC-17-025 eCRF Completion Guidelines Version 3.0 dated October 22, 2018 
• REC-17-025 eCRF Version 3.0 dated June 7, 2018  
 
The principles in the following guidance documents are followed in preparation of this SAP: 
• ICH E3 (1995): Structure and Content of Clinical Study Reports 
• ICH E6 (1996): Guideline for Good Clinical Practice 
• ICH E9 (1998): Statistical Principles for Clinical Trials 
In the event that a discrepancy is found between the descriptions in the statistical section of the 
protocol and this document, the description in this document supersedes the descriptions in the 
statistical section of the protocol. 
 
 


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Page 10 of 47 
 
2. 
OVERVIEW OF STUDY OBJECTIVES AND ASSESSMENTS   
The primary objective of this study is to assess the effect of preoperative administration of 
N1539 on opioid consumption in subjects undergoing open unilateral total knee arthroplasty 
compared to placebo. 
Secondary objectives are to assess: 
• 
The safety and tolerability of preoperative administration of N1539 compared to 
placebo 
• 
The effect of preoperative administration of N1539 on postoperative pain compared 
to placebo 
• 
The effect of preoperative administration of N1539 on healthcare utilization costs 
compared to placebo. 
Each subject is expected to receive at least two doses of study drug, with the first dose (T0) to be 
administered following the administration of spinal anesthesia and before the start of surgery (ie, 
time of first incision) according to randomization.  Additional doses of study drug will be 
administered every 24 hours (±1 hour) after the first dose.  Dosing will continue until the subject 
is either discharged from the hospital or until IV study drug analgesia is no longer clinically 
appropriate. 
After first dose of study drug, all subjects will then undergo the surgical procedure according to 
the investigator’s clinical practice and in accordance with institutional standards. At the end of 
the surgical procedure (Hour 0, defined as the time of last suture, staple, or steri-strip placement) 
and through hospital discharge, postoperative pain management will be according to the 
protocol; other standard of care procedures associated with the surgical procedure will be carried 
out according to the investigator’s clinical practice and in accordance with institutional 
standards.   
Subjects will remain as inpatients for at least 24 hours or until inpatient care is no longer 
clinically indicated.  Upon discharge, subjects will be provided a standard of care regimen for 
pain management and for physical therapy as determined by the investigator. 
Twenty-four hours and 48 hours after hospital discharge qualified study staff will conduct 
telephone interviews to assess opioid medication use, pain intensity, physical therapy visits, and 
utilization of healthcare resources (ie, hospital readmission, use of skilled nursing facilities, 
unscheduled phone calls and/or office visits related to pain, and emergency room [ER] visits 
related to pain and/or other medical issues).  An office follow-up visit is to be scheduled on 
Post-operative day (POD) 10-14 days and a final telephone interview will be conducted onPOD 
30 to assess for AEs, opioid use, and utilization of healthcare resources.  After the POD 30 
telephone interview, subjects will be discharged from the study. 
Assessments of efficacy will include total opioid consumption, pain intensity according to an 11-
point numeric pain rating scale (NPRS; 0 - 10) at a set of predefined time points, before and 
during ambulation, before use of any rescue analgesic, and at time discharge, Patient Global 


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Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 11 of 47 
 
Assessment (PGA) of pain control, Overall Benefit of Analgesia Score Questionnaire (OBAS), and a 
panel of healthcare utilization assessments.  
Study safety assessments will monitor adverse events, change in clinical laboratory tests, and 
wound healing assessments. Study procedure schedule (Protocol Appendix A) is included here 
for the convenience of review  
 
 
 


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2.1. 
Study Endpoints  
2.1.1. 
Efficacy Endpoints 
The primary efficacy endpoint is total use of opioid analgesia from Hour 0 through 24 hours. 
Secondary endpoints include: 
1. Sum of pain intensity from the time of first dose of study drug through 24 hours (SPI24) 
2. Percentage of subjects who are opioid free from Hour 0 through 24 hours 
3. Time to first use of IV or oral opioid analgesia 
Other efficacy endpoints include: 
1. Total use of opioid analgesia from first dose of study drug through 24 hours (before 2nd 
dose of study drug) 
2. Total use of opioid analgesia from Hour 0 through 48 hours 
3. Total use of opioid analgesia from Hour 0 through hospital discharge 
4. Total use of opioid analgesia from hospital discharge through 24-hour telephone 
interview 
5. Total use of opioid analgesia from the 24-hour telephone interview through the 48-hour 
telephone interview 
6. Percentage of subjects that are opioid free from Hour 0 through 48 hours 
7. Percentage of subjects that are opioid free from Hour 0 through hospital discharge 
8. Percentage of subjects who used any opioid medication after hospital discharge through 
POD 30.   
9. Time to first IV opioid medication defined as the time from Hour 0 until time of first use 
of IV opioid medication 
10. Time to first oral opioid rescue medication defined as the time from Hour 0 until time of 
first use of oral opioid medication  
11. Pain intensity during first assisted ambulation  
12. Pain intensity during first unassisted ambulation 
13. SPI from time of first dose of study drug through first assisted ambulation 
14. SPI from time of first dose of study drug through first unassisted ambulation 
15. SPI from time of first dose of study drug through 48 hours 
16. SPI from time of first dose of study drug through hospital discharge or LSD+1, 
whichever comes first  


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17. Time to first assisted ambulation defined as the time from Hour 0 until time when first 
assisted ambulation occurs 
18. Time to first unassisted ambulation defined as the time from Hour 0 until time when first 
unassisted ambulation occurs 
19. Patient Global Assessment (PGA) of pain control on 5-point categorical scale on each 
postoperative day, starting on POD 1 and continuing through hospital discharge or 
LSD+1, whichever occurs first.   
20. The OBAS total score and opioid distress dimension subscore on each postoperative day, 
starting on POD 1 and continuing through hospital discharge or LSD+1, whichever 
occurs first 
21. Pain intensity at the following follow-up time points: 24 hours and 48 hours post 
discharge, and POD 10-14, and POD 30 
2.1.2. 
Healthcare Utilization Endpoints 
Healthcare utilization endpoints include: 
1. Length of hospital stay defined as days from hospital admission until the hospital 
discharge order is written. 
2. Total cost of hospitalization (taken from the UB-04/hospital claims form) 
3. Duration of time in the PACU (time in through time out of PACU) 
4. Percentage of subjects with hospital readmission through POD 30 
5. Total number of postsurgical physical therapy visits through POD 30 
6. Percentage of subjects who required a skilled nursing facility from hospital discharge 
through POD 30 
7. Total time spent in skilled nursing facility from hospital discharge through POD 30 
8. Percentage of subjects who made a phone call related to postsurgical pain from hospital 
discharge through POD 30 
9. Total number of phone calls per subject related to postsurgical pain from hospital 
discharge through POD 30 
10. Percentage of subjects who had an unscheduled visit related to postsurgical pain from 
hospital discharge through POD 30 
11. Total number of unscheduled visits per subject related to postsurgical pain from hospital 
discharge through POD 30 
12. Percentage of subjects who had an emergency room visit for postsurgical pain from 
hospital discharge through POD 30 
13. Total number of visits to the emergency room per subject for postsurgical pain from 
hospital discharge through POD 30 


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Note: tabulation for the Health Utilization endpoints will be covered by this SAP; a separate 
analysis pertaining to the cost elements of the Health Care Utilization endpoints will be covered 
by a separate analysis plan. 
 
2.1.3. 
Safety Endpoints 
The safety endpoints include  
1. Incidence of treatment-emergent adverse events (TEAEs) 
2. Incidence of potentially clinically significant abnormal clinical laboratory values 
3. Investigator satisfaction with wound healing before hospital discharge and during the 
follow-up visit (POD 10 to 14). 


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3. 
GENERAL CONSIDERATIONS  
3.1. 
Analysis Population 
The following analysis sets will be identified for this study. 
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include randomized subjects.  This 
dataset may also be referenced as the ‘Randomized Set’.  The ITT subjects may or may not 
receive randomized treatment.    
Safety Set:  The safety set will include all treated subjects and will be used for safety and 
tolerability assessments.   
Efficacy Set:  The efficacy population will consist of all subjects who receive at least one injection of 
study drug and have the scheduled surgery.  This is also referenced as the modified intent-to-treat 
(mITT) Analysis Set.  All efficacy evaluations will be based on the mITT population. 
  
3.2. 
Test Hypothesis and P Value Justification 
The null hypothesis is that there is no difference between N1539 30 mg and placebo groups.  The 
alternative hypothesis is that the treatment groups are different. 
Differences between N1539 30 mg dose and placebo group will be evaluated via a 2-sided 
2-sample t-test at the 0.05 level of significance.  Nominal p-values will be reported as is.     
3.3. 
Procedures for Handling Missing Data  
Missing data imputation rules for pain intensity will be discussed extensively in Section 3.5.  
No missing data imputation will be performed for safety parameters.  However, AEs with 
missing severity assessments will be tabulated as “severe,” and AEs with missing relationship 
assessments will be tabulated as “related” for the purpose of analysis; and the missing data will 
be presented in data listing as is. 
3.4. 
Analysis Center  
This is a multicenter study; investigative center will be included in the analysis model as a 
covariate. Centers with small enrollment may be pooled to form an analysis center.  The final 
decision on pooling will be made prior to database hard lock. 
 
 


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3.5. 
Definitions and Derived Variables 
3.5.1. 
Definitions  
To facilitate the opioid consumption data summary, the following phrases and definitions are 
introduced. 
3.5.1.1. 
Study Period   
The study duration for each subject is divided into 4 periods 
1. Screening Period: The duration from signing informed consent until before receiving the 
first dose of study drug will be described as the screening period.  The last measurement 
taken prior to receiving the first dose of study drug is the Baseline measurement. 
Hence, Baseline measure could be either a scheduled assessment or an unscheduled 
assessment. 
2. Peri-operative period: this period starts when the subject receives the first dose of study 
drug and ends at time of end of surgery (T0 to H0). 
3. Post-operative period: postoperative period starts at the end of surgery and ends when the 
subject is discharged from the hospital or when the subject has reached 1 day after the 
last dose of study drug (LSD+1) timepoint before being discharge from the hospital. 
a. Post-Surgery Day (PSD): A post-operative day is a 24-hour period from the time 
of end of surgery.  Hence, a PSD start time and stop time varies from subject to 
subject, depending on the time of surgery stop time.    
b. In-patient period: This period starts at the end of surgery to actual hospital 
discharge.  This period is used to determine if a subject is at risk for opioid 
consumption analysis.   
4. Post discharge period: this period starts after the subject is discharged from the hospital 
through end of study.   
5. End of Study period (EOS): end of study for a subject is the last follow up visit (POD 30 
± 4 days) 
 
3.5.1.2. 
Treatment Period and Time of End of Treatment 
The treatment period covers the duration from the date/time of the first dose of study drug (T0) 
through 24 hours after the last dose of study drug (LSD+1).  However, it is expected that, for the 
majority of subjects, the treatment period ends when the subject is discharged from the hospital.  
Hence, the treatment period would be described as the time period from the first dose (T0) 
through hospital discharge or LSD+1, whichever comes first.   
Time of End of Treatment Period (EOT) for a subject could be mathematically expressed as  


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Time of EOT =min (date/time of discharge, data/time of LSD+1), where min is the 
function of minimal. 
 
3.5.1.3. 
Time 0 and Hour 0  
Time 0 (T0) is referred to the date/time of first dose of study drug, whereas Hour 0 (H0) is 
referred to the date/time of End of Surgery.   Hour 0 is typically used as the starting point for 
postoperative measurements, for example, opioid consumption (see Section 3.5.4 for details) and 
time to rescue and time to ambulation; T0 is used to schedule pain intensity assessments at 
scheduled time points (see Section 3.5.10). 
 
3.5.2. 
Analysis Visit   
Efficacy data will be mapped to Analysis Visit using the following benchmarks: 
1. Relative to the time of end of surgery. A 24-hour period is referred to as a Post-surgery 
Day (PSD).  This analysis will be based on the assessment date and time and the 
reference point is end of surgery (H0). 
2. Relative to the surgery date. This analysis will be based on the assessment date only and 
will be referred to as the Post-operative Day (POD) where the date of surgery is POD 0.  
Analysis visit (POD vs PSD) will be clearly spelled out for each efficacy endpoint. The 
difference between POD and PSD can be illustrated in the following 3 examples.  
1. In example 1 the assessment time was within 24 hours after the end of surgery, therefore 
it is assigned to PSD 1 for Post-surgery Day analysis; and the date of the assessment was 
the same date of surgery, therefore, the POD=0 is assigned. 
2. In example 2 the assessment time was > 24 and <48 hours after the end of surgery, 
therefore it is assigned to PSD 2 for Post-surgery Day analysis; but the date of the 
assessment was 1 day after the date of surgery, therefore, the POD 1 is assigned for 
Post-operative Day Analysis. 
3. In example 3 the assessment time was >48 and less than 72 hours after the end of surgery, 
therefore it is assigned to PSD 3 for Post-operative Day analysis; and the date of the 
assessment was 2 days after the date of surgery, therefore, the POD 2 is assigned for 
Post-surgery Day Analysis. 
 
 


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Table 1:  Analysis Visit Using Post-operative Day and Post-surgery Day  
Example 
End of Surgery Time 
Assessment Time 
Post-Surgery Day 
Post-Operative Day 
1 
2018-03-12T11:01 
2018-03-12T16:45 
PSD 1 
Surgery Day (POD 0) 
2 
2018-03-12T11:01 
2018-03-13T18:45 
PSD 2 
POD 1 
3 
2018-03-12T08:05 
2018-03-14T12:05 
PSD 3 
POD 2 
 
 
3.5.3. 
Subjects at Risk  
A subject is at risk if the subject is still available for assessment.  This concept is used for several 
analyses that pertain to a period. For example, for analysis of opioid consumption from Hour 48 
to Hour 72 after end of surgery, if a subject has been discharged before Hour 24, this subject will 
be considered ‘Not At Risk’ for H48-72 hour opioid consumption.  Table 2 provides examples of 
subjects at risk for 13 periods used in the opioid consumption analysis. 
 
 


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Table 2:  Subjects at Risk for 16 Periods Defined for Opioid Summary   
ID 
Interval / Period 
Subject at Risk 
1 
Pre-operative Period 
mITT subject 
2 
Intra-operative Period 
mITT subject 
3 
T0 - H0 (Perioperative) 
mITT subject 
4 
T0 to T24 (Excluding Dose 2) 
mITT subject 
5 
H0 - H24 (PSD 1) 
mITT subject 
6 
H24 - H48 (PSD 2) 
mITT subject with in-patient duration ≥24 hours 
7 
H48 - H72 (PSD 3) 
mITT subject with in-patient duration ≥48 hours 
8 
H0 - H48 (PSD 1-2) 
mITT subject 
9 
H0 - H72 (PSD 1-3) 
mITT subject 
10 
H0 - EOT (postoperative) 
mITT subject 
11 
0-24 hours post discharge 
mITT subject who was discharged  
12 
24-48 hours post discharge 
mITT subject who was discharged 
13 
0-48 hours post discharge 
mITT subject who was discharged  
14 
24 hours before POD 10-14 visit 
mITT subject who was discharged 
15 
EOT - EOS (post discharge to EOS) 
mITT subject who was discharged 
16 
Total in Study 
mITT subject 
 
 


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3.5.4. 
Total Opioid Consumption in IVMED (mg) 
All concomitant medications will be coded according to WHO Drug library. Opioid medications 
will be identified per ATC level 2 and level 3.  The dose from each identified opioid record will 
then be converted to IV Morphine Equivalent Dose (IVMED) in mg; examples of IVMED of 
some commonly used analgesics are provided in Table 3. 
 
Table 3:  IV Morphine Equivalent Dose (mg) For Commonly Used Analgesics  
Generic Opioid Name 
1 Unit 
Route 
IV MED (mg) 
Morphine 
mg 
IV 
1 
Morphine 
mg 
PO 
0.333 
Methadone 
mg 
IV 
1 
Methadone 
mg 
PO 
0.333 
Nalbuphine 
mg 
IV 
1 
Nalbuphine 
mg 
PO 
0.333 
Buprenorphine 
mg 
IV 
25 
Fentanyl 
µg (mcg) 
IV 
0.1 
Sufentanil 
µg (mcg) 
IV 
1.00 
Alfentanil 
µg (mcg) 
IV 
0.02 
Hydromorphone 
mg 
IV 
6.67 
Hydromorphone 
mg 
PO 
1.3 
Codeine 
mg 
PO 
0.05 
Meperidine 
mg 
PO 
0.025 
Pentazocine 
mg 
PO 
0.1 
Oxycodone 
mg 
PO 
0.5 
Hydrocodone 
mg 
PO 
0.3 
 
The eCRF page for opioid medications uses the following indications to identify study periods: 
• Intraoperative:  All opioids used before and during the surgery, the opioid used before 
surgery includes all opioids used after the first dose of study drug; this corresponds to 
the peri-operative period defined in Section 3.5.1.  
• Rescue: all opioids used during the in-patient period defined as end of surgery to 
hospital discharge or LSD+1.  This corresponds to the post-operative period defined 
in Section 3.5.1.  


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• Pain management: opioids used post hospital discharge or post LSD+1 until end of 
study.  This corresponds to the post-discharge period defined in Section 3.5.1.  
• Medical history: opioids taken for medical history events 
• Other: opioids that do not fall under any of the above 4 categories  
Opioids for medical history events are excluded from the total opioid consumption analysis.  The 
opioids with indication of ‘OTHER’ may be excluded depending on the specification. Those 
records (MEDICAL HISTORY + OTHER) will be reviewed carefully and queried if there are 
any doubts/questions on records prior to exclusion.   
3.5.5. 
Missing Date/time Imputation for Opioid Records 
After all efforts to clean up the database, if date or time is missing for opioid medications, the 
following rules will apply during programming to create the analysis dataset.  
1. If start and stop dates are unknown, the record will be queried and excluded if 
confirmed.   
2. If a partial date/time is entered and the indication is not ‘Medical History’ the following 
imputation rules will be applied: 
➢ If start date is present and stop date is missing, the stop date is set to be the start date 
and vice versa. 
➢ When the start date and stop date are present:  
1. If start date is equal to the stop date 
i. If the start time is missing but the stop time is present, the start time is set 
to be the stop time and vice versa. 
ii. When both start and stop times are missing: 
1) If indication is Intraoperative: missing start time is set 1 minute 
after surgery start time and missing stop time is set to 1 minute 
before surgery stop time. 
2) If indication is Rescue:  If date=surgery date: missing start and 
stop start time will be set to 1 minute after end of surgery. If date 
> surgery date: missing start time will be set to 00:01 and missing 
stop time will be set to 23:59. 
3) If indication is Pain Management: If date=discharge date: 
missing start and stop start time will be set to 1 minute after 
discharge time. If date > discharge date: missing start time will be 
set to 00:01 and missing stop time will be set to 23:59. 
 
 


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2. When start date is not equal to stop date: 
i. If start time is missing: 
1) If indication is Rescue and start date=surgery date then missing 
start time will be set to 1 minute after end of surgery 
2) If indication is Rescue start date > surgery date the missing start 
time will be set to 00:01. 
3) If indication is Pain Management and start date=discharge date: 
missing start time will be set to 1 minute after discharge time. 
4) If indication is Pain Management and start date >discharge date: 
missing start time will be set to “00:01”. 
ii. If stop time is missing: 
1) If indication is Rescue and stop date = surgery date the missing 
stop time will be set to 1 minute after end of surgery. 
2) If indication is Rescue and stop date > surgery date the missing 
stop time will be set to 23:59. 
3) If indication is Pain Management and stop date=discharge date: 
missing stop time will be set to 1 minute after discharge time. 
4) If indication is Pain Management and stop date >discharge date: 
missing stop time will be set to 23:59. 
 
After all the opioid records that have the appropriate start and stop time, the start and stop time 
relative time (hours) to Hour 0 (end of surgery) or discharge will be determined for each record.  
Total dose will be calculated for the following time points.   Note: if a record indicates that 
the start and stop time extends beyond one period, the total dose from this record will be 
split into appropriate period using linear interpolation of hourly dose. 
 


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Table 4:  Definition of Opioid Consumption Period  
ID 
Time Interval  
Interval Description 
Interval Expression [1] 
1 
Pre-operative Period 
From hospital admission to surgery start  
[ADM, SGST) 
2 
Intra-operative Period 
From surgery start to surgery end  
[SGST, SGEN] 
3 
T0 - H0 
From first dose start time to end of surgery  
[FSD, SGEN] 
4 
T0 to T24 (Excluding Dose 2) 
From first dose start time to but not include the second dose start time  [FSD, SSD) 
5 
H0 - H24 (PSD 1) 
From surgery stop time to 24 hours after end of surgery  
(SGEN, SGEN+24] 
6 
H24 - H48 (PSD 2) 
From 24 hours after end of surgery to 48 hours after surgery  
(SGEN+24, SGEN+48] 
7 
H48 - H72 (PSD 3) 
From 48 hours after end of surgery to 72 hours after surgery  
(SGEN+48, SGEN+72] 
8 
H0 - H48 (PSD 1-2) 
From end of surgery to 48 hours after surgery 
(SGEN, SGEN+48] 
9 
H0 - H72 (PSD 1-3) 
From end of surgery to 72 hours after surgery 
(SGEN, SGEN+72] 
10 
H0 - EOT  
From end of surgery to end of treatment 
(SGEN, EOT] 
11 
0-24 hours post discharge 
From discharge to 24 hours after discharge 
(ADC, ADC+24] 
12 
24-48 hours post discharge 
From 24 hours post discharge to 48 hours post discharge 
(ADC+24, ADC+48] 
13 
0-48 hours post discharge 
From discharge to 48 hours after discharge 
(ADC, ADC+48] 
14 
24 hours before POD 10-14 visit 
24 hours before POD 10-14 telephone interview 
[POD10-24, POD10]  
15 
EOT - EOS  
From end of treatment to end of study 
(EOT, EOS] 
16 
Total in Study 
From hospital admission to end of study 
[ADM, EOS] 
[1] Abbreviations for intervals in (hours):  
ADM: hospital admission date/time;  
SGST=surgery start date/time;  


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SGEN=surgery stop date/time;  
FSD=study drug first dose start date/time; 
SSD=study drug second dose start date/time;  
ADC=actual hospital discharge date/time;  
EOT=end of treatment date /time, defined as hospital discharge date/time or LSD+1, whichever comes first) and LSD+1 is 24 hours after the last dose of 
study drug, hence, LSD+1 = last dose date/time + 24 hours 
POD10= POD 10-14 telephone interview date. Because the time of interview is not captured, the analysis will be based on the calendar date.  Any 
records with date of the interview and the date before the interview will be included. 
EOS=end of study date/time; where the end of study visit date is the POD 30 telephone interview date and the time is set to 23:59 
The square brackets, [ ], means inclusive whereas the parentheses, ( ), means exclusive   
 


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3.5.6. 
Opioid Free Subjects  
A subject who did not use any opioids is classified as an opioid free subject.  The status of opioid 
free (OPFREE = Yes/No/NA) will be determined for each period based on the following rules: 
In-Patient Phase (Intervals 1 to 10): 
1. If any opioid records are found in the opioid concomitant medication page for 
corresponding period regardless if the total dose was known or unknown, the subject is 
assigned OPFREE=No; otherwise, OPFREE=Yes. 
2. If a subject is discharged from hospital (based on actual discharge date/time) prior to the 
start of a period (e.g., H48-H72 period), the subject is assigned to OPFREE=NA for this 
period (Not at risk). 
Post-Discharge Phase (Intervals 11 to 14): 
1. Post discharge telephone interviews are to be done at 24 hours and 48-hours post 
discharge, an in-person office visit on POD10-14, and a final telephone interview on 
POD 30.  Subject is asked if any of the opioid medication prescription given to the 
subject at discharge for pain related to surgery since discharge (at 24 hour post 
discharge call) or since last study contact (at other 3 follow-up call or visit)  The 
response to this question will be used to determine the opioid free status for post 
discharge time point regardless if the total dose was or was not captured on the eCRF. 
2. If any opioid records found on the opioid page that corresponds to the defined interval 
for a subject: the subject is considered Not opioid free for that interval regardless if the 
total dose is known or unknown. 
      
3.5.7. 
Time to First Rescue 
Rescue opioid (IV opioid or oral opioid analgesic) will be those opioid records with ‘Rescue’ as 
the indication in the database.     
Time (hours) from first dose to the start time of the rescue opioid will be calculated for each 
opioid record.  
Time (hours) = start date/time of analgesics – date/time of end of surgery (Hour 0)  
A rescue opioid record without a start date and/or start time (although those records may 
have imputed date/time) will be excluded from the time to rescue analysis in general with 
one exception, that is, if this is the only record for this route of administration then this 
record will be included. In this case, the imputed missing date/time will be used.  See 
Section 3.5.5 for missing date/time imputation rules. 
Following the determination of the time from end of surgery (Hour 0) to the rescue start time for 
each rescue record the following data derivations will be performed:  


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1. when a subject has both IV and oral rescue opioid records, the time to first rescue (IV or 
Oral) will be the first rescue record based on the start time, mathematically, it can be 
expressed as 
Time to first rescue = min (time to first IV rescue, time to first oral rescue) if both 
events have occurred.   
2. When a subject did not have any IV rescue opioid but have oral rescue opioid:  
• This subject will not be censored for the time to first rescue (IV or Oral) analysis; 
time to first rescue will be set to be the same as the time of first oral rescue  
• This subject will be censored for time to first IV rescue.  The censored time will 
be date/time of first oral rescue.     
3. When a subject did not have any Oral rescue opioid but have IV rescue opioid:  
• the time to first rescue (IV or Oral) will be set to the time to first IV rescue opioid 
(subject is not censored) 
• this subject will be censored to EOT for the time to first oral rescue analysis.    
4. When a subject does not have any rescue opioid records: 
• this subject will be censored for all 3 time to rescue endpoints.  The censored time 
will be EOT. 


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3.5.8. 
Missing Date/time Imputation for Ambulation Records 
Each time a subject ambulates, the eCRF will record the following information 
1. ambulation type [assisted vs unassisted (ie, independent)] 
2. pre-ambulation PI score and assessment date/time.  
3. the worst pain score during walk and assessment date/time 
The assessment date/time of the pain score prior to ambulation is used as the proxy for this 
ambulation start date/time.  Time to First Ambulation will be derived from this field.  When an 
ambulation occurs but the PI assessment was not performed, the date/time of ambulation will be 
captured in the comments field; hence, programming effort will be used to extract this 
information from the comments for this analysis.  
The following rules will apply for partial date/time of an ambulation record:  
• If assessment time for pain score prior to ambulation is unknown but the assessment 
time for ‘The worst PI score during the ambulation’ is known, the missing time for 
prior to ambulation PI score will be set to 15 minutes BEFORE the time for the worst 
PI score.  For example, if the worst pain assessment time is 11:00, the imputed time 
pain score prior to ambulation will be 10:45.  
• If assessment time for the worst pain score during an ambulation is unknown, the 
assessment time for prior to ambulation is known, the missing time for the worst pain 
score will be set to 15 minutes AFTER the assessment time for the pain score prior to 
this ambulation.  For example, if the pain prior to ambulation assessment time is 
11:00, the imputed assessment time for the worst pain during ambulation will be 
11:15.  
• If both assessments have unknown times (time of pain prior to ambulation and time of 
the worst pain during the ambulation), the ambulation record will be EXCLUDED 
from the time to first ambulation analysis (see Section 3.5.9). This record will also be 
EXCLUDED from the Sum of Pain Intensity analysis (See Section 3.5.10).  But the 
ambulation record will be INCLUDED in the total number of ambulation analysis 
(see Section 5.3.3). 
 
3.5.9. 
Time to First Ambulation 
Ambulation records with partial time will be imputed using the rules specified in Section 
3.5.8.  Time (hours) from first dose to each ambulation record will be determined as follows: 
Time (hours) = date/time of ambulation – date/time of end of surgery (Hour 0)  
The first assisted ambulation record and the first independent ambulation record will be 
identified for each subject.  The following rules will be applied when:  


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• a subject did not have any assisted ambulation records, but this subject has records for 
independent ambulation, this subject will not be censored for time to assisted ambulation.  
The time of assisted ambulation will be set to the same as time to first independent 
ambulation for analysis. 
• a subject has assisted ambulation records, but this subject did not have records for 
unassisted ambulation, this subject will be censored for time to first independent 
ambulation.  The censored time will be the time of EOT.  
• a subject does not have any ambulation event (response on eCRF for ambulation was 
‘None’), this subject will be censored at EOT for both time to assisted ambulation and 
time to independent ambulation. 
3.5.10. 
Sum of Pain Intensity (SPI)  
A total of 14 pain intensity scores are scheduled: 13 PI scores are to be collected within the first 
48 hours after end of surgery plus a PI score at the time of hospital discharge. The time points for 
scheduled PI scores include 
• Upon arrival at the PACU 
• Time points relative to first dose of study drug (Time 0):  4 hours ± 15 minutes, 6 
hours ±15 minutes, 8 hours ± 30 minutes, 10 hours ± 1 hour, 12 hours ± 1 hour, 16 ± 
1 hour, 20 hours ± 1 hour, 24 hours ± 1 hour (before study drug administration, if 
indicated), 30 hours ± 2 hours, 36 hours ± 2 hours, 42 hours ± 2 hours, and 
48 hours ± 2 hours (before study drug administration, if indicated), when the subject 
is awake 
• Before hospital discharge      
In addition, unscheduled PI assessments will be performed prior to use of rescue analgesic; PI 
will also be assessed prior to each ambulation attempt, and the worst pain intensity during an 
ambulation will also be collected; however, the worst pain score during ambulation will not be 
included in the SPI analysis. 
In order to calculate the weight for SPI, the assessment time from each pain score is required.  
When the assessment time for a non-missing pain score is unknown, the following rules will 
apply: 
• If it is one of the scheduled pain assessments the nominal time will be used. For 
example, Hour 8 pain score nominal time is 8 hours after the first dose of study drug. 
• If it is a PI score prior to use of rescue opioids, and the opioid medication start time is 
non-missing, the medication start time will be used as the assessment time of this PI 
score.  If the medication start time is also missing, and the missing time was imputed 
for opioid consumption, the imputed medication start time will be used.  If the 
missing time was not imputed, then the pain score will be EXCLUDED from the 
analysis.  


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• If the pain score prior to ambulation has unknown assessment time the imputed 
ambulation start date/time will be used (see Section 3.5.8).  If both assessments had 
missing time (time of pain prior to ambulation and time of the worst pain during the 
ambulation), the ambulation record will be EXCLUDED from the Sum of Pain 
Intensity analysis. 
Sum of PI score (SPI) is time-weighed cumulative pain intensity from first dose.  The weight 
factor at each time point is the time elapsed since the previous observation.  SPI for this study 
will be derived for the following intervals 
• Time 0 to time of first assisted ambulation (inclusive), this will be referred to as SPIAA.  
The last PI score for this parameter will be the PI score prior to the first assisted 
ambulation.  Subjects who do not have any assisted ambulation but who have 
independent ambulation will be based on time to first independent ambulation.   Subjects 
who do not have any ambulation attempts will be excluded.  
• Time 0 to first independent (unassisted) ambulation (inclusive); this will be referred to as 
SPIIA. The last PI score for this parameter will be the PI score prior to first independent 
ambulation.  Subjects who did not have any independent ambulation attempts will be 
excluded.  
• Time 0 to hospital discharge. This will be referred to as SPIDC.  SPIDC will include all PI 
scores collected from this subject prior to hospital discharge.   
SPI is mathematically expressed as 
SPIp = ∑ (PIt ● Wt), where PIt is the pain intensity at time point t, and Wt = time in 
minutes elapsed since the previous observation (date/timet – date/timet-1).  
SPI will include all non-missing PI scores (scheduled plus the unscheduled PI scores).  Weight 
will be the elapsed time between 2 consecutive PI assessments regardless the type of PI scores.  
Therefore, the magnitude of SPI is affected by not only the pain intensity score but also the 
duration of assessment and the number of pain scores collected in this duration.  That is, the 
totality from the following factors is contributed to the size of the SPI for a subject: 
1) Pain intensity score 
2) Duration of pain intensity assessments, for example, a subject who is discharged about 30 
hours after end of surgery would have a fewer pain assessments than another subject who 
is not discharged until 60 hours after the end of surgery. 
3) Number of PI scores prior to use of rescue opioids  
4) Number of PI scores prior to assisted ambulation 
5) Number of PI scores prior to independent ambulation  
 


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The impact of those factors will be identified for each subject and treated as a covariate during 
the analysis (see Section 5.2.1.1 for details).  In addition, an hourly pain score will be derived for 
each subject as follows: 
Hourly Pain Score = SPI / Duration of Pain Assessment. 
where the duration of pain assessment (hours) = date/time of last PI score – date/time of end of 
surgery; and the duration of PI assessments for each SPI may or may not be the same for a 
subject. 
  
3.5.11. 
Overall Benefit of Analgesia Score (OBAS)  
All OBAS assessments will be mapped to Analysis Visit using the Post-operative Day 
benchmark (see Section 3.5.2).  In addition, the last observation prior to discharge will also be 
included as ‘Prior to Discharge’ time point.  
OBAS (ie, domain score) at each time point is the sum of scores in items 1–6 and add (4 - score 
in item 7).  For example, a subject with minimal pain (Item 1=0), severe vomiting (Item 2=4), no 
itching (Item 3=0), no sweating (Item 4=0), no freezing (Item 5=0), slightly dizzy (Item 6=1), 
and is not very satisfied with his postoperative pain treatment (Item 7=1) has an OBAS of 8 
(OBAS = [0+4+0+0+0+1]+ [4-1]).  Hence, a lower OBAS score indicates a higher analgesia 
benefit.  
Opioid Distress Dimension Score (ODDS, sub-domain score): ODDS is the sum of scores in 
items 2–6.  The ODDS for the example above would be 5 [severe vomiting (Item 2=4) and no 
itching (Item 3=0), sweating (Item 4=0), and freezing (Item 5=0) and is slightly dizzy (Item 
6=1)].  Hence, a lower ODDS score indicates a lower opioid distress.  
 
 


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Table 5:  Overall Benefit of Analgesia Questionnaire and Rating 
1. Please rate your current pain at rest on a scale between 0=minimal pain and 
4=maximum imaginable pain 
2. Please grade any distress and bother from vomiting in the past 24 hours (0=not at 
all to 4=very much) 
3. Please grade any distress and bother from itching in the past 24 hours (0=not at 
all to 4=very much) 
4. Please grade any distress and bother from sweating in the past 24 hours (0=not at 
all to 4=very much) 
5. Please grade any distress and bother from freezing in the past 24 hours (0=not at 
all to 4=very much) 
6. Please grade any distress and bother from dizziness in the past 24 hours (0=not at 
all to 4=very much) 
7. How satisfied are you with your pain treatment during the past 24 hours (0=not at 
all to 4=very much) 
OBAS = [sum of scores in items 1-6] + [4 - score in item7] 
ODDS = sum of scores in item 2-6 
 
Item Score: The scores in items 1 to 7 will be analyzed as is.  That is, the directional 
transformation for item 7 score for OBAS computation will not be done when item 7 score is 
analyzed separately.  Hence, in item 7, a high score indicates a higher degree of satisfactory with 
the pain management treatment.     
Missing Data: The following rules will be following to handle missing data: 
1. For OBAS and ODDS: if only 1 item is missing, the missing data will be imputed to the 
worst score (4 for items 1 to 6, and 0 for item 7). 
2. If there is more than 1 item with missing data, the total score will not be calculated.  
Hence, the OBAS and ODDS will be set to missing.   
3. Missing data will not be imputed for summary and analysis of the individual item. 
Additional imputation method may be explored if data warrants.   


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3.5.12. 
Patient Global Assessment of Pain Control (PGA)  
All PGA assessments will be mapped to Analysis Visit using the Post-operative Day benchmark 
(see Section 3.5.2).  In addition, the last observation prior to discharge will also be included as 
‘Prior to Discharge’ time point. 
Study staff will ask subjects to respond to the following question: 
“Overall, please rate how well your pain has been controlled during the last 24 hours?”  
Poor (0) 
Fair (1) 
Good (2) 
Very Good (3) 
Excellent (4) 
Subjects with ratings of 2 (good), 3 (very good) or 4 (excellent) will be grouped as responders 
(ie, subjects satisfied with pain control) for PGA analysis.  
3.5.13. 
Physical Therapy     
Physical therapy (PT) assessments will be mapped to Analysis Visit using the Post-surgery Day 
benchmark (see Section 3.5.2).  Number of sessions within a PSD will be derived for each 
subject, including 
1. Number of PT sessions performed 
2. Number of PT sessions not performed due to pain     
3. Number of PT sessions completed  
4. Number of PT sessions not completed due to pain     
5. Number of PT sessions that the subject hit the target functional range of motion  
6. Number of PT sessions that the subject did not hit the target functional range of motion 
due to pain     
 
 


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3.5.14. 
Additional Health Care Utilization Endpoints     
Each of the following events will be mapped using the PSD Analysis Visit benchmark (see 
Section 3.5.2).  The following endpoints will be derived for each subject from discharge to end 
of study (post-operative day 30 (POD 30)).  
1. Number of times admitted to a Skilled Nursing Facility 
2. Number of times a phone call made to the doctor due to post surgery pain 
3. Number of times had unscheduled doctor visits due to post surgery pain 
4. Number of times visited Emergency Room (ER) due to post surgery pain 
5. Number of all-cause Hospital Readmissions 
6. Total cost of hospital Stay 
 
 


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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 
(randomized (ITT), all treated subjects (Safety), subjects who completed study).  After the POD 
30 telephone interview, subjects will be discharged from the study. Hence, Completed Study will 
be defined based on completion of POD 30 following up visit. Subjects (%) by reasons for end of 
study drug treatment will also be included.  
Primary reason for early termination of study includes 
1) Adverse Event 
2) Study Non-compliance  
3) Lost to Follow-Up 
4) Physician Decision 
5) Sponsor Decision 
6) Subject Decision 
7) Other 
Primary reason for subject no longer requiring study drug treatment includes: 
1) IV access removed 
2) Subject discharged 
3) Adverse event 
4) Physician decision 
5) Subject decision 
6) Other 
 
A summary table (Table 14.1.1.2) will provide number of subjects in each analysis population 
by site. The table will display the site with the highest enrollment (ITT analysis set) first. 
 
4.2. 
Demographics and Baseline Characteristics 
The demographic summary (Table 14.1.2) will include descriptive statistics for age, age group 
(age <65, age >=65), sex, race, ethnicity, weight, height, and BMI at baseline for overall and by 
treatment group.  
Baseline characteristics and patient population characteristics will include: 


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1) Surgery site (left or right knee), was a transfusion required (Yes/No), was the quadriceps 
tendon spared during the surgery (Yes/No), time (hours) stayed in the PACU, disposition 
post PACU. 
2) Time (hours) from first dose to surgery start; time (hours) from first dose to surgery stop; 
surgery duration (hours) 
3) Time (hours) from end of surgery to end of treatment (EOT)  
Demographics and baseline characteristics will be tabulated for the safety analysis set with no 
formal inferential tests.  If the mITT set and safety set are different, a second table will be 
prepared for the mITT analysis set.  
4.2.1. 
Other Medical History 
All medical history data will be available in the SDTM dataset without a formal data summary 
and data listing. 
4.3. 
Protocol Deviations 
All protocol deviations will be identified and will be classified as either an ‘Important Protocol 
Deviation’ or ‘Protocol Deviation’. 
Important Protocol Deviation: An Important Protocol Deviation is a protocol deviation that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being. Examples may include: 
➢ Failure to meet all entry criteria; 
➢ Non-compliant with study drug treatment regimen; 
➢ Did not receive randomized treatment; 
➢ Did not receive correct randomization treatment; 
➢ Use of prohibited concomitant medications; 
Protocol Deviation: Any alteration/modification, divergence or departure from the IRB-approved 
protocol.  A protocol deviation is an unanticipated or unintentional divergence or departure from 
the expected conduct of an approved study that is not consistent with the current research 
protocol, or consent document. 
All protocol deviations will be tabulated by protocol type, protocol deviation category for each 
treatment group and study overall (Table 14.1.4). 
 
4.4. 
Treatment Compliance 
Doses of study medication (N1539 30 mg or Placebo) will be administered to the study subjects 
under the observation of study personnel while confined to the study site.  The exact time of 
administration of study medication will be documented within each subject’s eCRF.   


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A subject is expected to receive at least 2 doses of study drug.  All doses after dose 1 are to be 
given every 24 hours (± 1 hour, i.e., window=23-25 hours from previous dose).  The last dose 
may be given up to 4 hours earlier from previous dose (i.e., window=20-25 hours from previous 
dose) if the last dose is given on the day of discharge.   
Compliance relative to dosing window will be checked based on dosing interval (hours). 
Mathematically dosing interval will be derived as (date/time of dose(n+1) – date/time of dosen).   
Dosing interval will be calculated for each dose starting dose #2.  Dosing intervals outside the 
dosing widow (23-25 hours or 20-25 if it is the last dose given on the day of discharge) will be 
considered non-compliance.  
In addition, all subjects will receive 650 mg of acetaminophen Q8H PO as tolerated until 
LSD+1.  Compliance associated with concomitant acetaminophen usages will also be checked. 
Compliance data will be tabulated with study drug total exposure (see Section 7.1). 
4.5. 
Prior and Concomitant Medications 
All prior and concomitant medications will be available in a SDTM dataset without formal data 
summaries and data listings. 


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5. 
EFFICACY ANALYSIS 
5.1. 
Opioid Consumptions 
Opioid consumption will follow an risk approach (see 3.5.1 Subjects at Risk).  The following 16 
periods will be included in the summary table. 
ID 
Time Interval  
Note 
1 
Pre-operative Period 
 
2 
Intra-operative Period 
 
3 
T0 - H0 
 
4 
T0 to T24 (Excluding Dose 2) 
 
5 
H0 - H24 (PSD 1) 
This is the primary efficacy endpoint for the study 
6 
H24 - H48 (PSD 2) 
 
7 
H48 - H72 (PSD 3) 
 
8 
H0 - H48 (PSD 1-2) 
 
9 
H0 - H72 (PSD 1-3) 
 
10 
H0 - EOT  
 
11 
0-24 hours post discharge 
 
12 
24-48 hours post discharge 
 
13 
0-48 hours post discharge 
 
14 
24 hours before POD 10-14 visit 
 
15 
EOT - EOS  
 
16 
Total in Study 
 
The following 3 analyses will be included for each period (Table 14.2.1.1). 
5.1.1. 
Number (%) Subjects Opioid Free 
A subject is opioid free if this subject did not use any opioid (IV or Oral) analgesic in this period. 
Number (%) subjects opioid free (Yes/No) will be tabulated by treatment group. The 
denominator for each period should include all subjects at risk (see Table 2:  Subjects at Risk): 
Treatment group difference in proportion of subjects who used rescue and 95% confidence 
intervals for the difference will be provided.  The difference will be evaluated using Cochran-
Mantel-Haenszel (CMH) test controlling for investigator center (CM general association 
statistic).   If positive treatment effect is observed the difference in proportion subjects rescued 
will also be expressed as number needed to treat (NNT=1/difference in proportion). 


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5.1.2. 
ANCOVA Analysis of Total Opioid Consumption  
Total opioid consumptions in IVMED (mg) per subject will be determined for each interval.  
Subjects who did not use any rescue medication in a period (ie, opioid free =Yes in Section 
5.1.1) will be set to zero ‘0’ for total opioid consumption analysis.  Total opioid from Hour 0 to 
Hour 24 post first dose is the primary efficacy endpoint for this study. 
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.  LS means from each group and difference in LS means and 
corresponding 95% CI for the difference and nominal p-values will be reported in the summary 
table. 
5.1.3. 
Rank Analysis of Total Opioid Consumption  
Total opioid consumption may not be normally distributed, hence, the statistical assumption for 
parametric analysis using ANCOVA specified in Section 5.1.2 above may not be held.  A 
confirmatory analysis using CMH ANOVA (Row Mean Scores Differ) on rank (a nonparametric 
approach) will also be performed for total opioid consumption.  The test will control for 
investigational site.   The rank will be produced within a time point using Nplus1 and ties=mean 
method.  P-value from the CMH test will be presented. 
5.1.4. 
 Time to First Rescue  
There are 3 time-to-first rescue events in this study associated with opioid analgesic (Table 
14.2.1.2): 
• time from hour 0 to first use of IV or Oral rescue analgesic  
• time from hour 0 to first use of IV rescue analgesic 
• time from hour 0 to first use of Oral rescue analgesic 
 
Summary tables will include  
• number (%) subjects with and without (censored) event,  
• Kaplan-Meier product limit estimates of quartiles of time to first event (25%, 50%, and 
75% tiles and 95% CIs) and  
• KM means (SE) of time to first event  
• the log rank test for homogeneity between the treatment groups.   
• Differences between the groups in time to event will be further analyzed using Cox 
proportional hazards analysis model that include the main effects of treatment and 
investigational sites.  Hazard ratio (N1539 30 mg / placebo) and 95% CIs and p-value 
from Wald’s chi-square test for treatment and investigational site will be presented.   


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Kaplan-Meier survival curves will be presented for each treatment group.  
5.1.5. 
Number of Times Used Rescue Analgesia 
Opioid records with indication of Rescue will be used for this analysis.  Total number of doses 
of rescue opioids will be derived for each subject from end of surgery (H0) to hospital discharge 
or LSD+1 (ie, end of treatment), H0-H24, H24-H48, and H48-H72.  A table (Table 14.2.1.3) 
will tabulate total doses by treatment group for each period without inferential statistics. 
5.2. 
Scheduled Pain Intensity (PI) Assessment 
5.2.1. 
Sum of Pain Intensity by Intervals 
SPIAA, SPIIA, SPIDC and the Hourly PI Score for each subject will be derived (see Section 
3.5.10).  Difference between the treatment groups will be evaluated using ANOVA model that 
includes treatment and investigator center.  LS mean for each treatment group, difference 
between treatment groups in LS mean (LSM) and 95% CI for the difference in LSM will be 
provided. 
A sensitivity analysis using CMH ANOVA (Row Mean Scores Differ) on rank controlling for 
investigator center will also be provided.      
Normal p-value at each time point will be reported as is without controlling for multiple 
comparisons. 
5.2.1.1. 
Evaluation of SPI Potential Covariates 
A sensitivity analysis will provide assessment of interactions between treatment and 
investigational site (Table 14.2.2.2.1) in SPIs parameters. 
The effect of the following potential covariates of SPI will also be formally assessed in the 
sensitivity analyses (Table 14.2.2.2.2): 
1. Number of times Used Rescue.  This value is the number of PI scores prior to rescue that 
are included in each specific SPI calculation.  Hence, it is period dependent.  For 
Example, number of times rescued prior to the time to first assistant ambulation (period 
corresponding to SPIAA) may or may not the same as the number of times rescued for the 
period of time to first independent ambulation (period corresponding to SPIIA). 
2. Number of times with assisted ambulation. This value is the number of PI scores prior to 
assisted ambulation that are included in each specific SPI calculation.  This covariate is 
irrelevant for SPIAA. 
3. Number of times with independent ambulation. This value is the number of PI scores 
prior to independent ambulation that are included in each specific SPI calculation.  This 
covariate is irrelevant for SPIAA and SPIIA. 
4. Duration of PI assessment. This value is the elapsed hours from the end of surgery to the 
last PI score used in a specific SPI calculation.  This covariate is irrelevant for Hourly PI 
score.   


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5.2.2. 
Scheduled Pain Intensity by Time Points 
Pain intensity at each scheduled time point (14 data time points, Table 14.2.2.3; pain intensity 
after discharge, Table 14.2.2.4) will be tabulated with descriptive statistics; difference between 
the treatment groups will be evaluated using ANOVA model that includes treatment and 
investigator center.  LS mean for each treatment group, difference between treatment groups in 
LS mean (LSM) and 95% CI for the difference in LSM will be provided.  Missing PI score at a 
scheduled time point will not be imputed with one exception:  if a subject is discharged 
before 48 hours, the last scheduled PI assessment prior to discharge will also be used as the 
PI score prior to discharge.    
A sensitivity analysis using CMH ANOVA (Row Mean Scores Differ) on rank controlling for 
investigator center will also be provided.      
Normal p-value at each time point will be reported as is without controlling for multiple 
comparisons. 
5.3. 
    Ambulation Assessments 
5.3.1. 
Time to First Ambulation Events  
There are 2 time-to-event parameters related to ambulation in this study; they are 
• time from hour 0 to first assisted ambulation  
• time from hour 0 to first independent ambulation 
Summary table (Table 14.2.3.1) will include  
• number (%) subjects with and without (censored) event,  
• Kaplan-Meier product limit estimates of quartiles of time to first event (25%, 50%, and 
75% tiles and 95% CIs) and  
• KM means (SE) of time to first event  
• the log rank test for homogeneity between the treatment groups.   
• Differences between the groups in time to event will be further analyzed using Cox 
proportional hazards analysis model that include the main effects of treatment and 
investigational sites.  Hazard ratio (N1539 30 mg / placebo) and 95% CIs and p-value 
from Wald’s chi-square test for treatment and investigational site will be presented.   
Kaplan-Meier survival curves will be presented for each treatment group.  
5.3.2. 
Pain Before and the Worst Pain During Ambulation 
Pain intensity (0-10) prior to each ambulation and the worst pain intensity (0-10) during an 
ambulation will be collected.  Each ambulation will be assigned a sequential number (referred to 


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as ambulation attempt identification number according to the date/time within an ambulation 
type (assisted vs not assisted).   
PI score will be tabulated by treatment and ambulation ID with descriptive statistics (Table 
14.2.3.2 - assisted ambulation; Table 14.2.3.3 - independent ambulation).  POD will be assigned 
based on the calendar date, with the date of surgery being POD 1.  Difference between the 
groups will be evaluated using an ANOVA model that include treatment and investigator center.  
Difference between the treatment groups in LSM and 95% CI for the difference will be provided 
along with p-value for the effect of treatment and investigational site. 
A sensitivity analysis using CMH ANOVA (Row Mean Scores Differ) on rank controlling for 
investigator center will also be provided.      
Normal p-value at each time point will be reported as is without controlling for multiple 
comparisons. Pain intensity analysis will include only the subjects with PI assessment prior to 
and during ambulation.  That is, subjects without ambulation assessments and subjects without 
PI assessment prior to and/or during ambulation will be excluded.    
5.3.3. 
Number of Times of Ambulation  
Total number of times a subject ambulated before hospital discharge will be tabulated by 
treatment group and ambulation type (assisted vs not assisted, Table 14.2.3.4).  Differences 
between the treatment groups will be evaluated via ANCOVA.  Ambulation records with a date 
but with unknown time (see Section  3.5.9) will be included in this analysis. 
5.4. 
Patient Global Assessment (PGA) of Pain Control  
PGA records will be tabulated using POD benchmarked.   In addition, the last observation prior 
to discharge will also be included as ‘Prior to Discharge’ time point. 
Number (%) subjects by PGA ratings will be tabulated along with mean (SD) of the rating by 
treatment and time point (Table 14.2.4).  Proportion of subjects with positive response 
[including ratings of 2 (good), 3 (very good) or 4 (excellent)] vs proportion of subjects with non-
positive response [including ratings of 0 (poor) or 1 (fair)] will be compared between treatment 
groups using CMH test (general association) controlling for investigational site.     
5.5. 
Overall Benefit of Analgesic Questionnaire  
OBAS, ODDS, and score from each item will be tabulated for each POD by treatment (see 
Section 3.5.11 for parameter derivation method).  In addition, the last observation prior to 
discharge will also be included as ‘Prior to Discharge’ time point. 
ANCOVA models with main effects of treatment and investigational sites will be used to 
compare LSM between treatment groups at each time point.  Summary table (Table 14.2.5) will 
provide descriptive for observed score, the estimated LSM, difference in LSM and 95% CI for 
the difference, and p-value for treatment effect and investigational site effect.  
 


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6. 
HEALTHCARE RESOURCE UTILIZATION 
The following healthcare resource utilizations endpoints will be tabulated by Treatment groups 
without inferential statistics.  
6.1. 
Total Cost of Hospital Stay 
Total cost of hospitalization will be tabulated by treatment group.  The summary will provide 
descriptive summary, including n mean, standard deviation, median, minimum, maximum 
(Table 14.2.6).     
6.2. 
Hospital Readmission, ER Visits, Doctor Visits, and Phone Calls  
A summary table (Table 14.2.7) will include the following events from discharge to POD 30 (ie, 
EOS) 
1. Subjects with >=1 all cause hospital readmission  
2. Total number of all-cause readmissions by subjects 
3. Subjects with >=1 ER visit due to pain 
4. Total number of ER visits due to pain by subjects 
5.  Subjects with >=1 unscheduled doctor visit due to pain 
6. Total number of unscheduled doctor visits due to pain by subjects 
7. Subjects with >=1 phone calls due to pain 
8. Total number of phone calls due to pain by subjects 
6.3. 
Physical Therapy Sessions from Post Surgery to POD 30 
A summary table (Table 14.2.8) will include the following data from physical therapy (PT) from 
end of surgery to POD 30 (ie, EOS) 
1. Total number of PT sessions performed per subject 
a. Total number of PT sessions that were scheduled but not performed due to pain 
per subject  
2. Total number of PT sessions completed per subject 
a. Number of PT sessions that were not completed due to pain 
3. Total number of PT sessions performed and target function range of motion that was met 
per subject 
a. Total number of PT sessions that did not meet the target function range of motion 
due to pain (while subject is in hospital) 
The summary table will include group summary of mean, SD, median, minimum and 
maximum as well as number (%) subjects in the following range categories (note: the range 


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categories identified here may be modified as appropriate based on the data, each parameter 
may have a different set of range categories appropriate for that parameter). 
• 0 session 
• 1-5 sessions 
• 6-10 sessions 
• 11-15 session 
• 16 or more sessions  
6.4. 
Requiring a Skilled Nursing Facility from Post Discharge to POD 30 
A summary table (Table 14.2.9) will provide 
1. Number (%) of subjects who required a skilled nursing facility at least once from hospital 
discharge through POD 30 
2. Total time (days spent in skilled nursing facility from hospital discharge through POD 
30) 
3. Total number of times admitted to a skilled nursing facility per subject 
Time (days) spent in skilled nursing facility will be calculated for each admission as follows   
Time (days) = Date of Discharge – Date of Admission +1  
Total time (days) per subject is calculated as the sum of days across all admissions from 
discharge to POD 30 for each subject. 
 


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7. 
SAFETY AND TOLERABILITY EVALUATIONS 
7.1. 
Extent of Exposure 
The extent of exposure will be assessed by number of doses taken.  The summary will provide 
number of subjects (%) who had 1, 2, 3, …. etc. doses of study drug in the study.  Percentage 
will be calculated based on total number of treated subjects in each treatment group 
(Table 14.3.1.1). 
The exposure table will also include dosing compliance (see Section 4.4) information based on 
based on a subset of subjects who had ≥ doses of study drug.  The compliance data will include 
number of subjects (%) with all doses taken within dose interval and number subjects (%) with 
>=1 dose that was dosed outside the dosing interval will be tabulated by treatment group.    
In addition, number of subjects and total number of doses that are dosed <23 hours, <22 hours, 
<21 hours, and <20 hours from the previous dose will also be identified. 
Subjects compliance with concomitant acetaminophen usages will also be tabulated by treatment 
group (Table 14.3.1.2)  
7.2. 
Adverse Events 
Adverse events reported post dosing through the final follow-up (POD 30 ± 4 days) will be 
considered as treatment emergent adverse events (TEAEs).  The Medical Dictionary for 
Regulatory Activities (Version 20.1) will be used to classify all AEs with respect to system 
organ class and preferred term. 
The following summary tables will be produced for the TEAEs. All data summaries will provide 
number (%) subjects as well as total number of events in each category. 
1. a topline summary of TEAEs (Table 14.3.2.1) 
2. a summary table by preferred term in descending order of total incidence (Table 14.3.2.2) 
3. a detailed summary table by system organ class, preferred term and severity 
(Table 14.3.2.3.1) 
4. a detailed summary table by system organ class, preferred term and relationship 
(Table 14.3.2.3.2) 
5. a table of serious TEAEs by system organ class and preferred term (Table 14.3.2.4) 
 
 


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7.3. 
Change in Laboratory Tests 
Safety laboratory tests are scheduled to be performed at check-in and at hospital discharge.  
Additional unscheduled laboratory tests would be performed as clinical indicates.  Central lab 
will be provided by PPD Global Central Labs. 
Incidence of potentially clinically significant abnormal clinical laboratory values will be 
identified for selected laboratory tests of special interest.    
 
Table 6:  Selected Laboratory Tests of Special Interest 
Lab Category 
Description (Code) 
Chemistry 
Alkaline Phosphatase (ALP) 
 
Alanine Aminotransferase (ALT) 
 
Aspartate Aminotransferase (AST) 
 
Blood Urea Nitrogen (BUN) 
 
Direct Bilirubin (DBILI) 
 
Gamma Glutamyl Transferase (GAMMAGT) 
 
Serum Creatinine (CREATIN) 
 
Total Bilirubin (TBILI) 
 
 
Hematology 
Hematocrit (HCT) 
 
Hemoglobin (HGB) 
 
Platelet (PLT) 
 
White Blood Cell (WBC) 
 
 
Coagulation 
Activated Partial Thromboplastin Time (APTT) 
 
Thromboplastin Time (PT) 
 
Prothrombin time International Normalized Ratio (PTINR) 
 
A summary table (Table 14.3.3) will provide number (%) subjects with abnormal results that 
meet the criteria in Table 7 post baseline. All post baseline lab tests (scheduled plus 
unscheduled) will be included in the analysis. If a subject had more than 1 lab draw and all 
results are abnormal, this subject is counted only for this lab test but all events will be counted in 
the ‘total’ events.    
 
 


Protocol REC-17-025 
Statistical Analysis Plan 
 
April 30, 2019 
 
 
Page 47 of 47 
 
 
Table 7:  Definition of Potentially Clinically Significant Abnormal Results in Selected 
Laboratory Tests of Special Interest 
Category 
Test Code 
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 
 
 
Total Bilirubin 
1) 1 to < 1.5 times of ULN 
2) ≥ 1.5 to <2 times of ULN 
3) ≥ 2 to < 2.5 times of ULN 
4) ≥ 2.5 to < 3 times of ULN 
5) ≥ 3 times of ULN 
 
Coagulation tests 
PTT, PT, INR 
1) Shift from Normal to Abnormal, Low 
2) Shift from Normal to Abnormal, High 
 
[1] ULN = Upper limit of normal range; LLN = Lower limit of normal range. 
 
7.4. 
Wound Healing 
Wound healing progress will be assessed at hospital discharge and at the follow-up visit (POD 
10-14).  Wound evaluation assessments will include investigator satisfaction score 
(0=completely unsatisfied and 10=completely satisfied).    
The summary table (Table 14.3.4) will include number (percent) subjects in each response 
category; Group mean, median, and standard deviation will also be provided. Differences 
between the groups be assessed using Cochran-Mantel-Haenszel ANOVA (Row Mean Scores 
Differ) on response controlling for investigational sites.