Clinical trial NCT02915978
Conditions: Pain
Sponsor: INSYS Therapeutics Inc
Start date: 2016-12-01; Completion date: 2017-02-10
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to evaluate analgesic efficacy of Fentanyl Sublingual Spray compared with placebo in participants with postoperative pain after a bunionectomy.

Detailed description:

Arms: arm 1: Lower dose Fentanyl delivered via sublingual spray every 4 hours. arm 2: Higher dose Fentanyl delivered via sublingual spray every 4 hours. arm 3: Placebo (matching Fentanyl) delivered via sublingual spray every 4 hours.
Interventions: intervention 1: Fentanyl intervention 2: Placebo
Intervention descriptions: intervention 1: Fentanyl delivered via sublingual spray intervention 2: Matching placebo delivered via sublingual spray

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
A Phase 2 Multicenter, Randomized, Double-Blind, Multiple-Dose, 
Parallel-Group, Placebo-Controlled Study of Fentanyl Sublingual Spray 
for the Treatment of Moderate to Severe Post-Operative Pain 
Protocol Number: 
Protocol Amendment l Date: 
Protocol Version: 
Investigational Product: 
IND Number: 
Sponsor: 
Principal Investigator: 
INS002-16-092/ NCT02915978
21 Dec 2016 
2.0 
Fentanyl Sublingual Spray 
121254 
Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
Medical Monitor: 
, MD 
Insys Development Company, Inc. 
 
Phone: 
 
Fax: 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements. The confidential information in this document is provided to you as an investigator, 
potential investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB). It is understood that the information will not be 
disclosed to others without written authorization from Insys Development Company, Inc., except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be administered. 





















































































































































SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN  
FOR PROTOCOL FENTANYL SUBLINGUAL SPRAY INS002-16-092 
Sponsor: 
www.insysrx.com 
Protocol Number: 
Insys Development Company, Inc. 
1333 South Spectrum Blvd,  
Suite 100 
Chandler, AZ 852866 
INS002-16-092/ NCT02915978
Protocol Title: 
A Phase 2 Multicenter, Randomized, Double-Blind, 
Multiple-Dose, Parallel-Group, Placebo-Controlled Study of 
Fentanyl Sublingual Spray for the Treatment of Moderate to 
Severe Post-Operative Pain 
Protocol Date / Version: Version 1.0 / 19-Sep-2016 
SAP Author: 
USA 
Telephone:   
Plan Version: 
SAP - Final Version 1.0 
Plan Date: 
04 Jan 2017 
--- confidential--- 


Protocol: INS002-l6-092 
Insys Development Company, Inc. 
Protocol Number: 
Protocol 
Version/Date: 
Protocol Name: 
Sponsor: 
Prepared by: 
SAP Version: 
SAP Date: 
Statistical Analysis Plan 
Page2 
INS002-16-092
Version 1.0 I 19-Sep-2016 
A Phase 2 Multicenter, Randomized, Double-Blind, 
Multiple-Dose, Parallel-Group, Placebo-Controlled Study 
of Fentanyl Sub lingual Spray for the Treatment of 
Moderate to Severe Post-Operative Pain 
Insys Development Company, Inc. 
1333 South Spectrum Blvd, 
Suite 100 
Chandler, AZ 852866 
SAP - Final Version 1.0 
04 Jan 2017 
I have read and approve the Statistical Analysis Plan specified above and agree with its 
content: 
20170104 INS002-16-092 SAP Final Version} 0.docx 
-
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1 3 :Jon 2.,, I?-­
Date 
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Date 
Confidential 


Protocol: INS002-16-092 
Statistical Analysis Plan 
Insys Development Company, Inc.    
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
Section   
Page 
LIST OF ABBREVIATIONS ................................................................................................. 6 
1. 
INTRODUCTION ............................................................................................................... 9 
2. 
PROTOCOL DESIGN AND OBJECTIVES ...................................................................... 10 
2.1 
Study Objectives .................................................................................................... 10 
2.2 
Design Overview .................................................................................................... 10 
2.3 
Study Duration ....................................................................................................... 13 
2.4 
Study Treatments and treatment assignments ............................................................ 13 
2.4.1 
Treatment Groups ...................................................................................... 13 
2.4.2 
Method of Treatment Assignment, Randomization Ratio, and Stratification ... 13 
2.5 
Blinding ................................................................................................................. 14 
2.5.1 
Maintenance of Blinding ............................................................................ 14 
2.5.2 
Time to Un-blinding .................................................................................. 15 
3. 
STUDY ASSESSMENTS/ ENDPOINTS ............................................................................ 15 
3.1 
Efficacy Endpoints ................................................................................................. 15 
3.1.1 
Primary Efficacy Endpoint ......................................................................... 15 
3.1.2 
Secondary Efficacy Endpoints: ................................................................... 15 
3.2 
Safety Assessments ................................................................................................. 16 
4. 
SAMPLE SIZE DETERMINATION AND RATIONALE, STATISTICAL POWER, 
AND SIGNIFICANCE LEVEL .......................................................................................... 16 
5. 
INTERIM ANALYSIS ....................................................................................................... 16 
6. 
ANALYSIS POPULATIONS ............................................................................................. 16 
6.1 
Intent-to-Treat (ITT) population ............................................................................... 16 
6.2 
Per Protocol (PP) Population ................................................................................... 17 
6.3 
Safety Population ................................................................................................... 17 
7. 
DATA CONVENTION AND RELATED DEFINITIONS .................................................. 17 
7.1 
Baseline Definition ................................................................................................. 17 
7.2 
Duplicate Data ....................................................................................................... 17 


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7.3 
Handling of Missing Data ........................................................................................ 17 
7.3.1 
Handling of Missing Data for Efficacy Assessments ..................................... 17 
7.3.2 
Handling of Missing Data For Safety Evaluations ........................................ 18 
7.4 
Sensitivity Analyses ................................................................................................ 20 
7.4.1 
Missing as Missing .................................................................................... 20 
7.4.2 
Multiple Imputation ................................................................................... 20 
7.5 
Multiple Clinical Trials ........................................................................................... 21 
7.6 
Multiple Comparisons and Type I Error Rate Multiplicity adjustments ........................ 21 
7.7 
Covariates and Prognostic Factors ............................................................................ 21 
7.8 
Subgroups and Exploratory Analysis ........................................................................ 21 
7.9 
Standard Calculations ............................................................................................. 21 
7.9.1 
Age .......................................................................................................... 21 
7.9.2 
Height ...................................................................................................... 22 
7.9.3 
Weight ...................................................................................................... 22 
7.9.4 
Body Mass Index (BMI)............................................................................. 22 
7.9.5 
Pain Intensity (PI) ...................................................................................... 22 
7.9.6 
Pain Intensity Difference (PID) ................................................................... 23 
7.9.7 
Summed Pain Intensity Difference (SPID) ................................................... 23 
7.9.8 
Pain Relief (PAR) ...................................................................................... 24 
7.9.9 
Total Pain Relief (TOTPAR) ...................................................................... 24 
7.9.10 
Two-Stopwatch Assessment of Pain Relief .................................................. 25 
7.9.11 
Time to onset of analgesia .......................................................................... 25 
7.9.12 
Peak Pain Relief ........................................................................................ 25 
7.9.13 
Time to Peak Pain Relief ............................................................................ 25 
7.9.14 
Time to first Perceptible Relief ................................................................... 25 
7.9.15 
Time to meaningful relief ........................................................................... 26 
7.9.16 
Rescue Medication Use .............................................................................. 26 
7.9.17 
Time to First Use of Rescue Medication ...................................................... 26 
7.9.18 
Subject’s Global Evaluation of Study Drug .................................................. 26 
8. 
STATISTICAL METHODS ............................................................................................... 26 
8.1 
Summarizing and Tabulating the Collected Data ....................................................... 26 
8.1.1 
Subject Disposition and Withdrawals .......................................................... 27 
8.1.2 
Protocol Deviations ................................................................................... 27 
8.1.3 
Demographics and Baseline Characteristics ................................................. 27 


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8.1.4 
Prior and Concomitant Medications ............................................................ 28 
8.1.5 
Exposure and Compliance .......................................................................... 28 
8.2 
Analysis of Efficacy Data ........................................................................................ 28 
8.2.1 
Primary Endpoint ...................................................................................... 28 
8.2.2 
Secondary Endpoints ................................................................................. 28 
8.2.3 
Analysis of Safety Data .............................................................................. 32 
8.2.4 
Adverse Events ......................................................................................... 32 
8.2.5 
Clinical Laboratory Evaluations .................................................................. 33 
8.2.6 
Serum Pregnancy Test ............................................................................... 33 
8.2.7 
Physical Examination / Oral Examination .................................................... 33 
8.2.8 
ECG ......................................................................................................... 34 
8.2.9 
Vital Signs ................................................................................................ 34 
9. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS .............................................................. 35 
10. 
APPENDIX 2 – PLANNED TLG ....................................................................................... 39 
10.1 
Planned by-subject listings ...................................................................................... 39 
10.2 
Planned Summary Tables ........................................................................................ 40 
10.3 
Planned Summary Figure ........................................................................................ 41 
11. 
VERSION HISTORY ........................................................................................................ 42 
12. 
REFERENCES .................................................................................................................. 43 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ACL 
Access Control List 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ASA 
American Statistical Association  
BMI 
body mass index 
BP 
Blood Pressure 
°C 
Celsius 
CFR 
Code of Federal Regulations 
C.I. 
Confidence Interval 
cm 
Centimeter 
CM 
Concomitant Medications 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
DMC 
Data Monitoring Committee 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ET 
Early Termination 
°F 
Fahrenheit 
FDA 
U.S. Food and Drug Administration 
FUV 
Follow-Up Visit 
GCP 
Good Clinical Practice 
IA 
Interim Analysis 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Based System 
MedRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
mm 
Millimeter 
NCS 
Not Clinically Significant 
NRS 
Numeric Rating Scale 
PI 
Principal Investigator 
PID 
Pain Intensity difference 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SL 
Sublingual 
SOP 
Standard Operating Procedure 
SPID 
Summed pain intensity difference 
SPID-4 
Summed Pain Intensity Scores over 1 to 4 hours 
SPID-8 
Summed Pain Intensity Scores over 1 to 8 hours 
SPID-24 
Summed Pain Intensity Scores over 1 to 24 hours 
SPID-48 
Summed Pain Intensity Scores over 1 to 48 hours 
SSL 
Secure Socket Layer 


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TEAE 
Treatment Emergent Adverse Event 
TOTPAR 
Total Pain Relief 
TOTPAR-4 
Total Pain Relief over 0 to 4 Hours 
TOTPAR-8 
Total Pain Relief over 0 to 8 Hours 
TOTPAR-24 
Total Pain Relief over 0 to 24 Hours 
TOTPAR-48 
Total Pain Relief over 0 to 48 Hours 
TV 
Treatment Visit 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analyses and reporting for the clinical trial 
protocol INS002-16-092, sponsored by Insys Development Company, Inc. The reader of this 
Statistical Analysis Plan (SAP) is encouraged to review the complete protocol as this plan contains 
only a limited overview of protocol information.  The main objective of this plan is to provide 
details pertaining to statistical methodology, data conventions, and processes used for the analysis 
of data from this trial.  
The format and content of this Statistical Analysis Plan are structured to provide sufficient detail to 
meet the requirements specified by the International Conference on Harmonization (ICH) E9: 
Guidance on Statistical Principles in Clinical Trials. All work planned and presented in this 
Statistical Analysis Plan will follow the ethical guidelines published by the American Statistical 
Association (ASA). 
The following documents and references [1-6], were reviewed in preparation of this Statistical 
Analysis Plan: 
• Version 1.0, protocol 19 September 2016 
• US Federal Register, Department of Health and Human Services, FDA, Guidance on Statistical 
Principles for Clinical Trials (1998) 
• ASA Ethical Guidelines for Statistical Practice (1999) 
• The Royal Statistical Society: Code of Conduct (1993) 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3, 1996) 
• ICH Guideline on General Considerations for Clinical Trials (ICH E8, 1997) 
• ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1997) 
 
 
 


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2. 
PROTOCOL DESIGN AND OBJECTIVES 
2.1 Study Objectives 
The primary objective of this study is to evaluate analgesic efficacy of Fentanyl Sublingual Spray 
compared with placebo in subjects with postoperative pain after a bunionectomy. 
Secondary objectives are to evaluate the safety of Fentanyl Sublingual Spray compared with 
placebo in subjects with moderate to severe postoperative pain after a bunionectomy, evaluate the 
time to onset of analgesia for Fentanyl Sublingual Spray, and evaluate the time to rescue medication 
following administration of Fentanyl Sublingual Spray.  
2.2 Design Overview 
This is a Phase 2 multicenter, randomized, double blind, multiple dose, parallel group, and placebo 
controlled study to evaluate the safety and efficacy of up to 2 dosing regimens of Fentanyl 
Sublingual Spray (100 µg [q4h] or 200 µg [q4h]) and/or matching placebo in subjects with 
moderate to severe postoperative pain after a bunionectomy. 
The study will comprise 4 periods: Screening Period (Days -28 to -1), Surgical Period (Day 0), 
Treatment Period (48 hours; Days 1 to 3), and Follow-up Period (Day 7 ± 2 days). The study design 
is represented schematically in Figure 1. 
Figure 1: Study Design Schematic 
 
Screening
(Days -28 to -1)
Surgical 
Period
(Day 0)
Treatment 
Period
(Days 1 to 3)
Follow-Up 
Period
(Days 5 to 9)
 
 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 0), will 
remain at the study site until Postoperative Day 3 (a total of 3 nights at the study site), and will 
return for the Follow up Visit on Day 7 ± 2 days (5 to 9 days after surgery). 


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During the Screening Period, subjects who meet all inclusion and no exclusion criteria will be 
eligible for enrollment. After providing written Informed Consent, subjects will undergo study 
specific screening procedures. Eligible subjects will complete all screening procedures within 28 
days before the surgery (Days -28 to 1). 
On Day 0, regional anesthesia will be established using a Mayo block, using standardized 
techniques, after which subjects will undergo primary, unilateral, first metatarsal bunionectomy 
with osteotomy and internal fixation. When the regional anesthetic wears off and the subjects 
request pain medication, they will be asked to rate their pain intensity using an 11-point (0-10) 
Numeric Rating Scale (NRS). During the 9-hour period after discontinuation of the anesthetic 
block, subjects who experience a pain intensity rating of ≥4 on the NRS are eligible to be enrolled 
in the study. Pulse oximetry will be monitored continuously after the procedure as a safety measure. 
An electrocardiogram (ECG) will be conducted after surgery but before the first dose of the study 
drug and serve as a baseline for comparison to subsequent tracings. The time of the NRS 
assessment before study drug administration is defined as Baseline; the time of administration of 
the first dose of study drug is defined as Time 0. Study drug will be provided by blinded study 
personnel in a predefined manner to ensure adequate blinding and appropriate dosing regimens for 
the active drug and placebo. Study drug will be administered by study subjects according to the 
directions provided by study staff. Subjects should not have anything orally except room-
temperature water within 15 minutes of each dose. The Treatment Period will continue through 48 
hours after Time 0. Pulse oximetry will be continuously monitored and SpO2 data will be recorded 
at select time points including baseline before first dose of study drug and 30, 60 and 90 minutes 
and 12, 24, and 48 hours after Time 0. Additional ECGs will be performed at 90 minutes, 12 hours, 
24 hours, and 48 hours after Time 0. 
Ibuprofen 400 mg will be allowed orally every 4 to 6 hours as needed for rescue medication after 
study drug treatment has begun. If subjects are unable to tolerate 400 mg ibuprofen or if there is 
insufficient pain relief, 30 mg of ketorolac tromethamine (i.e., Toradol®) may be administered 
intravenously or intramuscularly every 6 to 8 hours as needed for pain. The total daily (24 hour) 
dosage of ibuprofen medication should not exceed 2400 mg and ketorolac should not exceed 90 mg. 


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During the Treatment Period subjects will be allowed to use assigned study medication for primary 
rescue medication no more frequently than 4 hours from previous study medication dose and no 
more than 6 times in a 24-hour period. Subjects will be encouraged to wait for at least 1 hour after 
the first dose of study drug before receiving rescue medication to allow time for the study drug to 
exert its pharmacologic effect. 
During the Treatment Period, subjects whose pain cannot be adequately managed (in the 
investigator’s opinion) by a combination of study drug and rescue medication, or who develop 
unacceptable side effects during the study, will be discontinued from further study participation. 
Their pain will be managed according to usual standard of care at the investigator’s discretion. 
Pain will be assessed on an 11-point Numeric Rating Scale (NRS) at Baseline before Time 0. 
Thereafter, subjects will rate their pain intensity (NRS) and pain relief (on a 5-point categorical 
scale) and record their assessments in an inpatient subject diary at scheduled times during the 48-
hour period after Time 0 (at 2.5, 5, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 
24, 32, 40, and 48 hours) and immediately before each use of rescue analgesia during the Treatment 
Period. Time to perceptible pain relief and meaningful pain relief will be evaluated using the 2 
stopwatch method (after the first dose only). Time to each rescue medication from the prior IP dose 
will be evaluated. Subjects will complete a subject’s global evaluation of the study drug at the end 
of the Treatment Period (Day 3) before discharge from the study site. 
If a subject discontinues the study prematurely, pain intensity, pain relief, and the subject’s global 
satisfaction with study treatment should be assessed and recorded immediately before 
discontinuation. 
Before discharge from the study site on Day 3, study personnel will dispense a prescription for 
outpatient pain medication (if not already dispensed) and subjects will be given an outpatient 
subject diary in which they will be instructed to record concomitant medications taken and adverse 
events (AEs) experienced after discharge. Subjects will also be instructed to return the outpatient 
subject diary to study personnel at the Follow-up Visit on Day 7 ± 2 days (5 to 9 days after 
surgery). 


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The Schedule of Assessments for the study is presented in the Appendix I of this SAP.  
2.3 Study Duration 
Subjects will be confined for approximately 72 hours at the study site for the Surgical and 
Treatment Periods. The maximum study duration for each subject is approximately 6 weeks. This 
duration includes up to 28 days of Screening Period, 1 day (Day 0) of Surgical Period, up to 9 hours 
post-surgery, 48 hours of treatment and inpatient assessments, and 5 to 9 days after surgery of 
follow up or early withdrawal.  
2.4 Study Treatments and treatment assignments 
2.4.1 Treatment Groups 
The three treatment groups to be evaluated in this trial are described in Table 2-1 below  
Table 2-1: Treatment Groups 
Treatment 
group 
Day 1 
Day 2 
Dose 1 
 
Dose 2 
 
Dose 3 
 
Dose 4 
Dose 5 
Dose 6 
 
Dose 1 
 
Dose 2 
 
Dose 3 
 
Dose 4 
 
Dose 5 
Dose 6 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
100 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
200 µg 
Matching 
Placebo 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
 
2.4.2 Method of Treatment Assignment, Randomization Ratio, and Stratification  
Subjects who have met all of the inclusion and none of the exclusion criteria, have provided written 
informed consent, and have experienced a pain intensity rating of ≥4 on the NRS during the 9-hour 
period after discontinuation of the anesthetic block are eligible to be enrolled in the study. They will 
be randomly assigned to 1 of 3 treatment groups: Fentanyl Sublingual Spray 100 µg q4h, 200 µg 


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q4h, or matching placebo. The randomization will be stratified by center and use mixed blocks with 
a 1:1:1 ratio to ensure even distribution of subjects across each treatment group in every site.  
In addition, an enrollment anticipated at each of the sites in the following: 
• 
 (PI: Dr. 
) = approximately 30 subjects 
• 
 (PI: Dr. 
) = approximately 15 subjects 
The actual randomization assignment will be made through an Interactive Web Based System 
(IWRS) called 
).  
 is a Secure 
Socket Layer (SSL) web portal that allows 24/7 access to clinical trial information.  Authorization 
is based on approved access control list (ACL) that determines a user’s access to the site.  The 
, who is not otherwise involved with the study, is responsible for 
the implementation and maintenance of 
.  Each user will be trained in how to use the 
website.  A 
 user manual will be supplied to all study personnel with instructions on using 
the website.   
The Randomization/Supply module of 
 allows authorized users to request randomization 
(Site Personnel only) into the trial.  The detailed description and instructions are included in the 
 user manual. 
 has further documentation and validation of 
 specifically with regards to preserving the blinding of this study. 
2.5 Blinding 
As this is a double-blind trial, all subjects and study personnel involved in the conduct of the study, 
including data management, will be blinded to treatment assignment. 
2.5.1 Maintenance of Blinding 
The randomization lists containing the assignment of subjects to treatment groups will be securely 
provided to the person involved in randomizing the subjects (i.e. the WebMaster), who has no role 
in screening, enrolling, qualifying, or evaluating study subjects. No other study personnel other than 
the WebMaster and the randomization code generator will have access to the randomization codes 
for the study.  


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2.5.2 Time to Un-blinding 
Treatment un-blinding and release of the randomization codes of the investigational product (IP) 
assignments for the study will only occur 1) due to emergency un-blinding because of safety 
reasons or 2) at the time of database lock when all randomized subjects have completed the study or 
discontinued from the study and after all clinical data have been received and data inconsistencies 
have been resolved. 
3. 
STUDY ASSESSMENTS/ ENDPOINTS 
3.1 Efficacy Endpoints 
3.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the NRS summed pain intensity difference (NRS SPID) 
(calculated as a time weighted average) over 0 to 48 hours (NRS SPID-48) after Time 0. 
3.1.2 Secondary Efficacy Endpoints:  
The secondary endpoints are the following: 
• NRS SPID over 0 to 24 hours (NRS SPID-24), over 0 to 8 hours (NRS SPID-8), and over 0 
to hours (NRS SPID-4) after Time 0 
• Total pain relief (TOTPAR) over 0 to 48 hours (TOTPAR-48), over 0 to 24 hours 
(TOTPAR-24), over 0 to 8 hours (TOTPAR-8), and over 0 to 4 hours (TOTPAR-4) after 
Time 0 
• Subject’s global evaluation of study drug 
• Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
meaningful pain relief using the 2-stopwatch method) 
• Pain relief score on a 5-point categorical scale at each scheduled time point after Time 0 
• Peak pain relief 
• Time to peak pain relief 
• Time to first perceptible pain relief 


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• Time to meaningful pain relief 
• Proportion of subjects using rescue medication 
• Time to first use of rescue medication (duration of analgesia) following each dose of IP 
• Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 hours 
• NRS pain intensity difference (NRS PID) at each scheduled time point after Time 0 
• NRS pain intensity score at each scheduled time point 
3.2 Safety Assessments 
Safety assessments will include the evaluation of AEs, physical and oral examinations, vital sign 
measurements, pulse oximetry, and 12-lead ECGs. Clinical laboratory tests will be performed at 
Screening only. 
The safety endpoints are the incidence of treatment-emergent adverse events (TEAEs), physical and 
oral examination findings, and changes in vital signs, pulse oximetry, and ECG measurements. 
4. 
SAMPLE SIZE DETERMINATION AND RATIONALE, STATISTICAL POWER, 
AND SIGNIFICANCE LEVEL 
A total of 45 subjects are planned to be enrolled for the study. A sample size of 15 subjects per 
treatment group will provide ≥80% power to detect a minimal standardized effect size of 0.5 
between the 100 µg q4h, 200 µg q4h active treatment arms, and placebo in NRS SPID-48 using a 3-
group analysis of covariance (ANCOVA) with baseline NRS score as the covariate with a 0.05 two-
sided significance level (EAST v6). 
5. 
INTERIM ANALYSIS  
No Interim Analysis is planned for this study. 
6. 
ANALYSIS POPULATIONS  
6.1 Intent-to-Treat (ITT) population 
The intent to treat (ITT) population will consist of all subjects who are randomized. The ITT 


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population is the primary population for the efficacy analysis. 
6.2 Per Protocol (PP) Population 
The per protocol (PP) population will consist of all ITT subjects who receive at least 1 dose of 
study drug, who remain in the study for at least 48 hours of treatment, and who do not incur a major 
protocol violation that would challenge the validity of their data. This population will be used to 
evaluate the sensitivity of the primary efficacy analysis. 
6.3 Safety Population 
The safety population will include all subjects who are treated with at least one study drug. The 
safety population is the population for all safety assessments. 
7. 
DATA CONVENTION AND RELATED DEFINITIONS   
7.1 Baseline Definition 
For all parameters, baseline will be defined as the last available value before the randomized 
treatment administration.   
7.2 Duplicate Data  
For unplanned duplicate data within a protocol-specified visit, the last measured value will be used 
for the analysis. If it is not possible to identify the “last measured value” the average of the 
duplicate values will be used.  
No data will be excluded.  All collected data will be listed.  
7.3 Handling of Missing Data  
7.3.1 Handling of Missing Data for Efficacy Assessments   
Use of Rescue Medication: Any pain intensity or pain relief score occurring within 4 hours after a 
subject has taken rescue medication for pain will be replaced by the last pain intensity or pain relief 
score prior to that use of rescue medication. If a second rescue medication for pain is used within 
that 4 hour duration, the pain intensity or pain relief scores from the time of the first rescue 
medication will be replaced by the assessment prior to the second rescue medication for the next 4 


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hours. The same method will be employed for a third and subsequent rescue medication. 
Missing due to Dropouts:  Missing values for pain intensity after a subject drops out of the study 
will be imputed as follows in the primary analysis:  
- 
For SPID endpoints, the last available SPID (truncated SPID) will be used for analysis (e.g., 
if a subject dropped out after 32 hours of initiation of treatment, the truncated SPID 
calculated using timepoints up to 32 hours will be used as the post 32 hour timepoints like 
40 hours and 48 hours) .  
- 
For TOTPAR endpoints, the last available TOTPAR (truncated TOTPAR) will be used for 
analysis 
- 
For PID endpoints, the last available pain intensity will be used to impute the missing pain 
intensity and to calculate the PID 
In addition, a sensitivity analysis using 1) missing as missing (i.e., no imputation) for dropouts and 
2) multiple imputation will be performed for the primary endpoint to explore the impact of missing 
data after a subject drops out. The details of the sensitivity analysis are described in Section 7.4. 
7.3.2 Handling of Missing Data For Safety Evaluations  
Adverse Event (AE) Summaries 
With respect to summaries of AEs, only AEs that were treatment emergent will be tabulated.  
Treatment–emergent is defined as AEs with start date ≥ date of first treatment administration. 
1) If AE start date is completely missing, the date of first treatment administration will be 
taken as the start date of the event.  
2) If AE start date is partially missing:  
a. If the day part of the start date is missing, the start date will be estimated to be equal 
to the date of first treatment administration, provided the start month and year are the 
same as the date of first treatment administration and the stop date either after the 


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date of first treatment administration or completely missing. Otherwise, the AE will 
be assumed to have started on the first day of the month (01/MMM/YYYY) 
b. If the month part of the start date is missing, the start month will be estimated to be 
equal to the month of the date of first treatment administration or the following 
month after the month of the date of first treatment administration depending on the 
day part of the start date provided that the start year is the same as the year of date of 
first treatment administration and the stop date is either after date of first treatment 
administration or completely missing. Otherwise, the AE will be assumed to have 
started on the first month of the year (DD/Jan/YYYY) 
c. If both the day and month parts of the start date are missing, the start date will be 
estimated to be equal to the date of first treatment administration, provided the start 
year is the same as year of date of first treatment administration and the stop date is 
either after the date of first treatment administration or completely missing. 
Otherwise, the AE will be assumed to have started on first day and first month of the 
year (01/Jan/YYYY) 
d. If all day, month and year parts of the start date are missing, the start date will be 
estimated to be equal to the date of first treatment administration (and thus treatment 
emergent) provided that the stop date is either after the date of first treatment 
administration or completely missing. Otherwise, the start date will be estimated to 
be the first day of the same year as the stop date.  
3) If AE stop date is partially or completely missing:   
a. If only the day portion of the stop date is unknown, the day will be assumed to be 
last date of the month (e.g., ??-Jan-2004 will be treated as 31-Jan-2004). 
b. If both the day and month of stop date are unknown, the event will be assumed to 
have ceased on the last day of the year (e.g., ??-???-2004 will be treated as 31-Dec-
2004). 


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c.  If the stop date is completely missing, the event will be assumed to be “Ongoing”.  
 
Concomitant medications (CM) Summaries  
1) If CM start date is completely missing then the date of first treatment administration will be 
taken as the start date of the medication  
2) If CM start date is partially missing:  
a. If the Day part of the start date is missing, the CM will be assumed to have started 
on the first day of the month (01/MMM/ YYYY) 
b. If the month part of the start date is missing, the CM will be assumed to have started 
on the first month of the year (dd/Jan/YYYY) 
c. If both the day and month parts of the start date are missing, the CM will be assumed 
to have started on first day and first month of the year (01/Jan/YYYY) 
7.4 Sensitivity Analyses  
A sensitivity of the primary analysis using multiple imputation for missing data will be performed 
for the primary endpoint to assess the impact of missing data after subject's have dropped out. For 
the primary endpoint the following two sensitivity analyses will be conducted:  
7.4.1 Missing as Missing  
The primary endpoint analysis will be conducted without any imputation. 
7.4.2 Multiple Imputation 
All missing data for these subjects will be imputed using multiple imputation procedures. However, 
the multiple imputation is used for subjects that have some baseline and postbaseline data, i.e., if a 
subject is missing all pre and post baseline data, no data will be imputed.  
The imputation will be carried out in SAS version 9.4 or later,  using the full conditional 
specification method (FCS) with a regression model approach (Carpenter and Kenward, 2013). The 
variables included sequentially in the model are: 


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• Treatment as a main effect  
• Site and baseline pain intensity as covariates 
• SPID for each time point as the dependent variable   
The analysis model will be an analysis of covariance (ANCOVA) with NRS-SP1D 48 as the 
dependent variable, treatment as a main effect and site and baseline pain intensity as the covariates.  
The ANCOVA results from the multiply imputed datasets will be combined using the usual Rubin's 
rules for multiple imputation (Little and Rubin, 1987) and will be done in SAS using PROC 
MIANALYZE. A significance test of the treatment difference at the two-sided 0.05 level and 
corresponding 95% confidence intervals will be calculated.       
7.5 Multiple Clinical Trials 
This is a multi-center clinical trial with two sites.    
7.6 Multiple Comparisons and Type I Error Rate Multiplicity adjustments 
There will also be no Type I error adjustment on the hypotheses testing of this Phase 2 study.  
7.7 Covariates and Prognostic Factors 
Baseline pain intensity and site would be used as covariates for the analysis of the primary efficacy 
endpoint. Other prognostic factors may be included in the analysis model if they are found to be 
contributing factors.  
7.8 Subgroups and Exploratory Analysis  
There is no planned subgroup analysis; however subgroup and exploratory analysis may be 
conducted as postHoc analysis.  
7.9 Standard Calculations  
7.9.1 Age 
Age will be calculated as the number of completed years between the date of informed consent and 
the subject’s birth date.  


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Age (years) = integer of [(date of informed consent – date of birth)/ 365.25+ 0.5] 
7.9.2 Height 
For summary purposes height will be expressed in centimeters.  Entries made in inches will be 
converted to centimeters using the formula noted below.  
Height (cm) = Height (in)*2.54 
7.9.3 Weight 
For summary purposes weight will be expressed in kilograms.  Entries made in pounds will be 
converted to kilograms using the formula noted below.  
Weight (kg) = Weight (lb)/ 2.2046 
7.9.4 Body Mass Index (BMI)  
BMI will be calculated using height (in cm) and weight (in kg) according to the formula noted 
below. 
BMI (kg/m2) = weight (kg) / [height (cm)/100]2 
7.9.5 Pain Intensity (PI) 
Subjects will assess their current pain intensity using an 11-point (0 to 10) Numerical Rating Scale 
(NRS). Each subject will be instructed to mark the number indicating his or her current pain 
intensity.  
The subject is to record pain intensity (NRS) in the inpatient subject diary at Baseline before the 
first dose of study drug (Day 1), at Time 0. Thereafter, the subject is to record NRS pain intensity 
assessments at the following time points during the 48-hour period after Time 0: 
• 2.5, 5, 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 32, 40 and 48 
hours after Time 0, and immediately before each use of rescue analgesia. 
i 
Nominal Ti (hours) 
0 
0 
1 
0.0417 


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i 
Nominal Ti (hours) 
2 
0.0833 
3 
0.25 
4 
0.5 
5 
0.75 
6 
1 
7 
1.5 
8 
2 
9 
3 
10 
4 
11 
5 
12 
6 
13 
7 
14 
8 
15 
12 
16 
16 
17 
20 
18 
24 
19 
32 
20 
40 
21 
48 
 
7.9.6 Pain Intensity Difference (PID) 
Pain intensity difference (PID) is to be calculated by subtracting the pain intensity at each time 
point from the pain intensity at time 0.  
PIDi  = PIi - PI0 
7.9.7 Summed Pain Intensity Difference (SPID) 
The summed pain intensity difference (SPID) is to be calculated by multiplying the PID score at 
each post dose time point by the duration (in hours) since the preceding time point and then 
summing the values over the relevant time period.   


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SPID-48= ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐼𝐷𝑖
21
𝑖=1
 
SPID-24 =  ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐼𝐷𝑖
18
𝑖=1
 
SPID-8 =  ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐼𝐷𝑖
14
𝑖=1
 
SPID-4 =  ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐼𝐷𝑖
10
𝑖=1
 
Where 𝑇0 = 0, 𝑇𝑖 is the actual time, and 𝑃𝐼𝐷𝑖 is the PID score at time 𝑇𝑖. 
 
The durations between nominal time points will be calculated using the actual times of the pain 
score measurement. If the actual time is missing the nominal planned time will be used. 
7.9.8 Pain Relief (PAR) 
Subjects will assess their current pain relief using a 5-point categorical scale. Each subject will be 
instructed to mark the number indicating his or her current pain relief.  
The subject is to record pain relief (5-point categorical rating scale) in the inpatient subject diary at 
the following time points during the 48-hour period after Time 0: 
• 2.5, 5, 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 32, 40 and 48 
hours after Time 0, and immediately before each use of rescue analgesia. 
7.9.9 Total Pain Relief (TOTPAR) 
Total pain relief (TOTPAR) is calculated by multiplying the pain relief score at each time point by 
the duration (in hours) since the preceding time point and then summing these over the relevant 
time period.  
TOTPAR-Tk = ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐴𝑅𝑖
𝑘
𝑖=1
 
TOTPAR-48 = ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐴𝑅𝑖
21
𝑖=1
 
TOTPAR-24 = ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐴𝑅𝑖
18
𝑖=1
 
TOTPAR-8 = ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐴𝑅𝑖
14
𝑖=1
 
TOTPAR-4 = ∑
൫𝑇𝑖−𝑇(𝑖−1)൯∗𝑃𝐴𝑅𝑖
10
𝑖=1
 
 
 


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7.9.10 Two-Stopwatch Assessment of Pain Relief 
Time to perceptible pain relief and meaningful pain relief will be evaluated using the 2 stopwatch 
method (after the first dose only). The study staff will start 2 stopwatches as soon as the first dose 
of study drug is administered. Each subject will be instructed to stop the first stopwatch when he or 
she experiences any perceptible pain relief and the second stopwatch when he or she experiences 
pain relief that is meaningful to them. Subjects will receive training for this procedure at their 
screening visit and prior to discontinuation of the regional anesthetic popliteal block. 
7.9.11 Time to onset of analgesia  
Time to onset of analgesia is the time that the first stopwatch is stopped (when the subject 
experiences first perceptible pain relief) given that the second stopwatch is stopped (when the 
subject experiences meaningful pain relief). If both stopwatches are not stopped or just one 
stopwatch is stopped, then the time to analgesia will be censored at the time of the second dose or 
the use of rescue medication, whichever comes first.   
7.9.12 Peak Pain Relief  
Peak pain relief is the highest value of pain relief experienced during the study. Values of pain 
relief after use of rescue medication for pain (up to four hours after use) will be replaced by the pain 
relief score collected prior to that use of rescue medication.  
7.9.13 Time to Peak Pain Relief  
Time to peak pain relief is the first time when the highest value of pain relief is observed. If no pain 
relief is observed then the time will be censored at the time of the last assessment.  
7.9.14 Time to first Perceptible Relief  
Time to first perceptible relief is the time when the subject experiences any perceptible pain relief 
after administration of study drug and stops the first stopwatch (irrespective of the second 
stopwatch). If it is not stopped, time will be censored at the time that the second stopwatch is 
stopped, the time of the second dose, or the first time that rescue medication was used, whichever 
comes first.  


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7.9.15 Time to meaningful relief  
Time to meaningful relief is the time when the subject experiences relief that is meaningful after the 
administration of study drug and stops the second stopwatch, irrespective of the first stopwatch. If it 
is not stopped, time will be censored at the time of the second dose or the first use of rescue 
medication whichever comes first. 
7.9.16 Rescue Medication Use  
Total use of rescue medication is the number of times that a subject used rescue medication for pain 
during the specified time periods (0-24h and 0-48h). The proportion of subjects taking rescue 
medication for pain during each period will also be presented. A subject taking any amount of 
rescue medication during the specified period will be counted in this proportion.  
7.9.17 Time to First Use of Rescue Medication  
Time to first use of rescue medication for pain is defined as the time from Time 0 to the first use of 
rescue medication. Rescue medications for pain will be identified by the sites on the Concomitant 
Medications eCRF. If rescue medication for pain is not taken, the time will be censored at the time 
of the last pain assessment.  
7.9.18 Subject’s Global Evaluation of Study Drug 
Subjects will complete a subject’s global evaluation of study drug at the end of the treatment period 
(Day 3) before discharge from the study site or immediately before Early Withdrawal if a subject 
discontinues prematurely. The subject will be instructed to score his or her global evaluation of the 
study treatment on a 5-point categorical scale where 0 = poor, 1 = fair, 2 = good, 3 = very good, and 
4 = excellent. 
8. 
STATISTICAL METHODS 
All data collected during this study will be presented in subject data listings. All statistical analyses 
will be performed using SAS® for Windows, version 9.4 or later.    
8.1 Summarizing and Tabulating the Collected Data  
All data collected will be summarized according to the variable type:  


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o Continuous data summaries will include number of observations, mean, standard 
deviation, median, and minimum and maximum values.   
o Categorical data summaries will include frequency counts and percentages.  
8.1.1 Subject Disposition and Withdrawals 
There will be a detailed accounting of all subjects that signed the informed consent to participate in 
this trial. The following will be summarized by treatment group:   
• The number of subjects who signed the informed consent 
• The number of subjects who are randomized 
• The number of subjects who are randomized and not treated 
• The number of randomized and treated  
• The number of subjects who completed the treatment phase  
• The number of subjects who completed the follow up phase 
• The number of subjects who discontinued  
Reasons for discontinuation will also be summarized.  
In addition, there will also be a listing of all discontinued subjects, which will provide the clinical 
trial center, treatment group and the specific reason for discontinuation.   
8.1.2 Protocol Deviations 
Protocol deviations will be identified and classified as minor or major before un-blinding.  
Protocol deviations occurring during the clinical trial will be summarized descriptively and also be 
presented as by-subject listings. 
8.1.3 Demographics and Baseline Characteristics 
Demographic and baseline characteristics (including age, gender, race, weight, height, BMI, surgery 
duration, and baseline pain intensity) will be summarized by treatment group and for the overall 
population by descriptive statistics. No formal statistical analyses will be performed. Medical 
history, clinical laboratory test results, and urine drug screen, alcohol breathalyzer test, X-ray and 
podiatric examination assessments will be listed. 


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The analyses of demographics and baseline characteristics will be conducted for the safety 
population. 
8.1.4  Prior and Concomitant Medications 
Prior and concomitant medications will be summarized by treatment group and by the number and 
percentage of subjects taking each medication. They will also be classified by using the World 
Health Organization Drug Dictionary Anatomical Therapeutic Chemical classes and preferred 
terms. 
8.1.5 Exposure and Compliance 
The exposure to study medication will be summarized by descriptive statistics. As the dose 
administration is under the control of the study sites, compliance is not excpected to be an issue.  
8.2 Analysis of Efficacy Data 
8.2.1 Primary Endpoint  
The primary efficacy endpoint is the NRS summed pain intensity difference over 0 to 48 hours after 
Time 0 (NRS SPID-48). The formula for SPID-48 calculation is presented in Section 7.9.7. The 
primary variable will be analyzed using an analysis of covariance (ANCOVA) model, which will 
include treatment and site as main effects and baseline pain intensity as the covariate. The least 
square (LS) mean, standard error (SE) and 95% confidence interval (CI) for each treatment group 
will be estimated. In addition, the mean (LS mean) difference between each treatment and placebo, 
SE, p-value and the associated 95% CI will also be computed. Descriptive summaries (including 
mean, SD, median, minimum and maximum) will also be presented by treatment group. Missing 
values for pain intensity will NOT be imputed in the primary analysis. 
8.2.2 Secondary Endpoints 
Analysis of the secondary endpoints will be summarized according to the variable type. The details 
are presented in the following sections.   


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8.2.2.1 NRS SPID over 0 to 24 hours (NRS SPID-24), over 0 to 8 hours (NRS SPID-8), and 
over 0 to hours (NRS SPID-4) after Time 0 
NRS SPID-24, SPID-8 and SPID-4 would be calculated using the formula specified in Section 
7.9.7. Similar methods used for analysis of the primary endpoint will be assessed differences 
between the treatment groups in these metrics.  
8.2.2.2 Total pain relief (TOTPAR) over 0 to 48 hours (TOTPAR-48), over 0 to 24 hours 
(TOTPAR-24), over 0 to 8 hours(TOTPAR-8), over 0 to 4 hours (TOTPAR-4) 
TOTPAR over 0-48, 0-24, 0-8 and 0-4 hours will be calculated using the formula specified in 
Section 7.9.9. The differences in TOTPAR between the treatment groups and placebo will 
compared using an analysis of covariance (ANCOVA) model, which will include treatment and site 
as main effects and baseline pain intensity as the covariate. The last square (LS) mean, standard 
error (SE) and 95% confidence interval (CI) for each treatment group will be estimated. In addition, 
the mean (LS mean) difference between each treatment and placebo, SE, p-value and the associated 
95% CI will also be computed. Descriptive summaries (including mean, SD, median, minimum and 
maximum) will also be presented by treatment group.  
8.2.2.3 Subject’s global evaluation of study drug 
Subject’s global evaluation of study drug will be analyzed using a proportional odds model (an 
extension of the logistic regression). This method allows for an ordinal response variable with more 
than two categories. This model will include factors site, treatment and baseline pain intensity. 
8.2.2.4 Time to onset of analgesia (measured as time to perceptible pain relief confirmed by 
meaningful pain relief using the 2-stopwatch method) 
Time to onset of analgesia will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 7.9.11. Treatments will be compared to placebo using a 
log-rank test which will compare the survival distributions of the treatments. 


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8.2.2.5 Pain relief score on a 5-point categorical scale at each scheduled time point after 
Time 0 
The differences in pain relief between the treatment groups and placebo will be compared using a 
proportional odds model (an extension of logistic regression model) which allows for an ordinal 
response variable with more than two categories. This model will include factors site, treatment and 
baseline pain intensity. 
In addition, the pain relief scores at each time point will also be summarized descriptive in tables 
and also presented as by-subject listings.  
 
8.2.2.6 Peak pain relief 
The peak pain relief score for each subject will be identified using the description in Section 7.9.12.  
The data for this endpoint will be analyzed using a proportional odds model (an extension of 
logistic regression model) which allows for an ordinal response variable with more than two 
categories. This model will include factors site, treatment and baseline pain intensity. 
8.2.2.7 Time to peak pain relief 
Time to peak pain relief will be summarized using Kaplan-Meier methods. The definition and 
censoring rules are described in Section 7.9.13. Treatments will be compared to placebo using a 
log-rank test which will compare the survival distributions of the treatments. 
8.2.2.8 Time to first perceptible pain relief 
Time to first perceptible pain relief will be summarized using Kaplan-Meier methods. The 
definition and censoring rules are described in Section 7.9.14. Treatments will be compared to 
placebo using a log-rank test which will compare the survival distributions of the treatments. 
8.2.2.9 Time to meaningful pain relief 
Time to meaningful pain relief will be summarized using Kaplan-Meier methods. The definition 
and censoring rules are described in Section 7.9.15. Treatments will be compared to placebo using a 


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log-rank test which will compare the survival distributions of the treatments. 
8.2.2.10 Proportion of subjects using rescue medication 
The definition of rescue medication use is presented in Section 7.9.16. The proportion of subjects 
using rescue medication for pain will be analyzed using logistic regression. The logistic regression 
model will include factors site, treatment and baseline pain intensity. 
8.2.2.11 Time to first use of rescue medication (duration of analgesia) following each dose 
of IP 
Time to time to first use of rescue medication will be summarized using Kaplan-Meier methods. 
Censoring will be applied as described in Section 7.9.17. Treatments will be compared to placebo 
using a log-rank test which will compare the survival distributions of the treatments. 
8.2.2.12 Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 hours 
The frequency of use of rescue analgesia will be calculated for each subject over 0 to 24 and 0-48 
hours. The differences in total use of rescue analgesia between the treatment groups and placebo 
will compared using an analysis of covariance (ANCOVA) model, which will include treatment and 
site as main effects and baseline pain intensity as the covariate. The last square (LS) mean, standard 
error (SE) and 95% confidence interval (CI) for each treatment group will be estimated for each 
time interval 0-24 hours and 0-48 hours. In addition, the mean (LS mean) difference between each 
treatment and placebo, SE, p-value and the associated 95% CI will also be computed. Descriptive 
summaries (including mean, SD, median, minimum and maximum) will also be presented by 
treatment group. 
8.2.2.13 NRS pain intensity difference (NRS PID) at each scheduled time point after Time 0 
The PID at each scheduled time point will be calculated using the formula specified in Section7.9.6. 
The differences in NRS PID between the treatment groups and placebo will compared using an 
analysis of covariance (ANCOVA) model, which will include treatment and site as main effects and 
baseline pain intensity as the covariate. The last square (LS) mean, standard error (SE) and 95% 


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confidence interval (CI) for each treatment group will be estimated. In addition, the mean (LS 
mean) difference between each treatment and placebo, SE, p-value and the associated 95% CI will 
also be computed. Descriptive summaries (including mean, SD, median, minimum and maximum) 
will also be presented by treatment group. 
8.2.2.14 NRS pain intensity score at each scheduled time point 
The differences in NRS pain intensity between the treatment groups and placebo will compared 
using an analysis of covariance (ANCOVA) model, which will include treatment and site as main 
effects and baseline pain intensity as the covariate. The last square (LS) mean, standard error (SE) 
and 95% confidence interval (CI) for each treatment group will be estimated. In addition, the mean 
(LS mean) difference between each treatment and placebo, SE, p-value and the associated 95% CI 
will also be computed. Descriptive summaries (including mean, SD, median, minimum and 
maximum) will also be presented by treatment group.  
In addition, the pain intensity scores at each time point will also be summarized descriptively in 
tables and figures. 
8.2.3 Analysis of Safety Data 
The safety population is the population for all safety assessments. No imputation will be used in the 
safety assessments. No inferential statistics are planned. No formal inferential analyses will be 
conducted for safety variables. 
For continuous variables data will be summarized by treatment using n, mean, SD, minimum and 
maximum values. For categorical variables data will be summarized by treatment using frequency 
and percentage.  
8.2.4 Adverse Events 
Adverse events will be classified by system organ class (SOC) and preferred term (PT) according to 
the most recent MedDRA dictionary (Version 19.1 or higher).    
All adverse events that occur on or after the date of first administration of clinical trial treatment 
until the end of study procedures are completed will be listed and summarized, using frequency 


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counts and percentages, by treatment group.   
• Overall (i.e., regardless of severity or relationship to treatment) 
• By severity grade (mild, moderate, severe,) 
• By relationship to clinical trial treatment (definitely related, probably related, possibly related, 
unlikely related, not related)  
Unless otherwise specified, at each level of subject summarization, a subject will be counted only 
once. If there is more than one occurrence of an event, the event of the worst severity or the worst-
case relationship category will be summarized. 
AEs leading to premature discontinuation of clinical trial treatment, AEs of special interest, AEs 
that lead to study discontinuation, AEs that lead to death and Serious Adverse Events (SAEs) will 
also be summarized by treatment group and relationship. Adverse Events leading to premature 
discontinuation of clinical trial treatment will be defined as any adverse event with an Action Taken 
equal to “study drug discontinued” or “drug withdrawn”. 
8.2.5 Clinical Laboratory Evaluations 
Laboratory data is only collected for the screening visit. All available results of the clinical 
laboratory evaluations (e.g., Hematology, Chemistry, and Urinalysis) will be listed and descriptive 
summaries (mean, SD, median, minimum and maximum) of actual (absolute) values will be 
presented for clinical laboratory values for each treatment group.   
8.2.6 Serum Pregnancy Test 
All the results for serum pregnancy test will be presented as a by-subject listing.  
8.2.7 Physical Examination / Oral Examination  
The number and percentage of subjects with normal and abnormal findings in the physical and oral 
examinations at the Follow-up or Early Termination Visit will be displayed for each treatment 
group. All physical/oral examination findings will also be presented as a by-subject listing.   


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8.2.8 ECG 
The number and percentage of subjects with clinically relevant abnormal ECG findings will be 
summarized for each treatment group at each time point. 
All available ECG data will also be presented as by-subject listing.  
8.2.9 Vital Signs  
Tabulations of raw data and change from baseline values will be presented by time point for each 
vital sign parameter [i.e., heart rate (beats/min), respiratory rate, oral body temperature (0C / 0F), 
systolic BP (mmHg), diastolic BP (mmHg), pulse oximetry (%)].   
Summary will include the number of observations, mean, standard deviation, median, and minimum 
and maximum values.  For change from baseline summaries, subjects with an undefined change 
from baseline, because of missing data, will be excluded. 


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9. APPENDIX 1: SCHEDULE OF ASSESSMENTS  
 
Screening  
(Days -28 to 
-1 before 
surgery) 
Surgery 
Day 0 
Treatment Period 
Follow-up  
Day 7 ± 2 days 
(5 to 9 days after 
surgery) or Early 
Withdrawal 
Day 1 
(Baseline; 
before 
dosing) 
Day 1  
First dose 
(Time 0) 
Days 2 and 3 
Subsequent 
doses 
Written informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X  
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
Xa 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
X 
Oral examinationc 
X 
 
 
X 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
Height, weight, and body mass index 
X 
 
 
 
 
 
Pulse oximetrye 
 
 
X 
X 
X 
 
12-lead electrocardiogramf 
X 
 
X 
X 
X 
 
Clinical laboratory tests (hematology, chemistry, urinalysis) 
X 
 
 
 
 
 
Pregnancy test for female subjectsg 
X 
X 
 
 
 
 
Urine drug screenh 
X 
X 
 
 
 
 
Alcohol breathalyzer test 
 
X 
 
 
 
 
X-ray and podiatric examinationi 
X 
 
 
 
 
 
First metatarsal bunionectomy procedure 
 
X 
 
 
 
 


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Screening  
(Days -28 to 
-1 before 
surgery) 
Surgery 
Day 0 
Treatment Period 
Follow-up  
Day 7 ± 2 days 
(5 to 9 days after 
surgery) or Early 
Withdrawal 
Day 1 
(Baseline; 
before 
dosing) 
Day 1  
First dose 
(Time 0) 
Days 2 and 3 
Subsequent 
doses 
Discontinue anesthetic block at approximately 3:00 AMj 
 
 
X 
 
 
 
Assign randomization number 
 
 
X 
 
 
 
Pain assessmentsk 
 
 
X 
X 
X 
 
Administer study drugl 
 
 
 
X 
X 
 
Start stopwatches for perceptible and meaningful pain reliefm 
 
 
 
X 
 
 
Subject’s global evaluation of study drugn 
 
 
 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
Dispense outpatient pain medication and outpatient subject 
diaryo 
 
 
 
 
X 
 
Discharge subject from the study sitep   
 
 
 
 
X 
 
Collect and review diary for completion 
 
 
 
 
 
X 
Abbreviations: ET=early termination; NRS=numeric rating scale 
a Medical history should be reviewed for any changes since Screening. 
b A complete physical examination (excluding the genitourinary examination) will be performed at Screening. An abbreviated physical examination, including an 
examination of the subject’s surgical site, will be performed at the Follow-up Visit. 
c The postdose oral examination should be conducted 1 hour (±10 minutes) after dosing. 


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d Vital signs, including blood pressure, heart rate, respiratory rate, and oral body temperature, will be measured after the subject has been in a resting position for 
5 minutes. Vital signs will be measured at Screening and before surgery on Day 0 immediately before and 1 hour (±10 minutes) after the first dose of study 
drug on Day 0, immediately before and 1 hour (±10 minutes) after the 24-hour and 40-hour doses, and at 48 hours (±10 minutes). Vital signs will also be 
measured before ET if a subject discontinues. 
e Pulse oximetry will be measured continuously for safety; pulse oximetry will be recorded at selected times (±10 minutes), including baseline before Time 0 and 
at 90 minutes and 12, 24, and 48 hours after Time 0 (Tmax). 
f An ECG will be performed before the first dose of study drug, and then at 90 minutes (±10 minutes), and at 12, 24, and 48 hours (±10 minutes) after Time 0. 
g A serum pregnancy test will be performed at Screening and a urine pregnancy test will be performed before surgery on Day 0. The test results must be negative 
for the subject to continue in the study. 
h A urine drug screen will be collected at Screening and before surgery on Day 0. The test results must be negative for the subject to continue in the study, except 
in cases where a valid physician’s prescription can be verified. 
i Radiographs taken within 6 months before Screening will be acceptable. 
j Immediately after the anesthetic block is discontinued, subjects will be instructed to request pain medication when they experience pain. 
k The subject will record pain intensity (numerical rating scale) in the inpatient subject diary at Baseline before the first dose of study drug (Day 1). Thereafter, 
pain intensity and pain relief (5-point categorical scale) assessments will be recorded at the following time points (± 5 minutes): 
• At 2.5, 5, 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 32, 40 and 48 hours after Time 0, and immediately before each use of rescue 
analgesia. 
• At Early Withdrawal if a subject discontinues prematurely. 
l The first dose of study drug will be administered within 9 hours (±10 minutes) after the anesthetic block has been discontinued when a subject’s pain intensity 
is ≥4 on the 11-point (0-10) NRS. Study drug will be administered from Time 0 through 48 hours within 10-minute windows. 
m Start stopwatches as soon as the first dose of study drug is administered. Stopwatches should be discontinued if the subject has not stopped them by the time of  
 the second IP dose or first use of rescue medication (whichever occurs first). 


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n Subjects will complete a subject’s global evaluation of study drug at the end of the Treatment Period (Day 3) before discharge from the study site or 
immediately before ET if a subject discontinues prematurely. 
o Outpatient pain medication and an outpatient subject diary will be dispensed before discharge from the study site on Day 3. 
p Subjects will be discharged from the study site on Day 3 (approximately 72 hours after completion of surgery) 
 


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10. APPENDIX 2 – PLANNED TLG 
10.1 Planned by-subject listings  
DISPOSITION/WITHDRAWALS (LISTINGS 16.2.1.X) 
ELIGIBILTY AND PROTOCOL DEVIATIONS (LISTINGS 16.2.2.X) 
EXCLUDED SUBJECTS (LISTINGS 16.2.3.X) 
DEMOGRAPHICS, 
POPULATION, 
AND 
BASELINE 
CHARACTERISTICS 
(LISTINGS 16.2.4.X) 
DRUG COMPLIANCE AND DRUG CONCENTRATION LISTINGS (LISTINGS 
16.2.5.X) 
EFFICACY RESPONSE DATA (LISTINGS 16.2.6.X) 
ADVERSE EVENT DATA (LISTINGS 16.2.7.X) 
SAFETY DATA (LISTINGS 16.2.8.1.X) 
 
 
 
 


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10.2 Planned Summary Tables  
 
POPULATION DISPOSITION AND PROTOCOL DEVIATIONS 
POPULATION DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
CONCOMITANT MEDICATION USAGE 
EFFICACY SUMMARIES 
SAFETY SUMMARIES  
ADVERSE EVENT SUMMARIES  
SERIOUS ADVERSE EVENTS  
LABORATORY 
VITAL SIGNS AND PE 
OTHER SAFETY 
 


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10.3 Planned Summary Figure  
KM Curves for time to endpoints  
Figures for Pain intensity and Pain relief 
 
 
 
 
 
 
 
 


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11. 
VERSION HISTORY  
This is the first Version of the document.  
 
 
 
 


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12. 
REFERENCES 
1. ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, August 7, 1999.  
2. The Royal Statistical Society: Code of Conduct (1993). 
3. E8 General Considerations for Clinical Trials, ICH Guidance, Federal Register, 1997. 
4. E9 Statistical Principles for Clinical Trials, ICH Guideline, Federal Register, 1997 
5. Guideline for the Format and Content of the Clinical and Statistical Section of an 
Application, 1988. 
6. Guideline for Industry:  Structure and Content of Clinical Study Reports (ICH E3), July 
1996. 
7. Guideline on Missing Data in Confirmatory Clinical Trials: EMA/CPMP/EWP/1776/99 
Rev. 1  
8. The Prevention and Treatment of Missing Data in Clinical Trials: National Research 
Council of the national academies