Conditions: Pain, Postoperative Dental Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 110
Healthy volunteers: yes

Brief summary:
To assess the safety, tolerability, analgesic, efficacy and pharmacokinetics of high dose acetaminophen relative to placebo and low dose acetaminophen relative to placebo over a 24 hour period in patient experiencing moderate to severe pain following the surgical removal of third molar.

Detailed description:
This will be a randomized, double-blind, single-site, placebo-controlled, parallel-group study to assess similarities in safety, tolerability, efficacy, and pharmacokinetics of high dose acetaminophen given relative to placebo, and low dose acetaminophen given relative to placebo over a 24-hour period in patients experiencing moderate to severe postsurgical pain within 7 hours following surgical removal of 2 or more molars

Arms:
arm 1: High Dose Acetaminophen Post Op arm 2: Low Dose Acetaminophen Post Op arm 3: Placebo Post Op

Interventions: intervention 1: Acetaminophen intervention 2: Placebo
Intervention descriptions: intervention 1: Acetaminophen is an analgesic and antipyretic intervention 2: Saline

Protocol document:
Prot_SAP_002.pdf: 






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Summary of Protocol Changes (from Version 1 to Version 2) 
Change 
Description 
Location 
Change in number of patients 
Decrease in number of participants 
from 140 to 110 with a 2:2:1 
randomization schedule 
Synopsis, Section 8 
Imputation of data following rescue 
medication 
Clarification that patients who 
receive rescue medication will have 
data censored but pain data will 
still be collected 
Synopsis, Section 10.7 
Change in Rescue Medication 
Change of Rescue Medication to 
200 mg ibuprofen 
Synopsis, Section 10.7 
Change of Efficacy Parameters 
Change to SPID and TOPTPAR 
over a 24-hour period, clarification 
that Pain Relief will be a 5-Point 
Categorical Pain Relief Assessment 
Synopsis, Section 7.2, Section 12.5 
Timing of Patient Global 
Evaluation 
Change to hour 24.25 
Synopsis, Section 3, Section 10.2 
Consistency in Inclusion/Exclusion 
Criteria 
Corrected lack of consistency in 
Inclusion/Exclusion Criteria at 
different places in the protocol 
Synopsis, Section 8.1, Section 8.2 
Adverse event documentation 
Clarify that adverse events will be 
recorded in the eCRF as they occur 
during the treatment phase of the 
study  
Synopsis, Section 11.4 
Blood volume 
Corrected the estimated blood 
volume required for PK testing 
Synopsis, Section 10.5 
Formatting 
Corrected formatting errors  
Multiple locations 
Sample size determination 
Provided further justification for 
sample size determination 
Synopsis, Section 12.1 
Statistical analysis 
Provided further detail on planned 
statistical methods and analysis 
Synopsis, Section 12 


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CRO, vendors and study personnel 
details 
These details have been added 
Title Page, synopsis, Section 11.4 
Summary of Protocol Changes (from Version 2 to Version 2.1) 
Change in type of vacutainer PK 
samples collected in 
Corrected the type of vacutainer 
PK samples collected in from 
K2EDTA to  K3EDTA tube 
Clinical Protocol Synopsis 
Pharmacokinetic 
Assesments (PK): 
Addtion of Dosing window time    
+ 10 minutes 
Updated dosing time points to 
reflect a window of dosing of + 10 
minutes 
Synopsis; Study Design 
Section 8 Summary of Study 
Design 
Section 9.4 Administration of 
Study Medication and Duration of 
Evaluation 
Summary of Protocol Changes (from Version 2.1 to Version 3) 
Addition of hematology safety labs 
Added hematology safety labs to 
meet exclusion criteria 1 
Table 3: Study flow chart, 
Synopsis,  
Section 10.2.1: screening 
assessments 
Section 10.5: Blood sampling, 
urine drug screen and pregnancy 
tests 
Administrative Clarification +/- 
specific added to all PK time points 
and removal of PK Time point 0 . 
Total PK samples from 19 to 18 
Administrative Clarification +/- 
specific added to all PK time points 
and  removal of PK Time point 0. 
Total PK samples from 19 to 18  
Synopsis : Pharmacokinetic 
Assessments (PK) 
Study Flow Chart: Foot Note #7 
Section 10.5: Blood Sampling, 
Urine Drug Screen and Pregnancy 
Tests: 
Clarification regarding vital sign 
time points 
Administrative clarification around 
vital sign time points to ensure 
these completed at screening, priror 
to surgery and every 4 hours post 
1st Dose. 
Synopsis: Other Measurements 
Study Flow Chart: Foot Note #1 
Section 10.4: Safety Assessments 


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Administrative Clarification 
regarding blood donation 
Clarified Whole Blood to 
Exclusion criteria #9  
Synopsis: Inclusion/Exclusion 
Criteria #9 
Section 8.2 Inclusion/Exclusion 
Criteria #9 
Addition of + 10 min window 
timepoint for PGE Assessment at 
24.25  
Added +10 min window timepoint 
for PGE Assessment at 24.25  
Section 8.0  Summary of Study 
Design 
Section 10.2.3 Postoperative 
Assessments   
 






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TABLE OF CONTENTS 
1. 
STUDY PROTOCOL SUMMARY .............................................................. 1 
2. 
CLINICAL PROTOCOL SYNOPSIS ......................................................... 11 
3. 
STUDY FLOW CHART (SCHEDULE OF ACTIVITIES) ....................... 21 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............. 23 
5. 
ETHICS ....................................................................................................... 26 
5.1. 
Institutional Review Board .......................................................................... 26 
5.2. 
Declaration of Helsinki ................................................................................ 26 
5.3. 
Patient Information and Consent ................................................................. 26 
6. 
INTRODUCTION ....................................................................................... 28 
6.1. 
Study Rationale ............................................................................................ 28 
6.2. 
Background .................................................................................................. 29 
7. 
OBJECTIVES, OUTCOMES, AND HYPOTHESIS .................................. 32 
7.1. 
Objectives .................................................................................................... 32 
7.2. 
Outcomes ..................................................................................................... 32 
7.2.1. 
Efficacy Outcome Measures ........................................................................ 32 
7.3. 
Hypothesis ................................................................................................... 33 
8. 
SUMMARY OF STUDY DESIGN............................................................. 33 
8.1. 
Inclusion Criteria ......................................................................................... 34 
8.2. 
Exclusion Criteria ........................................................................................ 35 
9. 
CLINICAL SUPPLIES ................................................................................ 37 
9.1. 
Study Medications and Dosages .................................................................. 37 
9.2. 
Packaging, Labeling and Medication Administration ................................. 37 
9.3. 
Assignment of Study Medication ................................................................ 37 
9.4. 
Administration of Study Medication and Duration of Evaluation ............... 38 
9.5. 
Study Medication Accountability ................................................................ 38 
9.5.1. 
Storage ......................................................................................................... 38 
9.5.2. 
Study Medication Inventory ........................................................................ 39 


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9.5.3. 
Return of Study Supplies ............................................................................. 39 
10. 
STUDY PROCEDURES ............................................................................. 39 
10.1. 
Study Conditions ......................................................................................... 39 
10.2. 
Schedule of Assessments ............................................................................. 40 
10.2.1. 
Screening Assessments ................................................................................ 40 
10.2.2. 
Pre-Operative Assessments and Study Drug Administration ...................... 41 
10.2.3. 
Post-Operative Assessments ........................................................................ 42 
10.3. 
Efficacy Assessments Post Study Medication Administration .................... 43 
10.3.1. 
Pain Intensity, Pain Relief, Stopwatch, & Global Evaluations.................... 43 
10.4. 
Safety Assessments ...................................................................................... 44 
10.5. 
Blood Sampling, Urine Drug Screen, and Pregnancy Tests ........................ 44 
10.6. 
Concomitant Medication ............................................................................. 45 
10.7. 
Rescue Analgesic ......................................................................................... 45 
10.8. 
Study Participant Discontinuation ............................................................... 45 
11. 
SAFETY ...................................................................................................... 46 
11.1. 
Patient Examinations ................................................................................... 46 
11.2. 
Patient Safety Information ........................................................................... 46 
11.3. 
Availability of Investigator .......................................................................... 46 
11.4. 
Adverse Events ............................................................................................ 46 
11.4.1. 
Definitions ................................................................................................... 46 
11.4.2. 
Reporting Adverse Events ........................................................................... 48 
11.4.3. 
Other Reportable Events .............................................................................. 49 
11.4.4. 
Adverse Event Recording and Reporting .................................................... 49 
11.4.5. 
Breaking the Blind ....................................................................................... 50 
11.4.6. 
Discontinuation of Study due to an SAE ..................................................... 50 
12. 
STATISTICAL METHODS AND DATA HANDLING ............................ 50 
12.1. 
Sample Size Determination ......................................................................... 51 
12.2. 
Analysis Populations ................................................................................... 51 
12.3. 
Demographic Data and Baseline Comparability ......................................... 51 


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12.4. 
Data Adjustments and Data Censoring ........................................................ 52 
12.4.1. 
Time Windows ............................................................................................. 52 
12.4.2. 
Data Censoring and Imputation ................................................................... 52 
12.5. 
Statistical Methods for Efficacy Evaluations .............................................. 52 
12.6. 
Multiple End Points and Multiple Comparisons ......................................... 54 
12.7. 
Safety Analysis ............................................................................................ 54 
13. 
STUDY ADMINISTRATION .................................................................... 54 
13.1. 
Investigator Study Binder ............................................................................ 54 
13.2. 
Patient Identification .................................................................................... 55 
13.3. 
Case Report Forms ...................................................................................... 55 
13.4. 
Monitoring of Study .................................................................................... 55 
13.5. 
Protocol Modifications and Deviations ....................................................... 56 
13.6. 
Discontinuation of Study by Sponsor or Principal Investigator .................. 56 
13.7. 
Disclosure of Data/Publications .................................................................. 56 
13.8. 
Informed Consent ........................................................................................ 56 
13.9. 
Institutional Review Board .......................................................................... 57 
13.10. 
Retention of Records ................................................................................... 57 
13.11. 
Responsibilities of Principal Investigator .................................................... 59 
13.12. 
Filing of Protocol with FDA ........................................................................ 59 
14. 
TEXT REFERENCES ................................................................................. 60 
APPENDIX 1. IMPACTION DIFFICULTY RATING SCALE ................................. 62 
APPENDIX 2. URINE DRUG SCREEN .................................................................... 63 
APPENDIX 3. PAIN SCALES .................................................................................... 64 
 
LIST OF TABLES 
Table 1: 
Study Medications ....................................................................................... 37 






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STUDY DESIGN: 
(cont.) 
 
 
 
 
point Pain Intensity (via 0-10 Numerical Pain Rating Scale) and Pain Relief 
(via 5-Point Categorical Pain Relief Assessment) measurements will be 
performed. For statistical purposes, pain assessments performed after any 
dose of rescue will be censored and imputed. The method of imputation will 
be described in the SAP, which will be finalized prior to unblinding of 
clinical trial subjects. Any subject requiring additional rescue medication may 
again receive ibuprofen 200mg and their data will be similarly censored and 
imputed. Pain scores and safety data will continue to be collected for  the 24-
hour observation period. Rescue medication will not exceed ibuprofen 200 
mg q3h or 2400 mg in a 24-hour period.   
Patient Global Evaluation of the study medication will be collected at 
Hour 24.25 or at the time of patient withdrawal (if applicable), whichever 
occurs first, using a 0-4 rating scale: (0) poor, (1) fair, (2) good, (3) very 
good, and (4) excellent. 
EFFICACY 
MEASUREMENTS: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Categorical Pain Intensity: (only at Baseline to determine study 
eligibility) Appendix 3 
 None (0)  
Mild (1)  
Moderate (2)   Severe (3) 
• 
Numerical Rating Scale Pain Intensity: (PI-NRS) Appendix 3 
(0 = no pain and 10 = worst imaginable pain) 
• 
Pain Relief  Appendix 3 
(5-Point Categorical Pain Relief Assessment) 
• 
 Stop Watches:  First Perceptible and Meaningful Relief Appendix 3 
(FPR= First Perceptible Relief-, MPR = Meaningful Pain Relief and 
FPR-C = FPR that is confirmed by MPR) 
• 
Global Evaluation: Appendix 3 
Poor (0) 
Fair (1)  
Good (2)  Very Good (3)  Excellent (4) 
Efficacy Parameters: 
• 
Time Weighted Sum of Pain Intensity Difference from 0 to 24hours 
(SPID24); 
• 
Time Weighted Sum of Pain Relief from  0 to 24 hours (TOTPAR24); 
• 
Time to Perceptible Pain Relief Confirmed (FPR-C); 
• 
Time to Meaningful Pain Relief (MPR); 
• 
Cumulative proportion of patients with pain half gone over time; 




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PHARMACOKINETIC 
ASSESSMENTS (PK): 
(cont.) 
Post Dose 1:  To be drawn at 0.25 hr.±3 min (end of 
 0.5 hr. ±3 min, 
0.75 hr. ± 3 min, 1 hr. ± 5 min, 2 hr. ± 5min , 4 hr.± 5 min, 6 hr.- 5 min (prior 
to the next planned 
 6.25 hr. ± 3 min (end of the 
 8hr. - 5 
min (prior to the next scheduled 
 8.25 hr. ± 3min (end of 
the  
 12 hr. - 5 min (prior to the next scheduled 
 12.25 hr. 
± 3 min (end of the 
 16 hr. - 5 min (prior to the next scheduled 
 16.25 hr. ±3 min(end of the 
 18 hr. - 5 min (prior to the 
next scheduled 
 18.25 hr. ± 3min (end of the 
 and at 24.25 
hr.± 15 min (after starting the very first 
 
 If a scheduled pain assessment and a scheduled PK sampling are at the same 
time point, the pain assessment should precede the PK sampling, but every 
attempt should be made to obtain the PK sample within the designated time 
window. 
The total amount of blood drawn for PK sampling is approximately 108 mL 
(18 blood samples of approximately 6 mL). 
The bioanalytical laboratory will perform the pharmacokinetic (PK) 
analysis on collected blood samples and provide a report on the plasma 
levels of acetaminophen. 
Actual sample collection time will be used for calculating the 
pharmacokinetic parameters. The peak concentration will be the observed 
maximum plasma drug concentration; the time to peak concentration (tmax) 
will be the collection time at which Cmax is first observed. Areas under the 
plasma concentration-time curve from time zero to the time of the last 
measurable concentration (AUC0-t) will be calculated by the linear 
trapezoidal method. AUC0-∞ will be extrapolated if allowed by the data.  
The PK Collection Lab Manual Guidelines for the site will be provided by 
the PK Lab. 
ESTIMATED 
DURATION OF 
PATIENT 
PARTICIPATION  
IN THE STUDY: 
The patients must have the surgical procedure within 30 days of screening. 
The inpatient part of the study will be approximately 24 hours and there will 
be a 7-day ± 2-day follow-up period. The approximate maximum number of 
days totals 40 from screening through completion of the study. 
DURATION OF 
STUDY: 
The study will be completed when the last patient completes the last follow 
up phone call. The expectation is that the study will be completed within 4 
months of the first patient entry. 
NUMBER OF 
PATIENTS: 
A sufficient number of male and female patients will be screened to enroll up 
to 110 patients that meet the American Society of Anesthesiologists (ASA) 
Category I (healthy) or Category II (mild systemic disease) guidelines. 


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SAMPLE SIZE 
DETERMINATION: 
 
The sample size was determined from past experience with the Dental 
Impaction Pain Model (DIPM) and analysis of the results from a previous 
Phase 2 study comparing the safety and efficacy of 
 APAP in combination 
with oral pregabalin (Nevakar Protocol CP-NVK-009-0001). SPID 24 data 
for 
 APAP in that study suggested that a sample size of 44 patients per 
active group and 22 patients in the placebo group should be adequate to 
evaluate similarities between the two active dose regimens vs placebo. 
INCLUSION 
CRITERIA: 
 
 
 
INCLUSION 
CRITERIA: (cont.) 
 
1. Patients must be capable of reading, comprehending, and signing the 
informed consent/assent form; 
2. Male and female patients between 17-55 years of age;  
3. Body Mass Index (BMI) ≤35.0 kg/m2 
4. Body weight of >50 kg 
5. Patients are ASA Category I or II and are in good physical health as judged 
by a thorough history and physical examination;  
6. Patients without infections in the area of the impacted teeth; 
7. Patients must agree to refrain from ingesting any systemic or applying any 
topical analgesic medication for 3 days or 5 half-lives of the drug prior to and 
during the study; 
8. No alcohol for a minimum of 24 hours prior to the surgery;  
9. Female patients must be of non-child bearing potential, defined as 
postmenopausal for more than 1 year or surgically sterile (hysterectomy, 
tubal ligation/occlusion) or practicing an acceptable method of 
contraception (hormonal oral, patch, or implant, double barrier method, 
intrauterine device, vasectomized or same sex partner, or abstinence). 
Patients using hormonal birth control must have been on a stable dose of 
treatment for at least 30 days and received at least 1 cycle of treatment prior 
to randomization. At Screening and at the day of surgery, all females of 
childbearing potential must have a negative (serum at screening and urine 
on day of surgery 1) pregnancy test and not be breastfeeding; 
10. Patients must have a negative urine drug screen for drugs of abuse at 
Screening and on the day of surgery. At the discretion of the Principal 
Investigator, a positive drug screen result may be permitted if the patient 
has been on a stable dose of an allowed medication for >30 days;  
11. Patients who are scheduled to undergo the surgical removal of up to 
4 third molars of which at least two have to be mandibular molars with a 
difficulty rating of 4 or 5 and meeting the following criteria: 
• 
two full bony impactions 


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• 
two partial bony impactions 
• 
one full bony impaction in combination with one partial bony 
impaction 
(see Appendix 1 for Impaction Difficulty Rating Scale); 
12. Patients able to comprehend and follow the requirements of the study 
(including availability on scheduled visit dates) based upon the research 
site’s judgment. 
EXCLUSION 
CRITERIA: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EXCLUSION 
CRITERIA: (cont.) 
 
1. Patients with a history of any significant medical condition that, in the 
opinion of the Principal Investigator or his designee, would place the 
patient at increased risk such as: hepatic, renal, endocrine, cardiac, 
neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or 
metabolic disorders, including glaucoma, diabetes, emphysema, and 
chronic bronchitis; 
2. Patients with a history of any type of malignancy within the past 5 years 
other than minor skin related cancers;  
3. Patients with a history of alcohol or substance abuse in the past three 
years according to DSM V and who do not satisfy Inclusion Criteria 10 
(including a positive urine drug screen test); 
4. Patients with a known allergy or hypersensitivity to any local anesthetic 
drug, acetaminophen, ibuprofen, or other NSAIDS; 
5. Patients who are taking any concomitant medications that might confound 
assessments of pain relief, such as psychotropic drugs, antidepressants, 
sedative hypnotics or any analgesics taken within three days or five times 
of their elimination half-lives, whichever is longer. Selective serotonin 
reuptake inhibitors (SSRIs) and selective noradrenaline reuptake 
inhibitors (SNRIs) are permitted if the patient has been on a stable dose 
for at least 30 days prior to screening; 
6. Patients who have smoked or chewed tobacco-containing substances 
within 48 hours prior to the day of surgery; 
7. Patients judged by the Principal Investigator  to be unable or unwilling to 
comply with the requirements of the protocol; 
8. Patients who have used an investigational drug within 30 days prior to the 
screening day or have previously participated in any Nevakar trial; 
9. Patients who have donated blood within 3 months prior to the screening 
day; 
10. Patients who are employees or relatives of employees of JBR Clinical 
Research or Nevakar, Inc. 


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11. Patients with liver function tests (ALT, AST) that are above the normal 
reference range. 
SAFETY 
EVALUATION: 
 
 
 
 
 
 
 
SAFETY 
EVALUATION: 
(cont.) 
All potential patients will undergo a urine drug screen, hematology, serology 
testing for HIV, Hepatitis B and Hepatitis C, and serum liver function testing 
at the screening visit. In addition, females will have a serum pregnancy test. 
Prior to Hour 24 (±30 minutes), liver function testing will be repeated. 
All of the study and rescue medications being evaluated in this study are 
marketed products in the United States. 
Adverse events (AEs) will be assessed and recorded in the eCRF. This 
information will be collected as they occur or are reported at screening and 
during the treatment and post treatment phase of the study patient regardless 
of severity or potential association with the study medication or study 
procedures. AEs will also be assessed and recorded in the eCRF at the time of 
follow-up telephone call at Day 7 (± 2 days) after discharge from the Clinical 
Research Unit. This follow-up telephone call designates that the patient has 
completed the study. In addition, patients/caregivers will be encouraged to 
report AEs of concern at any time in the interval between discharge and the 
follow-up call. 
Treatment-emergent AEs (TEAEs) will be summarized by incidence and 
severity and reported in the eCRF. The events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and summarized by 
system organ class (SOC) and preferred term (PT). The severity, relationship 
to treatment, action taken, and outcome of the events will be documented in 
the source and captured in the eCRF. The incidence of all adverse events and 
drug-related adverse events will be evaluated. In the event of any health-
related emergency, the clinical site will have trained medical staff and a fully 
equipped emergency crash cart on site. 
STATISTICAL 
ANALYSIS: 
 
 
 
 
 
 
 
 
 
 
 
All computations will be performed using SAS® version 9.4 (SAS Institute, 
Cary, NC). Since this is a proof-of-concept study, statistically significant 
treatment differences will be declared if p ≤ 0.10 (one-sided), and no 
adjustments for multiple comparisons/end points will be performed.  All 
confidence intervals will be one-sided 90% confidence intervals. 
The between-treatment comparisons that will be performed are: 
• 
 APAP 
 q8h versus Placebo 
• 
 APAP 
 q6h versus Placebo 
Descriptive statistics for numerical variables will include n (number of patients 
involved), mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be described by number and percent.   Treatment of 
missing data will be described in a statistical analysis plan and finalized prior 
to database lock.  


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STATISTICAL 
ANALYSIS: 
(cont.) 
Efficacy Data: 
Sum of Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR) 
from 0 to 24 hours will be analyzed using an analysis of variance (ANOVA) 
model with treatment group as a fixed effect and baseline pain intensity a 
covariate. Other covariates may be explored and the final model will be 
described in the Statistical Analysis Plan (SAP). Actual times will be used for 
calculating SPIDs and TOTPARs.  In addition, sensitivity analyses will be 
performed and will be described in the Statistical Analysis Plan.  
Time to Perceptible Pain Relief Confirmed (FPR-C, confirmed by achieving 
Meaningful Pain Relief), Time to Meaningful Pain Relief (MPR), and Time 
to Treatment Failure will each be analyzed using a log-rank test; the log rank 
test may be stratified by baseline pain intensity score (moderate / severe) or 
other variables as appropriate.  In addition, Kaplan-Meier curves will be 
presented by treatment group. 
The cumulative percentage of patients with pain at half gone over the 24-hour 
evaluation period will be summarized descriptively and plotted over time by 
treatment group. 
The Patient Global Evaluation at 24.25 hours or patient withdrawal (if 
applicable) whichever is first, will be analyzed using a model similar to the 
primary analysis model. 
Pain Intensity (PI), Pain Intensity Difference (PID), and Pain Relief (PR) 
Ratings at each observation time following Dose 1 administration will be 
summarized descriptively and plotted over time by treatment group. 
The cumulative percentage of patients with onset of FPR-C after Dose 1, 
MPR after Dose 1, and treatment failure after Dose 1 will each be 
summarized descriptively and plotted over time by treatment group.  
A detailed methodology for the statistical analyses of the data collected in 
this study will be documented in a SAP, which will be signed off prior to the 
database lock. The SAP may modify the plans outlined in the protocol and in 
cases where the documents are discrepant, the SAP shall be considered as 
correct; however, any major modifications to the primary endpoint definition 
will also be reflected in a protocol amendment.  The SAP will be detailed in 
an addendum to the protocol. The SAP will be finalized and included in the 
addendum prior to unblinding of the study.  
Safety Data: 
Tables of descriptive statistics by treatment group and listings will be 
presented for the actual values and the changes from Baseline for Systolic 
Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Respiratory Rate 
(RR), and Heart Rate (HR) at Baseline and at 4-hour intervals post surgically.  
Liver function tests will be compared from baseline to post treatment.  


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Analysis of the incidence and severity of all adverse events will also be 
performed. 
RESCUE 
ANALGESIC: 
 
 
 
 
 
 
 
 
RESCUE 
ANALGESIC: (cont.) 
Rescue medication will consist of one ibuprofen 200 mg tablet taken orally 
with at least 4 ounces of water. Prior to each dose of rescue medication, 11-
Point Pain Intensity (via 0-10 Numerical Pain Rating Scale) and Pain Relief 
(via 5-Point Categorical Pain Relief Assessment) measurements will be 
performed. For statistical purposes, pain assessments performed after any 
dose of rescue will be censored and imputed. The method of imputation will 
be described in the SAP, which will be finalized prior to unblinding of 
clinical trial subjects. Any subject requiring additional rescue medication may 
again receive ibuprofen 200 mg and their data will be similarly censored and 
imputed. Pain scores and safety data will continue to be collected for  the 24-
hour observation period. Rescue medication will not exceed ibuprofen 200 
mg q3h or 2400 mg in a 24-hour period. 
 


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3. 
STUDY FLOW CHART (schedule of activities) 
 
Screening 
Day of 
Surgery 
 
Post-Op  
Follow Up  
Post-Surgery Call 
Procedures 
Day -30 to 0 
Day 1 
Day 2 
Day 7 (±2 day) 
Written informed consent and/or assent 
X 
 
 
 
Demography: Age, height, weight & BMI 
X 
 
 
 
Inclusion / Exclusion assessment 
X 
X 
 
 
Significant medical history 
X 
X 
 
 
Physical Exam 
X 
 
 
 
Vital signs (BP, heart rate, respiratory rate, 
temperature)1 
X 
X 
X 
 
Serum pregnancy test for females 
X 
  
 
 
Serology testing for HIV, Hep B and Hep C 
X 
 
 
 
Serum liver function panel2 
X 
 
X 
 
Hematology  
X 
 
 
 
Urine pregnancy test for females (dipstick) 
 
X 
 
 
Urine drug testing (dipstick)  
X 
X 
 
 
Patient Assessment Training 
X 
X 
 
 
Dental Surgery & Randomization Criteria 
 
X 
 
 
Study medication administration  
 
X 
 
 
 Catheter Placement 
 
X 
 
 
4-Point Categorical PI and 11-point PI-NPRS 
at Baseline3 
 
X 
 
 
11-Point Pain Intensity (PI-NPRS) and Pain 
Relief (PR)4 
 
X 
X 
 
Perceptible & Meaningful Stopwatches  
1 & 2 after Dose 1 
 
X 
 
 
Rescue therapy if needed  
 
X 
X 
 
Patient Global Evaluation5 
 
  
X 
 
Prior and Concomitant Therapy6 
X 
X 
X 
X 
Patient Safety monitoring 
X 
X 
X 
X 
PK Blood Draws7 
 
X 
X 
 
Discharge 
 
 
X 
 




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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation/Term 
Definition 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANOVA 
Analysis of varianceVariance 
APAP 
Acetaminophen (acetyl-para-aminophenol) 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
eCRF 
Electronic Case Report Form 
CRU 
Clinical Research Unit 
DBP 
Diastolic Blood Pressure 
DIPM 
Dental Impaction Pain Model 
DSM V 
Diagnostic and Statistical Manual of Mental Disorders 
EDC 
Electronic Data Capture 
EIU 
Exposure in Utero 
FDA 
Food and Drug Administration 
FPR 
First Perceptible Relief 
FPRC 
First Perceptible Relief Confirmed  
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
IBU 
Ibuprofen 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IDRS 
Impaction Difficulty Rating Scale 


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Abbreviation/Term 
Definition 
IND 
Investigational New Drug  
 
 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD/IUS 
Intrauterine Device/ Intrauterine System 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg and mg/d 
Milligrams and milligrams per day 
mL 
Milliliter 
MPR 
Meaningful Pain Relief  
NNT  
Number Needed to Treat 
NPRS 
Numerical Pain Relief Scale 
NPO 
Nil Per Os (nothing by mouth) 
NRS 
Numerical Rating Scale 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
OTC 
Over the counter 
PBO 
Placebo 
PI 
Pain Intensity 
PID 
Pain Intensity Difference 
PK 
Pharmacokinetics 
PO 
Per Os (by mouth) 
PR 
Pain Relief 
PI-NPRS 
Pain Intensity-Numerical Pain Relief Scale 
RR 
Respiratory Rate 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SAE 
Serious Adverse Event 
SOC 
System Organs Class 
SPI 
Time Weighted Sum Pain Intensity 
SPID 
Time Weighted Sum Pain Intensity Difference 


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Abbreviation/Term 
Definition 
TEAE 
Treatment Emergent Adverse Events 
TESS 
Treatment Emergent Signs and Symptoms 
TMF 
Trial Master File 
TOTPAR 
Time Weighted Total Pain Relief 
US  
United States 
USP 
United States Pharmacopeia 
 
 


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5. 
ETHICS  
5.1. 
Institutional Review Board 
This protocol, informed consent form, and any amendments will be submitted to institutional 
review boards (IRBs) for review and approval. A copy of the written approval or vote must be 
available and sent to the Sponsor (Nevakar, Inc.) before study initiation. Any amendment made 
to the approved protocol must be forwarded to and approved by the same IRBs before its 
implementation. Any required regulatory authority notifications will also be in place and fully 
documented prior to study initiation. 
The Principal Investigator and appropriate representatives from the Sponsor will sign the 
protocol to document their willingness to adhere to this protocol and to conduct the study in 
accordance with the FDA guidelines and the International Conference on Harmonization (ICH) 
guidelines for Good Clinical Practice (GCP). 
5.2. 
Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and consistent with good clinical practice (GCP) as described by the 
United States Code of Federal Regulations (21CFR parts 50, 54, 56, and 312) and by the ICH 
Guidelines E6 (R2). 
5.3. 
Patient Information and Consent 
Written informed consent form (ICF), in accordance with local clinical investigation regulations 
(21 CFR Part 50 Protection of Human Patients), must be obtained from all patients prior to 
participation in the study. In addition, patients under 18 years of age also must have written 
parental or guardian consent. The Principal Investigator or his appropriate designee must 
provide a description of the study treatment (including any potential and possible hazards) and 
the study procedures to the study patients. Information must be given both in oral and written 
form. The patient information provided will be in English and may not include any language 
that appears to waive any of the patient’s legal rights, or appears to release the Investigators, the 
Sponsor, the Sponsor’s representative, or the institution, from liability or negligence. 
The Principal Investigator or his appropriate designee will provide the prospective study patient 
sufficient time to consider whether or not to participate, minimizing the possibility of coercion 
or undue influence, and will discuss any questions the patients may have. The Principal 
Investigator or his appropriate designee will explain to the patient that withdrawal from the 
study is possible at any time without detriment to care. The Principal Investigator or his 
appropriate designee will then ask the patient to give consent in writing.  
The consent must include acknowledgment that medical records and medical data derived from 
the study may be forwarded to the Sponsor, to the Sponsor’s representative, to the FDA or other 


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regulatory authorities. The informed consent will follow the FDA Regulations and ICH 
Guidelines E6 (R2). 














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Upon initiation of the 
 of Dose 1, two stopwatches will be started.  The patients will 
first be given stopwatch #1 and asked to press the stopwatch if and when they first perceive any 
relief (FPR). At this time, patients will be given the second stopwatch and asked to press this 
stopwatch if and when the pain relief becomes meaningful to them (MPR). If a patient requires 
a rescue analgesic after Dose 1, the time of rescue as well as PI-NPRS and PR will be collected 
at that time and collection of stopwatch data will cease. Patients who do not experience any pain 
relief after Dose 1 will be encouraged, but not required, to wait at least 1 hour before using 
rescue therapy. Patient Global Evaluation (PGE) of the study medication will be collected at 
Hour 24.25 (+ 10 min) or at the time of patient withdrawal, whichever occurs first, with a 0-4 
categorical rating scale: (0) Poor, (1) Fair, (2) Good, (3) Very Good, and (4) Excellent. 
A randomization code will be generated that will randomly assign patients to treatment groups. 
A sufficient number of male and female patients will be screened to enroll up to 110 patients 
that fit the American Society of Anesthesiologists (ASA) Category I (healthy) or Category II 
(mild systemic disease) classification.  
8.1. 
Inclusion Criteria 
Individuals may be included in the study provided they meet all of the following inclusion 
criteria: 
1. Patients must be capable of reading, comprehending, and signing the informed  
consent form; 
2. Male and female patients between 17-55 years of age;  
3. Body Mass Index (BMI) ≤35.0 kg/m2; 
4. Body weight of >50 kg; 
5. Patients are ASA Category I or II and are in good physical health as judged by thorough 
history and physical examinations;  
6. Patients without infections in the area of the impacted teeth; 
7. Patients must agree to refrain from ingesting any systemic or applying any topical 
analgesic medication for 3 days or 5 half-lives of the drug prior to and during the study; 
8. No alcohol for a minimum of 24 hours prior to the surgery;  
9. Female patients must be of non-child bearing potential, defined as postmenopausal for 
more than 1 year or surgically sterile (hysterectomy, tubal ligation/occlusion) or 
practicing an acceptable method of contraception (hormonal oral, patch, or implant, 
double barrier method, intrauterine device, vasectomized or same sex partner, or 
abstinence). Patients using hormonal birth control must have been on a stable dose of 
treatment for at least 30 days and received at least 1 cycle of treatment prior to 
randomization. At Screening and at the day of surgery, all females of childbearing 


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potential must have a negative (serum at Screening and urine on Day 1) pregnancy test 
and not be breastfeeding; 
10. Patients must have a negative urine drug screen for drugs of abuse at Screening and at 
the day of surgery. At the discretion of the Principal Investigator, a positive drug screen 
result may be permitted if the patient has been on a stable dose of an allowed medication 
for >30 days;  
11. Patients who are scheduled to undergo the surgical removal of up to 4 third molars of 
which at least two have to be mandibular molars with a difficulty rating of 4 or 5 and 
meeting the following criteria: 
• two full bony impactions 
• two partial bony impactions 
• one full bony impaction in combination with one partial bony impaction 
(see Appendix 1 for Impaction Difficulty Rating Scale);  
12. Patients able to comprehend and follow the requirements of the study (including 
availability on scheduled visit dates) based upon the research site's judgment. 
8.2. 
Exclusion Criteria 
Individuals are not eligible for participation in the study if any of the following are noted:  
1. Patients with a history of any significant medical condition that, in the opinion of the 
Principal Investigator or his designee, would place the patient at increased risk such as: 
hepatic, renal, endocrine, cardiac, neurological, psychiatric, gastrointestinal, pulmonary, 
hematologic, or metabolic disorders, including glaucoma, diabetes, emphysema, and 
chronic bronchitis; 
2. Patients with a history of any type of malignancy within the past 5 years other than minor 
skin related cancers; 
3. Patients with a history of alcohol or substance abuse in the past three years according to 
DSM V and who do not satisfy inclusion criteria 10 (including a positive urine drug 
screen test); 
4. Patients with a known allergy or hypersensitivity to any local anesthetic drug, 
acetaminophen, ibuprofen, or other NSAIDs; 
5. Patients who are taking any concomitant medications that might confound assessments 
of pain relief, such as psychotropic drugs, antidepressants, sedative hypnotics or any 
analgesics taken within three days or five times  of their elimination half-lives, 
whichever is longer. Selective serotonin reuptake inhibitors (SSRIs) and selective 
noradrenaline reuptake inhibitors (SNRIs) are permitted if the patient has been on a 
stable dose for at least 30 days prior to screening; 


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6. Patients who have smoked or chewed tobacco-containing substances within 48 hours prior 
to the initiation of surgery; 
7. Patients judged by the Principal Investigator to be unable or unwilling to comply with the 
requirements of the protocol; 
8. Patients who have used an investigational drug within 30 days prior to the screening day 
or have participated in any previous Nevakar trial; 
9. Patients who have donated whole blood within 3 months prior to the screening day; 
10. Patients who are employees or relatives of employees of JBR Clinical Research or 
Nevakar, Inc. 
11. Patients with liver function tests (ALT, AST) that are above the normal reference range. 






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9.5.2. 
Study Medication Inventory 
Upon receipt at the study site, the study medication supplies will be stored in the CRU study 
medication storage room. At the study initiation, an appropriate unblinded designee, and the 
unblinded monitor will conduct an inventory and complete the study medication inventory 
record. The medication inventory record will be sent to the Trial Master File (TMF), and the 
Principal Investigator at the end of the study, after the study has been unblinded. Any interim 
shipments will be inventoried by the unblinded designee. For all interim shipments, a study 
medication inventory record will be completed. The medication inventory record will be 
returned to TMF by the unblinded monitor and the Principal Investigatorat the end of the study, 
after the study has been unblinded. 
The appropriate unblinded designee, upon dispensing the study medication, must record the 
information on a study medication dispensing/return log. For accounting purposes and assessing 
patient compliance, an unblinded monitor will review the study medication dispensing/return 
log, inventory the study medications, and inspect the storage facility at appropriate time 
intervals throughout the clinical investigation, depending on the length of the study. The 
unblinded CRU team must account for any discrepancy and/or deficiency. Study medications 
will be assigned as described in Section 9.3. The blinded Principal Investigator will provide 
oversight for all aspects of the study, including management of study medication as outlined in 
a separate study blinding plan. 
9.5.3. 
Return of Study Supplies 
At the conclusion of the study, an appropriate designee, and a representative of the Sponsor 
(monitor) will inventory all used and unused study medications. The study medication inventory 
record for returned study medications will then be completed.  Both the TMF and the  
Investigator will retain a copy for his files. 
After being inventoried, all unused study medications will either be disposed of by the 
unblinded CRU or returned to Nevakar, Inc. (as per 21 CFR 312.58), and a Study Medication 
Inventory Record/certificate of destruction will be sent to the Medical Monitor. 
10. 
STUDY PROCEDURES 
10.1. 
Study Conditions 
1. Only patients who satisfy all inclusion and exclusion criteria and provide written 
informed consent may participate in the trial. 
2. Patients should not be experiencing any oral infections or symptoms of a concomitant 
illness (e.g., respiratory tract infection) at the time of a scheduled surgery. 


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3. After surgery, patients will remain at the study site for up to 31 hours post-surgical 
monitoring. The evaluation time for efficacy and safety will be 24 hours following Dose 1. 
(the patient’s stay may be longer if there is safety reason to lengthen observation time, or 
if patient is not stable enough to transport themselves after discharge.) 
4. The surgery and post-surgical procedures will be performed at the CRU. Patients will be 
housed in a private room in the research facility.  
10.2. 
Schedule of Assessments  
10.2.1. 
Screening Assessments 
During the screening period, the Principal Investigator or his designee will examine each patient 
and complete a checklist of the inclusion and exclusion criteria (see Section 8.1 and Section 8.2, 
respectively) in order to determine the patient’s eligibility. The Principal Investigator or 
designee will enter the pertinent historical information (including any medication taken 
recently) and clinical findings (including vital signs) in the appropriate section(s) of the source 
documents. 
A Patient Screening Log (provided by the research site) will be maintained in the site central 
file to document all patients screened for entry into the study. Patients will be screened only 
once unless otherwise approved by the sponsor. All patients who meet the entrance criteria will 
be provided with a written informed consent document before participating in the study. 
Patients are required to read, comprehend, and sign the informed consent. The screening 
procedure will include: 
1. Informed Consent/Assent Form (no procedures can be performed prior to signing); 
2. Demography: Age, Height, Weight, and BMI; 
3. Inclusion/Exclusion assessment; 
4. Medical history; 
5. Physical examination; 
6. Vital signs (BP, temperature, heart rate, and respiratory rate in supine or reclining 
position); 
7. Urine drug screen (Appendix 2); 
8. Serum pregnancy test for females; 
9.   Hematology 
10. Serum liver function tests to include alanine aminotransferase; albumin, serum; alkaline 
phosphatase, serum; aspartate aminotransferase; bilirubin, direct; bilirubin, total; protein, 
total; 


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11. A serum sample will be collected to test for HIV antibody, hepatitis B surface antigen 
(HBsAg) and hepatitis C virus antibody (anti-HCV); 
12. Concomitant therapy; 
13. Safety monitoring (AEs); 
14. Appropriate screening information for eligible patients who are assigned a patient number 
and receive study medication will be transcribed onto the corresponding sections of the 
CRF. The surgical procedure must occur within 30 days of the screening visit.  
The following will be noted and recorded on the CRF: 
• Date of informed consent 
• Vital signs obtained 
• Date and time the surgery was initiated and completed 
10.2.2. 
Pre-Operative Assessments and Study Drug Administration 
• Patients are NPO after midnight the day before surgery. 
• Patients will report to the Clinical Research Unit (CRU) the morning of scheduled 
surgery. 
• Patient’s continued eligibility to participate in the study is confirmed; any additional 
medical history since screening will be recorded. 
• Vital signs. 
• Urine pregnancy test. 
• Urine drug test. 
• Placement of 2 
 catheters. 
• Pre-dose PK sample. 
• Dental surgery. 
• The assessments and drug administration will be completed in the patient’s CRU 
room. 
• The study coordinator will communicate to the unblinded dispenser that 
requirements for dosing have been met. 
• The unblinded dispenser will then assign the next available randomization number. 
• The unblinded dispenser will prepare study medication for each patient in a 
designated dispensing room. 


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• A second unblinded individual, with no other study involvement, will witness the 
preparation and dispensing process and confirm the correct study medication 
assignment.  
(No other study personnel will be present in the designated dispensing room at the 
time of study drug dispensing).  
• A double-blind label with the same randomization number as that assigned to the 
patient will be affixed respectively to the 
 study medication container and 
the tear-off portion of the label will be attached to the patient’s source documents. 
• Unblinded dispenser will complete the study drug dispensing record. The study drug 
dispensing record will remain in a secure and locked area, with access limited to the 
unblinded third- party dispenser, back-up staff member, and the aforementioned 
unblinded second dispensing-room witness.  
• Unblinded dispenser will dispense study drug to blinded study coordinator for 
administration to the patient. 
• Study coordinator will administer study drug to the patient. 
• Recording of concomitant therapy (e.g., anesthesia, etc.). 
• Safety monitoring (AE/SAEs). 
 
10.2.3. 
Post-Operative Assessments 
The time points of the post-baseline efficacy assessments are detailed in Section 8 of this 
protocol. These observations will take place at the initiation of Dose 1. Pain Intensity Numerical 
Pain Rating Scale (PI-NPRS) and Pain Relief (PR) will be collected at 0.5, 0.75, 1, 1.25, 1.75, 
and 2.25 hours (± 5 minutes) and then collected at Hours 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 
9.25,10.25, 11.25 and 12.25 (± 5 minutes), then 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 
10 minutes). 
Upon initiation of the 
 of Dose 1, two stopwatches will be started.  The patients will 
first be given stopwatch #1 and asked to press the stopwatch if and when they first perceive any 
relief (FPR). At this time, patients will be given the second stopwatch and asked to press this 
stopwatch if and when the pain relief becomes meaningful to them (MPR). If a patient requires 
a rescue analgesic after Dose 1, the time of rescue as well as PI-NPRS and PR will be collected 
at that time and collection of stopwatch data will cease.  
 
• Prior to initiation of Dose 1, the Baseline Pain scores on the 4-point categorical pain 
intensity scale and PI-NPRS will be recorded on the CRF. 






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10.6. 
Concomitant Medication 
No other medications expected to confound the evaluation of the study medication will be 
allowed during the study session. This includes, but is not limited to, the use of any systemic 
analgesics other than the prescribed rescue analgesic. All concomitant medications used during 
the study will be recorded in the CRF. It is permissible at any time after the surgical procedure for 
a single dose of 4-8 mg ondansetron (Zofran®) iv, by mouth or sublingual to be administered if a 
patient experiences nausea. 
10.7. 
Rescue Analgesic 
Rescue medication will consist of one ibuprofen 200 mg tablet taken orally with at least 4 ounces 
of water. Prior to each dose of rescue medication, 11-Point Pain Intensity (via 0-10 Numerical 
Rating Scale) and Pain Relief (via 5-Point Categorical Pain Relief Assessment) measurements 
will be performed. For statistical purposes, pain assessments performed after any dose of rescue 
will be censored and imputed. The method of imputation will be described in the SAP, which will 
be finalized prior to unblinding of clinical trial subjects. Any subject requiring additional rescue 
medication may again receive ibuprofen 200 mg and their data will be similarly censored and 
imputed. Pain scores and safety data will continue to be collected for  the 24-hour observation 
period. Rescue medication will not exceed ibuprofen 200 mg q3h or 2400 mg in a 24-hour period.  
10.8. 
Study Participant Discontinuation 
A patient will be considered discontinued from the study at any time under the following 
circumstances: 
1. Any patient who violates any condition of the entrance criteria after having been entered 
into the study; 
2. Any patient who develops a confounding concomitant illness (as determined by the 
patient, research coordinator or Principal Investigator), serious adverse event, or a 
hypersensitivity to the study medication; 
3. Any patient who becomes uncooperative, does not adhere to the requirements of the 
study protocol, or refuses to complete the study; 
4. Any patient who requires any concomitant medication during the course of the study 
that could confound the study results. 
If necessary, additional study medications will be provided to the study site for additional 
patients. A representative of the Sponsor or the Data Management Group will provide the 
additional number(s) to the study site. 
All discontinued patients will record no further assessments after their time of discontinuation, 
and any recorded efficacy data will be included in the Evaluable Population. All patients taking 
study medications with follow-up safety data will be included in the safety analysis. Details of 


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the reason(s) why a patient has been discontinued from the study should be recorded in the 
appropriate section of the CRF. 
11. 
SAFETY 
11.1. 
Patient Examinations 
To ensure the safety and well-being of each patient entered into the study, the patient must first 
be examined by the Principal Investigator or Sub-Investigator and medically cleared to participate 
as required by the protocol. Each patient will be observed for adverse events (AEs) and will be 
required to report any adverse events that develop during the course of the study and for 15 days 
post-drug treatment. If at any time during the study, the patient has a serious adverse event 
(SAE) or abnormality, the patient must be withdrawn from the study and appropriate care 
should be initiated. 
11.2. 
Patient Safety Information 
In accordance with the US regulatory requirements regarding informed consent (21 CFR Part 50, 
Protection of Human Patients), the patient will receive a copy of the informed consent form 
(ICF) when discharged from the clinic. The ICF will include the information needed to contact 
the Principal Investigator, along with a description of the study medications the patient may 
have received. 
11.3. 
Availability of Investigator 
Either the Principal Investigator or an appropriate designee will be available to the patient at all 
times during the study and names and phone numbers of the Principal Investigator and/or 
appropriate designee will be listed on the informed consent form. 
11.4. 
Adverse Events 
11.4.1. 
Definitions  
Adverse Event 
An adverse event (AE) will be defined as any untoward medical occurrence in a patient after the 
informed consent is signed. The adverse event does not necessarily have to have a causal 
relationship with the study medication. An AE can therefore be an unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease, which is a change from 
baseline and is temporally associated with the use of the study medication, whether or not it is 
considered related to the study medication. 
Severity 


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The following definitions will be used for grading severity of adverse events: 
Mild - Either asymptomatic or patient is aware of the sign, symptom or event, but it is easily 
tolerated. 
Moderate - Discomfort enough to cause interference with usual activity and may warrant 
intervention. 
Severe - Incapacitating with inability to do usual activities. 
Causal Assessment 
The causal relationship between an AE and the study medication will be determined by the 
Principal Investigator on the basis of his clinical judgment and the following definitions: 
• Associated: There is a reasonable possibility that the AE may have been caused by the 
study medication. This definition applies to those AEs that are considered definitely, 
probably, and possibly related to the use of the study medication. 
a. Definitely Related: An AE that:  
− follows a reasonable temporal sequence from administration of the study 
medication;  
− follows a known response pattern to the study medication;  
− and, when appropriate to the protocol, is confirmed by improvement after 
stopping the study medication (positive de-challenge) and by reappearance of the 
reaction after repeat exposure (positive re-challenge);  
− and cannot be reasonably explained by known characteristics of the patient’s 
clinical state or by other therapies; 
b. Probably Related: An AE that:  
− follows a reasonable temporal sequence from administration of the study 
medication;  
− follows a known response pattern to the study medication;  
− and, when appropriate to the protocol, is confirmed by improvement after de-
challenge;  
− and cannot be reasonably explained by the known characteristics of the patient’s 
clinical state or by other therapies; 
c. Possibly Related: An AE that: follows a reasonable temporal sequence from 
administration of the study medication and follows a known response pattern to the 
study medication but could have been produced by the patient’s clinical state or by 
other therapies. 


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• Not Associated: 
d. Unlikely: An AE that does not follow a reasonable temporal relationship after 
administration of the study medication or could have been produced by the patient’s 
clinical state or other therapies; 
e. Not related: An AE for which sufficient information exists to indicate that the etiology 
is unrelated to the study medication. Two or more of the following variables apply; 
− The AE does not follow a reasonable temporal sequence after administration of 
the study medication; 
− The AE is readily explained by the patient’s clinical state or other therapies; 
− Negative de-challenge—the AE does not abate upon dose reduction or cessation 
of therapy (assuming that it is reasonable to expect abatement of the AE within 
the observed interval). 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that occurs at any dose and: 
• Results in death; 
• Is life threatening; 
• Requires inpatient hospitalization or prolongation of an existing hospitalization;  
• Results in persistent or significant disability/incapacity;  
• Is a congenital anomaly/birth defect; 
• Is a medically important condition: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a SAE when, 
based upon appropriate medical judgment, the event(s) may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
11.4.2. 
Reporting Adverse Events 
Any SAE, regardless of causal relationship, must be reported immediately to the CRO Medical 
Monitor no later than 24-hours after awareness of the SAE. Initial SAE reports may be made by 
telephone, and then followed by faxing a completed “Serious Adverse Event Form” and 
confirming by telephone that the fax was received. Compliance with this time requirement is 
essential to comply with regulatory obligations. The Principal Investigator also will promptly 
notify the appropriate Institutional Review Board about the serious adverse event. 
Contact: 
CRO Medical Monitor: 




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For SAEs, the Principal Investigator will provide all documentation pertaining to the event (e.g. 
additional laboratory tests, consultation reports, discharge summaries, postmortem reports, etc.) 
to the CRO Medical Monitor in a timely manner. Reports relative to the patient’s course must 
be submitted to the CRO Medical Monitor until the event has subsided or, in the case or 
permanent impairment, until the condition stabilizes. 
Information about all adverse events, serious and non-serious, including the event’s severity, 
start and stop times/dates, chronicity, relatedness to study medication, and any actions taken, 
must be recorded on the appropriate CRFs. The information recorded will be based on the signs 
and symptoms detected during the physical examination and clinical evaluation of the patient as 
well as information recorded in the patient’s diary, when applicable. 
11.4.5. 
Breaking the Blind 
A set of tamper-proof sealed individual envelopes containing the medication code inside the 
envelope, will be sent to the investigative site. In the event of a medical emergency that 
necessitates breaking the code, the sealed envelope containing the medication code may be 
opened. The seal will only be broken by the Principal or Sub Investigator in the event of an 
emergency for which knowledge of the patient’s double-blind investigational product will have 
a direct impact on treatment decisions. Every effort will be made to discuss the decision to 
break the blind with the CRO Medical Monitor in advance.  
When the blind is broken, the Principal Investigator will notify the CRO Medical Monitor  
immediately in order to document the reason and date of the unblinding. The event will also be 
recorded on the CRF and in the source document. The Principal Investigator will submit a written 
explanation to the CRO Medical Monitor  describing the event within 5 business days. 
11.4.6. 
Discontinuation of Study due to an SAE  
The study will be discontinued for safety reasons if a serious adverse event occurs in more than 
one patient unless it is demonstrated that the serious adverse event is not related (as defined in 
Section 11.4.1 of this protocol) to study medication, in which case the study will not be required 
to stop. 
The IRB will be notified within 24 hours of any event that results in an SAE or in 
discontinuation of the study. 
12. 
STATISTICAL METHODS AND DATA HANDLING 
All computations will be performed using SAS® version 9.4 (SAS Institute, Cary, NC). Since 
this is a proof-of-concept study, statistically significant treatment differences will be declared if 
p ≤ 0.10 (one-sided), and no adjustments for multiple comparisons/end points will be 
performed.  All confidence intervals will be one-sided 90% confidence intervals.   
The between-treatment comparisons that will be performed are: 




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12.4. 
Data Adjustments and Data Censoring 
12.4.1. 
Time Windows  
SPID and TOTPAR analyses will be calculated using actual times.   
Unless otherwise described in the SAP no windowing will be performed for efficacy or safety 
endpoint summaries and data will be presented by nominal protocol timepoint. 
12.4.2. 
Data Censoring and Imputation 
For statistical purposes, pain assessments performed after any dose of rescue will be censored 
and imputed. The method of imputation will be described in the SAP, which will be finalized 
prior to unblinding of clinical trial subjects.  Details of the imputation methods for missing 
efficacy data will be described in the SAP.   Missing safety data will not be imputed. 
If a subject does not qualify for treatment failure, but prematurely discontinues from the study 
before 24 hours, then the subject will be censored at the time of discontinuation.  If a subject 
never qualifies as a treatment failure and completes the treatment phase of the study, then the 
subject will be considered censored at 24 hours. 
For the other time to event analyses (FPR-C, MPR) if a subject does not record 
perceptible/meaningful pain relief and prematurely discontinues from the study prior to 24 
hours, then the subject will be censored at 24 hours. If a subject does not record 
perceptible/meaningful pain relief prior to taking rescue medication, the subject will again be 
censored at 24 hours.   
12.5. 
Statistical Methods for Efficacy Evaluations 
The efficacy analyses will be based on the Evaluable  Population.  
The efficacy assessments are:  
• Numerical Pain Rating Scale Pain Intensity: (PI-NPRS) 
(0 = no pain and 10 = worst imaginable pain) 
• Pain Relief  (5-Point Categorical Pain Relief Assessment) 
• Stopwatches:  First Perceptible Relief and Meaningful Relief 
(FPR= First Perceptible Relief-, MPR = Meaningful Pain Relief and FPR-C = FPR 
that is confirmed by MPR) 
• Patient Global Evaluation (PGE):  
Poor (0) 
Fair (1)  Good (2)  
Very Good (3)  
Excellent (4) 
 
 


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Efficacy Parameters: 
• Time Weighted Sum of Pain Intensity Difference from 0 to 24 hours (SPID24) 
• Time Weighted Sum of Pain Relief from 0 to 24 hours (TOTPAR24) 
• Time to Perceptible Pain Relief Confirmed (FPR-C); 
• Time to Meaningful Pain Relief (MPR); 
• Cumulative proportion of patients with pain half gone over time; 
• Patient Global Evaluation of the study medication will be collected at Hour 24.25 or 
at the time of patient withdrawal (if applicable), whichever occurs first; 
• Pain Intensity Difference Rating (PID): scored on the 0-10 PI-NRS at each 
observation time after Dose 1 administration; 
• Pain Intensity Rating (PI): scored on the 0-10 PI-NRS at each observation time after 
Dose 1 administration; 
• Pain Relief Rating (PR): scored on a 5-Point Categorical Pain Relief Assessmentat 
each observation time after Dose 1 administration; 
• Time to treatment failure (i.e. time to first dose of rescue medication after Dose 1 or 
withdraw from the study due to lack of efficacy prior to rescue); 
• Cumulative % of patients with onset of First Perceptible Relief Confirmed;  
• Cumulative % of patients with Meaningful Pain Relief after Dose 1; 
• The cumulative proportion of treatment failures over time after Dose 1 
administration (failure defined as requiring rescue analgesic medication or withdraw 
from the study due to lack of efficacy); 
Sum of Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR) from  0 to 24 hours 
will be analyzed using an analysis of variance (ANOVA) model with treatment group as a fixed 
effect and baseline pain intensity as a covariate. Other covariates may be explored and the final 
model will be described in the Statistical Analysis Plan (SAP). Actual times will be used for 
calculating SPIDs and TOTPARs.  In addition, sensitivity analyses, that will be described in the 
statistical analysis plan (SAP), will be performed. 
Time to Perceptible Pain Confirmed (FPR-C, confirmed by achieving Meaningful Pain Relief), 
Time to Meaningful Pain Relief (MPR), and Time to Treatment Failure will each be analyzed 
using a log-rank test; the log rank test may be stratified by baseline pain intensity score 
(moderate / severe) or other variables as appropriate.  In addition, Kaplan-Meier curves will be 
presented by treatment group. 
The cumulative percentage of patients with pain at half gone over the 24-hour evaluation period 
will be summarized descriptively and plotted over time by treatment group. 


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The Patient Global Evaluation at 24 Hours or at patient withdrawal (if applicable), whichever is 
first, will be analyzed using an ANOVA model similar to that for the primary endpoint. 
Pain Intensity (PI), Pain Intensity Difference (PID), and Pain Relief (PR) Ratings at each 
observation time following Dose 1 administration will be summarized descriptively and plotted 
over time by treatment group. 
The cumulative percentages of patients with onset of FPR-C after Dose 1, MPR after Dose 1, 
and treatment failure after Dose 1 will each be summarized descriptively and plotted over time 
by treatment group.  
12.6. 
Multiple End Points and Multiple Comparisons  
There will be no corrections for multiple endpoints or comparisons. 
12.7. 
Safety Analysis 
The safety analyses will be based on the Safety Population. 
Adverse event (AE) analyses will include all AEs which initially occurred, or worsened 
following treatment (i.e., treatment emergentadverse events). TEAEs will be summarized by the 
MedDRA preferred term and by system organ class and classified according to their severity 
(mild, moderate, or severe) and relationship (“Associated” or “Not Associated”) to study 
medication. For the summary by severity, patients who have multiple occurrences of the same 
AE they will be classified according to the worst reported severity of the AE. Similarly, for the 
summary by relationship to the study medication, the patient will be classified according to the 
most related event.  
Tables of descriptive statistics and listings will be presented for the actual values and the 
changes from Baseline for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), 
Respiratory Rate (RR), Temperature, and Heart Rate (HR) at Baseline and at 4-hour intervals 
post surgically.  Liver function tests will be compared from baseline to post treatment.  Analysis 
of the incidence and severity of all adverse events will also be performed. 
13. 
STUDY ADMINISTRATION 
13.1. 
Investigator Study Binder 
An Investigator Study Binder must be maintained at the study site. Included in this binder will 
be tabbed sections for maintaining the following: study identification and study site staff 
signature list, monitoring visit record, protocol and amendments/administrative changes, 
curricula vitae, Institutional Review Board documentation, informed consent form, product 
receipt and accountability forms, correspondence, patient screening record, and master patient 


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log. This binder must be kept current and be available for review by representatives of the 
Sponsor and any official regulatory body. 
13.2. 
Patient Identification 
For purposes of confidentiality and to maintain anonymity, patients will be assigned 
identification numbers. Patients will be numbered sequentially as they enter the study. Once 
patients meet the entry criteria, they will be assigned a randomization number corresponding to 
study medication. Patients should be identified to the Sponsor only by their assigned number, 
initials and date of birth. The Principal Investigator or his designee will maintain a complete list 
of all patients enrolled in the study with their current mailing address on the master patient log. 
This list is necessary should contact of patients be required in the future. 
13.3. 
Case Report Forms 
Source Documents provided by CRU will be used to document all patient data and will be typed 
or printed legibly in black or blue ink. Data will be collected from the study site as eCRFs. Prior 
to submission to Nevakar, the Principal Investigator will review all eCRFs and sign where 
necessary. It is important that the eCRFs be completed in a timely manner for each patient 
evaluation in order that the progress and results of the study may be closely followed by the 
Sponsor. Corrections to eCRFs must not obscure the original entry; a single line through the 
original entry is sufficient. All corrections must be initialed and dated by the responsible 
individual. 
eCRFs are to be completed and held for retrieval by a representative of the Sponsor (monitor), 
unless otherwise directed. All study records must be retained in accordance with Section 13.10. 
A study site may use forms of their own design, following approval of the form by Nevakar, as 
source documents only. 
13.4. 
Monitoring of Study 
The study will be monitored by representatives of the Sponsor. On-site visits will be made 
before the study begins, at regular intervals during the conduct of the study, and at the 
completion of the study. Communication by telephone, mail, and facsimile may also be used to 
supplement on-site visits. 
The Monitor of the Sponsor will inspect all source documents and eCRFs and corresponding 
portions of the patient's original office and/or hospital records. These inspections are for the 
purpose of verifying adherence to the protocol and determining the completeness and exactness 
of the data entered on the eCRF and study medication log. 
As a part of monitoring and inspection of this study, the Principal Investigator agrees that Nevakar, 
its employees or representatives, Institutional Review Board, as well as representatives of the FDA 
will have the right to inspect and review pertinent medical records relating to this trial. In addition, 


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informed consent documents signed by study participants will indicate approval to release their 
medical records for review while maintaining their confidentiality.  
13.5. 
Protocol Modifications and Deviations 
As the study progresses, any necessary additions or changes to the protocol will be decided by 
mutual agreement of the Principal Investigator and the CRO Medical Monitor. An amendment to 
this effect will be submitted first to Nevakar for review and approval and then to the Institutional 
Review Board for review and approval prior to implementation. If the protocol change impacts 
the conduct of the study, the informed consent form will be amended, as appropriate. A protocol 
change to eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the reviewing Institutional Review Board is notified in accordance with 21 CFR 
56.104(c). Otherwise, no deviations will be permitted. Approved amendments will become part of 
the protocol and will be reported to the appropriate regulatory authority prior to implementation.  
All protocol deviations will be documented in the eCRFs and reported to the CRO Medical 
Monitor and Sponsor. 
13.6. 
Discontinuation of Study by Sponsor or Principal Investigator 
Nevakar reserves the right to discontinue the study for administrative reasons at any time. All 
CRFs will then be returned to the Sponsor and study medications properly disposed of. 
If the Principal Investigator discontinues the study prematurely, the Principal Investigator will 
return all study treatment and eCRFs to the Sponsor and provide a written explanation as to why 
the study was ended. 
13.7. 
Disclosure of Data/Publications 
All information obtained during the conduct of the study will be regarded as confidential. Written 
agreement from Nevakar must be obtained prior to disclosing any information relative to the study. 
Upon completion of the study, Nevakar may decide to publish the results with the Principal 
Investigator in a recognized scientific journal and/or present the results (as a poster or oral 
presentation) at a meeting of a recognized scientific association. In order to safeguard against 
disclosure of confidential information, however, Nevakar requires that it has the right to review 
any manuscript and/or abstract prior to submission. A draft manuscript must be reviewed by 
Nevakar 60 days prior to submission of the final version to the journal. Abstracts of 
presentations must be reviewed by Nevakar 15 days prior to submission. Nevakar assures the 
Principal Investigator that all manuscripts and abstracts will be reviewed promptly.  
13.8. 
Informed Consent 
Regulations require that written informed consent and/or assent must be obtained for each 
patient prior to entry into the study. Informed consent means the knowing consent of an 


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individual, so situated so as to exercise free power of choice without undue inducement or 
constraint or coercion. The informed consent form will include all elements required by the 
FDA. A copy of the consent form will be provided to the patient. For 17-year-old patient, both 
the patient and either a parent or legal guardian also must provide written assent. 
The Investigator will provide Nevakar with a copy of the consent form as approved by the 
Institutional Review Board used by the study site. 
The Principal Investigator will ensure that this study is in full conformance with the principles 
of the Declaration of Helsinki as well as GCP and ICH guidelines.  
13.9. 
Institutional Review Board 
Prior to initiating the study, the protocol and amendments, informed consent form, any 
advertisement, Principal Investigator’s and sub-investigators’ curriculum vitae, medical license, 
financial disclosure forms, questionnaires and investigational product brochure must be 
reviewed and approved by a properly constituted Institutional Review Board as required by the 
FDA and the International Conference on Harmonization Guidelines.  
The Principal Investigator must certify to Nevakar that the Institutional Review Board meets all 
the legal requirements as specified by the FDA. The Institutional Review Board must provide a 
signed and dated statement that the protocol, informed consent form, and other pertinent 
documents, such as recruitment advertisements (in any medium) have been approved by the 
Committee. If the study continues longer than one year, re-approval must be obtained from the 
Institutional Review Board on an annual basis. The Institutional Review Board must be 
informed of any changes in research activity including amendments to the protocol and/or 
informed consent form, advertisements, and serious adverse events. 
At the conclusion of the study, the Principal Investigator must submit a summary of the study to 
the Institutional Review Board with a copy forwarded to Nevakar no later than 60 days after the 
study closeout visit. 
13.10. 
Retention of Records 
The Principal Investigator /JBR Clinical Research shall retain the Study Records for the longer 
of:  
1. two (2) years after the FDA approves the New Drug Application (NDA) or Premarket 
Approval Application (PMA) for the Investigational Product; or 
2. two (2) years following the termination or withdrawal of the Investigational New Drug 
(IND) application or Investigational Device Exemption (IDE) application under which 
the Study was conducted; or 
3. the period required by federal laws and regulations.  


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The Sponsor shall reimburse the Principal Investigator /JBR Clinical Research for any expense 
the Principal Investigator /JBR Clinical Research incurs in retaining the Study Records beyond 
the first five (5) years after the end of the Study at JBR Clinical Research. After the required 
retention period, the Principal Investigator /JBR Clinical Research shall provide the Sponsor sixty 
(60) days’ written notice before destroying any Study Records. 
If at any time the Principal Investigator /JBR Clinical Research is no longer able to maintain the 
required study records, or if the Principal Investigator relocates or delegates custody of the 
records to another party, Nevakar must be notified in writing as soon as possible. In any case, 
Nevakar retains the right to reclaim all study records. If Nevakar reclaims the study records, the 
master patient log, which contains confidential information identifying and how to contact the 
study patients, will be provided to Nevakar in a sealed envelope labeled “confidential”. 
The Principal Investigator assumes the responsibility of retaining the following records: 
a. Signed and dated protocol and amendments, written authorization to allow enrollment 
of potentially ineligible patients or otherwise amend the protocol; 
b. Curriculum vitae of the Principal Investigator and sub-investigators; 
c. Investigational Product Brochure or full prescribing information, instructions to 
Principal Investigator, or other information provided by Nevakar for conducting the 
clinical study; 
d. Records of receipt and disposition of all product supplies, including: 
− Dates and amounts of product received from Nevakar 
− Lot numbers or other identification 
− Dates and quantity dispensed and returned for each patient 
− Dates and amounts of product returned to Nevakar 
(For this study, the study medications will be supplied by the study site using a 
local retail pharmacy.) 
e. Institutional Review Board approval, correspondence, interim reports, and final study 
summary; 
f. Documented informed consent for each patient; 
g. Completed eCRFs and diaries (if applicable) for each patient including all source 
documents from which the eCRFs were prepared; 
h. Patient screening record indicating disposition of each patient and reason for exclusion 
when appropriate; 
i. Master patient log indicating all patients enrolled in the study with their current 
mailing address; 


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j. Detailed medical histories for each patient containing medical history prior to 
enrollment with basic identifying information linking records to eCRFs, results of all 
diagnoses made, therapy provided, any other data on patient's physical state; 
k. Medical history during the study including documentation of enrollment, concomitant 
or concurrently administered therapy, observations on patient's condition during the 
study, any factors that might alter the effects of the test product, adverse event or 
laboratory abnormality reports and follow-up where appropriate; 
l. Copies of tests and/or examinations results required by the protocol, including 
laboratory normal values and accreditation, if applicable; 
m. Copies of interim and final reports issued to the Institutional Review Board or 
Nevakar; 
n. Documentation of contacts between Nevakar and the Principal Investigator and/or 
other study site personnel, including all correspondence; 
o. Copies of any reports on serious adverse events, death, or life-threatening symptoms; 
p. Roster of all study personnel with their signatures and signed initials; 
q. Monitoring visit record. 
13.11. 
Responsibilities of Principal Investigator 
In agreeing to conduct this study, the Principal Investigator assumes certain responsibilities 
mandated by FDA regulations: an Investigator is responsible for ensuring that an investigation 
is conducted according to the signed investigator statement, the investigational plan as defined 
by the protocol, and applicable regulations; for protecting the rights, safety, and welfare of 
patients under the Investigator's care; and for the control of the products under investigation. An 
Investigator will, in accordance with the appropriate regulations, obtain the informed consent of 
each human patient to whom the study medication is administered. The Investigator will retain 
all study documents as stipulated in Section 13.10. The Investigator certifies that he/she has not 
been disbarred by any regulatory agency from conducting clinical trials. The Investigator will 
comply with the requirements outlined in the CFR final ruling, Financial Disclosure by Clinical 
Investigators, effective February 2, 1999. 
13.12. 
Filing of Protocol with FDA 
This protocol, any amendments made to it, and data from this study will be submitted to the U.S. 
FDA. 






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APPENDIX 1. IMPACTION DIFFICULTY RATING SCALE 
 
The Impaction Difficulty Rating Score (IDRS) will be used to assess the projected surgical 
trauma for each impacted mandibular third molar. The oral surgeon will base the difficulty 
assessment on the radiographic appearance and the intraoral examination. Each mandibular 
molar will be rated from 1 to 5 using the following criteria: 
1= Erupted in tissue 
2= Soft tissue impaction 
3= Mild partial bony impaction  
(>30% erupted through the alveolar bone),  
4= Moderate to severe partial bony 
(at least 70% impacted in the alveolar bone) 
5= Full bony impaction  
(no penetration of the bone into the soft tissue).  
Only patients whose mandibular impactions are scored a “4” or “5” will be eligible to 
participate in the study. In addition, if during the surgical procedure extreme trauma or 
surgical complications arise, then that patient will not be continued in the study. 


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APPENDIX 2. URINE DRUG SCREEN 
 
 
 


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APPENDIX 3. PAIN SCALES 
CATEGORICAL PAIN INTENSITY 
 
None 
(0) 
 
Mild 
(1) 
 
Moderate 
(2) 
 
Severe 
(3) 
 
 
ASSESSMENT OF PAIN INTENSITY- 11-POINT NUMERICAL PAIN RATING SCALE (NPRS) 
On a scale of 0-10, please rate your pain by marking an ‘X” in the appropriate box that best 
describes your pain NOW. 
  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
worst  
pain 
imaginable 
 
5-POINT CATEGORICAL PAIN RELIEF ASSESSMENT (PR) 
 
Finish the statement by checking the appropriate box. “My pain relief at this time is:”  
 No Pain Relief        
 A Little Pain Relief    
 Some Pain Relief        
 A Lot of Pain Relief 
 Complete Pain Relief 
 


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TIME TO PAIN RELIEF 
 
Time to perceptible pain relief and time to meaningful pain relief will be collected using the double-
stopwatch methodology as follows: For each randomized subject, two stopwatches will be started 
immediately upon initiation of the first study dose 
 The first stopwatch will be given to each 
subject with the instructions to stop the watch when they first perceive pain relief to occur (time to 
perceptible relief). Once the first stopwatch is stopped, the second stopwatch will be given to the 
subject with the instruction to stop the watch when they are first experiencing meaningful pain 
relief (time to meaningful relief). Time to perceptible pain relief is confirmed only if the subject 
experiences meaningful relief. 
If a subject requires a rescue analgesic after Dose 1, the time of rescue as well as PI and PR 
assessments will be collected at that time and collection of stopwatch data will cease. 
 
5-POINT PATIENT GLOBAL ASSESSMENT (PGA) OF PAIN CONTROL 
 
The following question will be answered by the subject at hour 24.25 or at the time of subject 
withdrawal (if applicable), whichever occurs first: 
 
“Overall, please rate how well your pain has been controlled since you received study 
medication?” 
  Poor (0) 
  Fair (1) 
  Good (2) 
  Very Good (3) 
  Excellent (4) 


 
 
 
 
 
 
Statistical Analysis Plan 
 
A Randomized, Double-Blind, Multi-Dose, Single-Site, Placebo- and 
Active-Controlled, Efficacy, Tolerability, Safety and Pharmacokinetic 
Study of Two Different Dosing Regimens of Acetaminophen 
 
in Post-Surgical Dental Pain. 
Version 1.0; Dated: 09-AUG-2019 
Protocol number: CP-NVK009-0002 
Sponsor: Nevakar, Inc. NJ 08807 


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STATISTICAL ANALYSIS PLAN 
PHASE II 
 
VERSION: 1.0 
DATE OF PLAN: 
09-AUG-2019 
 
BASED ON: 
Protocol Version 3.0 Amendment 3 15APR2019 and CRF v3.0 22-MAY-2019 
 
STUDY DRUG: 
 acetaminophen 
 OR 
 acetaminophen 
 
  
PROTOCOL NUMBER: 
CP-NVK009-0002 
STUDY TITLE: 
A Randomized, Double-Blind, Multi-Dose, Single-Site, Placebo- and Active-Controlled, 
Efficacy, Tolerability, Safety and Pharmacokinetic Study of Two Different Dosing Regimens of 
Acetaminophen 
 in Post-Surgical Dental Pain. 
 
SPONSOR: 
Nevakar, Inc. 
 
 NJ  08807 
 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 


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APPROVALS 
 
 
 
 
 
  
 
Date: 
 
 
 
 
 
 
 
  
 
Date: 
 
 
 
 
 
Nevakar, Inc. 
 
 
 
Date: 


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TECHNICAL SUMMARY REPORT (TSR) 
Name of Sponsor/Company 
 
Nevakar, Inc. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
 acetaminophen 
 OR  
 
acetaminophen 
  
  
Page: 
 
Name of Active Ingredient: 
Acetaminophen 
 
 
Title of Study: 
A Randomized, Double-Blind, Multi-Dose, Single-Site, Placebo- and Active-Controlled, Efficacy, 
Tolerability, Safety and Pharmacokinetic Study of Two Different Dosing Regimens of Acetaminophen 
 in Post-Surgical Dental Pain. 
Investigators: 
Study Center(s): Single-Site (JBR Clinical Research) 
Studied period (years): 
Study is expected be completed 
within 4 months of the first 
patient entry. 
Phase of development:  
II 
Objectives: 
The objective of this study is to assess the safety, tolerability, analgesic efficacy, and pharmacokinetics 
of acetaminophen 
 dosed 
 (
 APAP) every eight hours (q8h) relative to placebo 
and of acetaminophen 
 dosed 
 every six hours (q6h) relative to placebo over a 
24-hour period in participants experiencing moderate to severe pain following surgical third molar 
removal. 


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Methodology: 
This will be a randomized, double-blind, single-site, placebo-controlled, parallel-group study 
to assess similarities in safety, tolerability, efficacy, and pharmacokinetics of 
 of 
 acetaminophen given in three doses, each 8 hours apart, relative to placebo, and 
 of 
 acetaminophen given in four doses, each 6 hours apart, relative to 
placebo over a 24-hour period in patients experiencing moderate to severe postsurgical pain 
within 7 hours following surgical removal of 2 or more molars.  
To maintain the double-blind conditions, patients will be receiving either a placebo (
 
 that looks like study drug) or the active study medication every 2 hours (+ 10 minutes) 
 over the first 18 hours after Dose 1.  
Patients who meet the randomization criteria (post-surgical pain of moderate to severe on the 
4-point Categorical Pain Intensity scale, and at least a score of 5 on the 11-point [0-10] pain 
intensity numerical pain rating scale [PI-NPRS] at baseline within 7 hours of last stitch from 
dental extractions) will be randomly assigned to one of three treatment groups.  
Approximately 110 patients will be randomized to receive either 
 APAP 
 three 
doses, each in 
 of total volume, 8 hours apart OR 
 APAP 
 four doses, each 
in 
 of total volume, 6 hours apart OR placebo, 
 total volume of normal 
 in 
a 2:2:1 allocation ratio. No less than approximately 30% of randomized patients will be either 
male or female.  In addition, no more than approximately 30% of patients will be 17 years of 
age at the time of screening. 
Number of Subjects (planned and analyzed): 
110 (44 subjects per active group and 22 subjects in the placebo group) 
Diagnosis and main criteria for inclusion: 
Male and female patients between 17-55 years of age will undergo surgical removal of at least two 
third molars. Maxillary third molars may be removed regardless of impaction level. The mandibular 
extractions must meet one of the following scenarios and must not result in a trauma rating of severe on 
the 4-point scale of mild, moderate, moderately severe, or severe:  
Two full bony impactions  
 
 
Patients must have body weight of >50 kg
2, not have infections 
in the area of the impacted teeth, and must meet the randomization criteria (post-surgical pain of 
moderate to severe on the 4-point Categorical Pain Intensity scale, and at least a score of 5 on the 11-
point [0-10] pain intensity numerical pain rating scale [PINPRS] at baseline within 7 hours of last 
stitch from dental extractions). 
Test product, dose and mode of administration: 
Acetaminophen 
 dosed 
 (
 APAP) every eight hours (q8h) OR  
Acetaminophen 
 dosed 
 (
 APAP) every six hours (q6h)  


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Duration of treatment: 
The study will consist of a screening period of up to 30 days (Day -30 to 0), day of surgery (Day 1), 
Day of discharge (Post-Op Day 2) and follow-up telephone call (Day 7 ±2 days). Duration of treatment 
is 24 hours. 
Reference therapy, dose and mode of administration: 
 Placebo 
Criteria for evaluation (see protocol section 7.2): 
Efficacy:  
Time Weighted Sum of Pain Intensity Difference from 0 to 24 hours (SPID24)  
 
e Pain Relief Confirmed (FPR-C)   
 
 
patient withdrawal (if applicable), whichever occurs first  
-10 PI-NRS at each observation time after 
Dose 1 administration  
-10 PI-NRS at each observation time after Dose 1 
administration  
-Point Categorical Pain Relief Assessment at each observation 
time after Dose 1 administration  
the study due to lack of efficacy prior to rescue)  
 
 
dministration (failure defined 
as requiring rescue analgesic medication or withdraw from the study due to lack of efficacy). 
 
Safety: Adverse events and vital signs. 


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Statistical methods: The null for this study is that 
 acetaminophen 
 dosed three 
times daily and 
 acetaminophen 
 dosed four times daily have similar safety, 
tolerability, and efficacy profiles when compared to placebo. 
 
Since this is a proof-of-concept study, statistically significant treatment differences will be declared if p 
-sided), and no adjustments for multiple comparisons/end points will be performed.  All 
confidence intervals will be one-sided 90% confidence intervals. 
An analysis of covariance (ANCOVA) model with treatment group as a fixed effect and baseline PI-
NPRS as a covariate will be used to compare the two active treatments to the placebo group with 
respect to Time-weighted Sum of Pain Intensity Difference from 0 to 24 hours (SPID24), Time-
weighted Total Pain Relief from 0 to 24 hours (TOTPAR24), and Patient Global Evaluation at 24 
Hours. The log rank test with Kaplan-Meier curves will be used to analyze and present time to event 
data by treatment group (FPR-C, MPR, and Time to Treatment Failure). Descriptive summaries and 
listings will be used for other efficacy and safety data. The two analysis populations that are specified 
in this study are:  
a) Safety Population, which will include all randomized patients who received the study medication. 
This population will be used for all safety summaries.  
b) Evaluable Population, which will include all randomized patients who, as documented prior to the 
breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered 
Dose 1. The efficacy analyses will be performed using this population. 
c) PK Evaluable Population, which will include all randomized subject who, as documented prior to 
the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were 
administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate 
pharmacokinetic parameters. 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.....................................................................................12 
2. 
INTRODUCTION ......................................................................................................14 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................16 
3.1. 
Study Objectives .........................................................................................................16 
3.2. 
Study Endpoints ..........................................................................................................16 
3.2.1. 
Efficacy Endpoints ......................................................................................................16 
4. 
STUDY DESIGN .......................................................................................................17 
4.1. 
Summary of Study Design ..........................................................................................17 
4.2. 
Definition of Study Drugs ..........................................................................................17 
4.3. 
Sample Size Considerations .......................................................................................17 
4.3.1. 
Sample Size Justifications ..........................................................................................17 
4.3.2. 
Sample Size Re-estimation .........................................................................................18 
4.4. 
Randomization ............................................................................................................18 
4.5. 
Clinical Assessments ..................................................................................................18 
4.5.1. 
Demographics and Baseline Characteristics ...............................................................18 
4.5.2. 
Medical/Surgical History ............................................................................................18 
4.5.3. 
Physical Examination .................................................................................................18 
4.5.4. 
Vital Signs ..................................................................................................................18 
4.5.5. 
Urine drug screen ........................................................................................................18 
4.5.6. 
Patient Assessment Training.......................................................................................18 
4.5.7. 
Qualifying 4-Point Categorical PI and 11-point PI-NPRS at Baseline ......................19 
4.5.8. 
11-Point Pain Intensity (PI-NPRS) .............................................................................19 
4.5.9. 
Pain Relief (PR) ..........................................................................................................19 
4.5.10. 
Perceptible & Meaningful Stopwatches 1 & 2 after Dose 1 .......................................19 
4.5.11. 
Patient Global Evaluation ...........................................................................................19 
4.5.12. 
Pregnancy test for females ..........................................................................................19 
4.5.13. 
Serology and liver function tests ................................................................................19 
4.5.14. 
Prior and Concomitant Medications ...........................................................................20 
4.5.15. 
Rescue Medication ......................................................................................................20 
4.5.16. 
Non-Medication Therapies .........................................................................................20 


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4.5.17. 
Adverse Events monitoring ........................................................................................20 
4.5.18. 
Pharmacokinetic (PK) Assessment .............................................................................20 
5. 
PLANNED ANALYSES ............................................................................................22 
5.1. 
Interim Analyses .........................................................................................................22 
5.2. 
Final Analyses ............................................................................................................22 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................23 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........23 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................23 
6.3. 
Data Management .......................................................................................................24 
6.4. 
Data Presentation Conventions ...................................................................................24 
6.5. 
Analysis Populations ..................................................................................................25 
6.5.1. 
Safety Population ........................................................................................................25 
6.5.2. 
Evaluable Population ..................................................................................................25 
6.5.3. 
PK Evaluable Population ............................................................................................25 
6.6. 
Baseline Definition .....................................................................................................25 
6.7. 
Derived and Transformed Data ..................................................................................25 
6.7.1. 
Baseline Age ...............................................................................................................25 
6.7.2. 
Study Day ...................................................................................................................26 
6.7.3. 
Change from Baseline .................................................................................................26 
6.7.4. 
Visit Windows ............................................................................................................26 
6.7.5. 
Multiple Assessments and Uninterpretable values .....................................................26 
6.8. 
Handling of Missing Data ...........................................................................................26 
6.8.1. 
Missing Efficacy Endpoints ........................................................................................26 
6.8.2. 
Missing Start and Stop Dates for Adverse Events ......................................................27 
6.8.3. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................28 
7. 
STUDY POPULATION .............................................................................................29 
7.1. 
Subjects Disposition ...................................................................................................29 
7.2. 
Protocol Deviations ....................................................................................................29 
7.3. 
Demographic and Baseline Characteristics ................................................................29 
7.4. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................29 


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7.5. 
Medical History and Medical Conditions Present at Entry ........................................29 
7.6. 
Prior Medication History and Medications Present at Entry ......................................29 
8. 
EFFICACY .................................................................................................................30 
8.1. 
Statement of the Hypothesis .......................................................................................30 
8.2. 
Subgroup Analyses .....................................................................................................30 
8.3. 
Multiple Comparisons and Multiplicity......................................................................30 
8.4. 
Analysis of the Efficacy Endpoints ............................................................................30 
8.4.1. 
Time Weighted Sum of Pain Intensity Difference from 0 to 24 hours 
(SPID24) .....................................................................................................................30 
8.4.2. 
Time Weighted Sum of Pain Relief from 0 to 24 hours (TOTPAR24) ......................31 
8.4.3. 
Time to Perceptible Pain Relief Confirmed (FPR-C) and Cumulative % of 
patients with onset of First Perceptible Relief Confirmed after Dose 1 
administration .............................................................................................................31 
8.4.4. 
Time to Meaningful Pain Relief (MPR) and Cumulative % of patients with 
onset of Meaningful Pain Relief after Dose 1 administration ....................................31 
8.4.5. 
Cumulative proportion of patients with pain half gone over time ..............................32 
8.4.6. 
Patient Global Evaluation of the study medication ....................................................32 
8.4.7. 
Pain Intensity Difference (PID) Rating at each observation time after Dose 1 
administration .............................................................................................................32 
8.4.8. 
Pain Intensity (PI) Ratings at each observation time after Dose 1 
administration .............................................................................................................32 
8.4.9. 
Pain Relief (PR) Ratings at each observation time after Dose 1 
administration .............................................................................................................32 
8.4.10. 
Time to treatment failure and Cumulative % of patients with treatment 
failure ..........................................................................................................................33 
8.4.11. 
Sensitivity Analyses of the Primary Efficacy Results ................................................33 
9. 
SAFETY AND TOLERABILITY ..............................................................................34 
9.1. 
Overall Summary of Tolerability ................................................................................34 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............34 
9.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects.................................34 
9.2.2. 
Missing and Partial AE Onset Dates ..........................................................................35 
9.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................35 
9.4. 
Concomitant and Other Medications ..........................................................................35 


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9.4.1. 
All medications and non-medical therapies captured in CRFs will appear in 
data listings. ................................................................................................................35 
9.5. 
Rescue Medications, and Compliance for Pre-Rescue NRS and Pain Relief .............35 
9.6. 
Routine Clinical Laboratory Data ...............................................................................35 
9.7. 
Vital Signs ..................................................................................................................35 
9.8. 
Physical Examination .................................................................................................36 
9.9. 
Study Termination Status ...........................................................................................36 
10. 
PHAMACOKINETIC EVALUATION .....................................................................37 
10.1. 
Pharmacokinetic Objectives .......................................................................................37 
10.2. 
Pharmacokinetic Sample Analysis and Modeling Process .........................................37 
10.3. 
Summary of Pharmacokinetic Concentrations ...........................................................38 
10.4. 
Statistical Analysis of Pharmacokinetic Parameters ...................................................39 
10.4.1. 
Differences in Daily Drug Exposure by Dose Regimen .............................................39 
10.4.2. 
Differences in Pharmacokinetics by Dose Regimen ..................................................39 
10.4.3. 
Drug Accumulation by Dose ......................................................................................39 
10.4.4. 
Steady State by Dose ..................................................................................................39 
11. 
REFERENCES ...........................................................................................................41 
12. 
APPENDIX.................................................................................................................42 
12.1. 
Table of Contents for Data Display Specifications ....................................................42 
12.2. 
7th wave 17-RS-610CL PKAP ...................................................................................46 
 


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LIST OF TABLES 
Table 1: List of A
 
Table 2: V
 
Table 3: T
 
 


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1. 
LIST OF ABBREVIATIONS 
 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report 
DOB 
Date of Birth 
DBP  
Diastolic Blood Pressure  
dy 
Days 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FPR 
First Perceptible Relief 
FPRC 
First Perceptible Relief Confirmed 
GCP 
Good Clinical Practices 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
 
 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
mg and mg/d 
Milligrams and milligrams per day 
MPR 
Meaningful Pain Relief 
mL 
Milliliter 
mo 
Months 


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N 
Total Sample Size 
NPRS 
Numerical Pain Relief Scale 
NRS 
Numerical Rating Scale 
PBO 
Placebo 
PI 
Pain Intensity 
PID 
Pain Intensity Difference 
PK 
Pharmacokinetics 
PR 
Pain Relief 
RR 
Respiratory Rate 
S 
Sex 
s.d. 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SBP 
Systolic Blood Pressure 
SOC 
System Organs Class 
SPI 
Time Weighted Sum Pain Intensity 
SPID 
Time Weighted Sum Pain Intensity Difference 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment Emergent Adverse Events 
TG 
Treatment Group 
TLFs 
Tables, Listings, and Figures 
TOTPAR 
Time Weighted Total Pain Relief 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization  
wLOCF 
windowed Last pain score Carried Forward 
yr 
Years 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol CP-NVK009-0002. 
Revisions to the protocol are shown below. 
 
Protocol Revision Chronology: 
Protocol 
15-JAN-2019 
Original 
Amendment 1 
06-MAR-2019 
Amendment No. 1: The key purposes of this 
amendment are to: 
1) Decrease the number of participants from 140 
to 110 with a 2:2:1 randomization schedule  
2) Clarification that patients who receive rescue 
medication will have data censored but pain data 
will still be collected 
3) Change to SPID and TOPTPAR over a 24-
hour period, clarification that Pain Relief will be 
a 5-Point Categorical Pain Relief Assessment 
4) Provided further justification for sample size 
determination 
5) Provided further detail on planned statistical 
methods and analysis  
Amendment 2 
25-MAR-2019 
Amendment No. 2: The key purposes of this 
amendment are to: 
1) Corrected the type of vacutainer PK samples 
collected in from K2EDTA to K3EDTA tube 
2) Updated dosing time points to reflect a 
window of dosing of ± 10 minutes. 
Amendment 3 
15-APR-2019 
Amendment No. 3: The key purposes of this 
amendment are to: 
1) Added hematology safety labs to meet 
exclusion criteria 1 
2) Administrative Clarification +/- specific added 
to all PK time points and removal of PK Time 
Point 0. Total PK samples from 19 to 18 
3) Administrative clarification around vital sign 
time points to ensure these completed at 
screening, prior to surgery and every 4 hours post 
1st Dose. 
4) Clarified Whole Blood to Exclusion Criterion 
#9 
5) Added +10 min window timepoint for PGE 
Assessment at 24.25 


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This SAP was developed in accordance with ICH E9 guideline. All decisions regarding final 
analysis, as defined in this SAP document, will be made prior to Database Freeze / unblinding of 
the study data. Further information can be found in the protocol. 
The SAP is based on Protocol No. CP-NVK009-0002, Amendment 3, dated April 15, 2019 and 
ICH guidelines E4 and E9 (Statistical Principles for Clinical Trials)  
The purpose of this document is to provide details on study populations and on how the variables 
will be derived, how missing data will be handled as well as details on statistical methods to be 
used to analyze the safety and efficacy data for Study Protocol No. CP-NVK009-0002. 
The document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests.  However, the final SAP must be finalized, approved by the 
Sponsor, and placed on file before database is locked.  Deviations from the final approved plan 
will be noted in the CSR. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
The objective of this study is to assess the safety, tolerability, analgesic efficacy, and 
pharmacokinetics of acetaminophen 
 dosed 
 (
 APAP) every eight hours 
(q8h) relative to placebo and of acetaminophen 
 dosed 
 every six hours 
(q6h) relative to placebo over a 24-hour period in participants experiencing moderate to severe 
pain following surgical third molar removal. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
Time Weighted Sum of Pain Intensity Difference from 0 to 24 hours (SPID24) 
Time Weighted Sum of Pain Relief from 0 to 24 hours (TOTPAR24) 
Time to Perceptible Pain Relief Confirmed (FPR-C)  
Time to Meaningful Pain Relief (MPR) 
Cumulative proportion of patients with pain half gone over time 
Patient Global Evaluation of the study medication will be collected at Hour 24.25, or at 
the time of patient withdrawal (if applicable), whichever occurs first 
Pain Intensity Difference Rating (PID): scored on the 0-10 PI-NRS at each observation 
time after Dose 1 administration 
Pain Intensity Rating (PI): scored on the 0-10 PI-NRS at each observation time after Dose 
1 administration 
Pain Relief Rating (PR): scored on a 5-Point Categorical Pain Relief Assessment at each 
observation time after Dose 1 administration 
Time to treatment failure (i.e. time to first dose of rescue medication after Dose 1 or 
withdraw from the study due to lack of efficacy prior to rescue) 
Cumulative % of patients with onset of First Perceptible Relief Confirmed 
Cumulative % of patients with Meaningful Pain Relief after Dose 1 
The cumulative proportion of treatment failures over time after Dose 1 administration 
(failure defined as requiring rescue analgesic medication or withdraw from the study due 
to lack of efficacy). 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This will be a randomized, double-blind, single-site, placebo-controlled, parallel-group study to 
assess similarities in safety, tolerability, efficacy, and pharmacokinetics of 
 of 
 
acetaminophen given in three doses, each 8 hours apart, relative to placebo, and 
 of 
 acetaminophen given in four doses, each 6 hours apart, relative to placebo over a 24-
hour period in patients experiencing moderate to severe postsurgical pain within 7 hours 
following surgical removal of 2 or more  molars.  
To maintain the double-blind conditions, patients will be receiving either a placebo (
 
that looks like study drug) or the active study medication every 2 hours (± 10 minutes) (infused 
 over the first 18 hours after Dose 1.  
Patients who meet the randomization criteria (post-surgical pain of moderate to severe on the 4-
point Categorical Pain Intensity scale, and at least a score of 5 on the 11-point [0-10] pain 
intensity numerical pain rating scale [PI-NPRS] at baseline within 7 hours of last stitch from 
dental extractions) will be randomly assigned to one of three treatment groups.  
Approximately 110 patients will be randomized to receive either 
 APAP 
 three doses, 
each in 
 of total volume, 8 hours apart OR 
 APAP 
 four doses, each in 
 
of total volume, 6 hours apart OR placebo, 
 total volume of normal 
 in a 2:2:1 
allocation ratio. No less than approximately 30% of randomized patients will be either male or 
female.  In addition, no more than approximately 30% of patients will be 17 years of age at the 
time of screening. 
4.2. 
Definition of Study Drugs 
The Study Drugs consist of either  
 APAP 
 three doses, each in 
 of total volume, 8 hours apart OR 
 APAP 
 four doses, each in 
 of total volume, 6 hours apart OR  
Placebo, 
 total volume of normal 
 
4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
The sample size was determined from past experience with the Dental Impaction Pain Model 
(DIPM) and analysis of the results from a previous Phase 2 study comparing the safety and 
efficacy of 
 APAP in combination with 
 pregabalin (Nevakar Protocol CP-NVK-009-
0001). SPID 24 data for 
 APAP in that study suggested that a sample size of 44 patients per 
active group and 22 patients in the placebo group should be adequate to evaluate similarities 
between the two active dose regimens vs placebo. 


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4.3.2. 
Sample Size Re-estimation 
Sample size re-estimation is not planned for the study. 
4.4. 
Randomization 
Treatment assignments will be determined by a computer-generated randomization schedule 
created by the Biostatistics Group.  
The non-stratified randomization schedule with block size of 5 will randomly assign one of the 
three treatments to the patients. The randomization numbers will be assigned to each patient in a 
sequential order as they qualify. The randomization number assigned to the patient will be 
recorded in the Case Report Form (eCRF). 
4.5. 
Clinical Assessments 
4.5.1. 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity. Baseline characteristics include 
height (cm), weight (kg), and body mass index (BMI; kg/m2). These are obtained at the screening 
visit. Prior to initiation of Dose 1, baseline pain scores on the 4-point categorical pain intensity 
scale and PI-NPRS are also assessed. 
4.5.2. 
Medical/Surgical History 
Medical and Surgical history, as collected at screening and prior to surgery, will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 to determine system 
organ class (SOC) and preferred term (PT).  
4.5.3. 
Physical Examination  
A complete physical examination including all major body systems will be performed at the 
Screening visit.  Abnormal or clinically significant physical exam findings will be recorded as 
AEs.  
4.5.4. 
Vital Signs 
Vital signs results including blood pressure (systolic and diastolic; mmHg), heart rate (beats per 
minute), respiration rate (breaths/min), and temperature in supine or reclining position are 
obtained at Screening, prior to surgery, and at Hours 4, 8, 12, 16, 20, and 24 following T0 (±10 
min).  
Baseline for vital signs measurements will be defined as the last evaluation before dosing with 
study medication.  
4.5.5. 
Urine drug screen 
Urine drug test is performed at Screening and Day 1 prior to surgery. Each test result will be 
defined to be 
 


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4.5.6. 
Patient Assessment Training 
Pain assessment training video and post-video test are completed at screening. Video pain 
assessment training only is completed prior to surgery. 
4.5.7. 
Qualifying 4-Point Categorical PI and 11-point PI-NPRS at Baseline 
This assessment will be done after surgery. Dose 1 will be given only when subjects report at 
least moderate pain on the 4-point categorical pain intensity scale of none (0), mild (1), moderate 
-10 PI-NPRS. This will be the baseline assessment 
for the 4-Point Categorical PI and 11-point PI-NPRS. 
4.5.8. 
11-Point Pain Intensity (PI-NPRS)  
Follow-up pain intensity (PI) measurements will be taken at the following times after initiation 
of Dose 1 (T0):  0.5, 0.75, 1, 1.25, 1.75, 2.25, 3.25, 4.25, 5.25,  6.25, 7.25, 8.25, 9.25, 10.25, 
11.25 and 12.25 Hours (±5 min), then at 14.25, 16.25, 18.25, 20.25, 22.25 and 24.25 Hours (±10 
min). 
4.5.9. 
Pain Relief (PR)  
Pain Relief (PR) will be measured using a 5-point categorical scale (0=No Pain Relief, 1=A 
Little Pain Relief, 2=Some Pain Relief, 3=A Lot of Pain Relief, 4=Complete Pain Relief) 
4.5.10. 
Perceptible & Meaningful Stopwatches 1 & 2 after Dose 1 
Upon initiation of the 
 of Dose 1, two stopwatches will be started.  The subjects will first 
be given stopwatch #1 and asked to press the stopwatch if and when they first perceive any pain 
relief (FPR). At this time, patients will be given the second stopwatch and asked to press this 
stopwatch if and when the pain relief becomes meaningful to them (MPR).  
If a patient requires a rescue analgesic after Dose 1, the time of rescue as well as PI-NPRS and 
PR will be collected at that time and collection of stopwatch data will cease. The stopwatches 
will be stopped at 24 hours, if not prior. 
4.5.11. 
Patient Global Evaluation 
Patient Global Evaluation (PGE) is assessed on a scale of 0 (Poor), 1 (Fair), 2 (Good), 3(Very 
Good) and 4 (Excellent) at 24.25 hours post-Dose 1 or at patient withdrawal (if applicable), 
whichever occurs first. 
4.5.12. 
Pregnancy test for females 
Serum pregnancy tests (for female subjects of childbearing potential) are performed at 
Screening, and urine pregnancy tests (dipstick) are performed pre-surgery.  
 


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4.5.13. 
Serology and liver function tests 
Liver Function test will be done at screening and Hour 24, while Serology test for HIV antibody, 
hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) will be done at 
Screening only. 
4.5.14. 
Prior and Concomitant Medications 
Medications expected to confound the evaluation of the study medication are not allowed during 
the study session. This includes, but is not limited to, the use of any systemic analgesics other 
than the prescribed rescue analgesic. It is permissible at any time after the Day 1 pre-surgery for 
a single dose of 4-8 mg ondansetron (Zofran®) iv, by mouth or sublingual to be administered if a 
patient experiences nausea, 
Prior medications/therapies are those that stop prior to the start of the study drug administration. 
Any medication/therapy that stops at or after this time or is ongoing at the time of 
discontinuation/completion is considered concomitant medication/therapy. Prior and concomitant 
medications will be collected at Screening through day of discharge and follow-up telephone 
call. Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical (WHO/ATC) classification index version 
September 1, 2015.  
4.5.15. 
Rescue Medication 
Rescue medication will consist of one ibuprofen 200 mg tablet taken orally with at least 4 ounces 
of water. Prior to each dose of rescue medication, 11-Point Pain Intensity (via 0-10 Numerical 
Rating Scale) and Pain Relief (via 5-Point Categorical Pain Relief Assessment) measurements 
will be performed. For statistical purposes, pain assessments performed after any dose of rescue 
will be censored and imputed for 4 hours. Any subject requiring additional rescue medication 
may again receive ibuprofen 200 mg and their data will be similarly censored and imputed. Pain 
scores and safety data will continue to be collected for the 24-hour observation period. Rescue 
medication will not exceed ibuprofen 200 mg q3h or 2400 mg in a 24-hour period. 
4.5.16. 
Non-Medication Therapies 
Non-Medication Therapies will be collected at Screening through day of discharge and follow-up 
telephone call. These will also be coded using World Health Organization Drug Dictionary 
Anatomical Therapeutic Chemical (WHO/ATC) classification index version September 1, 2015. 
4.5.17. 
Adverse Events monitoring 
Adverse events will be recorded by site staff when they are reported or observed. The recording 
study medication, regardless of the relationship to the study medication.  
4.5.18. 
Pharmacokinetic (PK) Assessment 
Blood samples for PK assessment are drawn at the following timepoints:   


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Prior to Dose 1: An initial baseline PK blood sample will be collected at least 5 minutes 
before administering Dose 1 of study medication.   
Post Dose 1: To be drawn at 0.25 hr.±3 min (end of 
 0.5 hr. ±3 min, 0.75 hr. ± 3 
min, 1 hr. ± 5 min, 2 hr. ± 5min , 4 hr.± 5 min, 6 hr.- 5 min (prior to the next planned 
 6.25 hr. ± 3 min (end of the 
 8hr. - 5 min (prior to the next scheduled 
 8.25 hr. ± 3min (end of the  
 12 hr. - 5 min (prior to the next 
scheduled 
 12.25 hr. ± 3 min (end of the 
 16 hr. - 5 min (prior to the 
next scheduled 
 16.25 hr. ±3 min(end of the 
 18 hr. - 5 min (prior to 
the next scheduled 
 18.25 hr. ± 3min (end of the 
 and at 24.25 hr.± 15 
min (after starting the very first 
  
If a scheduled pain assessment and a scheduled PK sampling are at the same time point, the pain 
assessment should precede the PK sampling, but every attempt should be made to obtain the PK 
sample within the designated time window. 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
No interim analyses are planned. 
5.2. 
Final Analyses 
Final analyses will occur after all data are entered, cleaned, and the database is locked. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study. Departures from these general policies may be provided in the specific detailed 
sections of this SAP. When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
Since this is a proof-of-concept study, 
0.10 (one-sided), and no adjustments for multiple comparisons/end points will be performed.  All 
confidence intervals will be one-sided 90% confidence intervals. 
The following conventions will be used in the study analysis as needed for intermediate 
calculations: 
Time 0 (T0) is the time of initiation of study drug administration. 
Assessment visit times are defined relative to T0. 
Duration of an AE will be computed in days for AEs lasting longer than 24 hours, and as 
hours for AEs lasting less than 24 hours.  Duration in hours will be calculated as the stop 
date/time of the event minus the start date/time.  Duration in days will be calculated by 
using stop date minus the start date +1 if AE occur on or after taking study medication.  If 
AE occurs prior to the study medication, then the duration will be calculated by using 
stop date minus the start date.  If reported as ongoing at the time of database lock, the AE 
will be listed as ongoing, and the duration will be calculated using the date of the last 
visit or the last date of any AE for the subject in the database, whichever is later.   
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Summary tables and listings (e.g., post-text tables and individual subject data listings are 
indicate as a minimum:
1. Date of data extraction.
2. Date of output generation.
3. SAS program name, including the path that generates the output.
4. Any other output specific details that require further elaboration.
Post-text tables also include reference(s) to the subject data listing(s) that supports the summary 
data.  The data extraction date links the output to the archived database that is locked to ensure 
the replication of the results.


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6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Post-text tables will be included in Appendix 14 and the individual subject data listings will be in 
Appendix 16.  All post-text tables will have a main number level 14 and the listings 16.  The 
subject accounting and disposition table be first in the first section of the report and numbered 
Table 14.1.  The supportive subject data listing would be Listing 16.1. 
Titles of post-text tables and listings will be complete, accurate, and concise.  The last line of the 
title will provide the analysis group being summarized (e.g., Evaluable Subjects or Safety 
Subjects).  If possible, the units of measurement for data contained in the table will appear in 
parentheses to conserve space in the body of the table and must be specified for all appropriate 
data. 
Variables being summarized and statistics being reported will appear in the left most column of 
the table.  The next columns for treatment groups will report the data from left to right for the 
investigational drugs, placebo, and (where appropriate) all treated subjects, respectively 
Listings will be sorted and presented by treatment group, and subject number.  All tables and 
listings will have explanatory notes that give data extraction date, output generation date, 
complete program name and path where it was executed. 
6.3. 
Data Management 
All computations will be performed using SAS® version 9.4 (SAS Institute, Cary, NC). For final 
tables, listings, and figures (TLFs), the domain (Study data tabulation Model [SDTM]) and 
analysis (Analysis Data Model [ADaM]) data sets will be taken as input to the SAS programs 
that generate the report ready TLFs. The submission ready SDTM and ADaM data sets will be 
provided to the sponsor along with display deliveries.  
6.4. 
Data Presentation Conventions 
Since this is a proof-of-concept study, statistically significant between-treatment differences will 
be declared if 
-sided), and no adjustments for multiple comparisons/end points will 
be performed.  All confidence intervals will be one-sided 90% confidence intervals.   
The following two between-treatment comparisons will be performed: 
 APAP 
 q8h versus Placebo 
 APAP 
 q6h versus Placebo 
All continuous study assessments will be summarized by treatment group and time point (as 
applicable) using the descriptive statistics n, mean, SD, median, minimum, and maximum. All 
categorical study assessments will be summarized by treatment group and time point (as 
applicable) using frequency counts and rates of occurrence (%). Changes from baseline for 
continuous outcomes will be presented as their corresponding continuous measures for post-
baseline visits if applicable. Only results from scheduled visit will be used in analysis. For 
continuous variable, if multiple measurements were done at the same visit, the last one will be 
used. All study data will be listed by treatment group, subject, and time point (as applicable).  


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No preliminary rounding will be performed; rounding will only occur after the analysis. To 
then round up. Means and medians will be presented with one more decimal place than the 
precision of the data. Standard deviations will be presented with two more decimal places than 
the precision of the data. Percentages will be presented with one decimal place. A percentage of 
100% will be reported as 100%. Minimums and maximums will be presented with the same 
precision as the original data.  
Date variables will be formatted as DDMMMYYYY for presentation. Time will be formatted in 
military time as HH:MM for presentation. 
The table and listing shells and table of contents as part of this SAP provide the expected layout 
and titles of the TLFs. Any changes to format, layout, titles, numbering, or any other minor 
deviation will not necessitate a revision to the SAP nor will it be considered a deviation from 
planned analyses. Only true differences in the analysis methods or data handling will necessitate 
such documentation. The appropriate listings supporting the tables will be included and are not 
specified in the individual sections throughout the document.  
6.5. 
Analysis Populations  
6.5.1. 
Safety Population 
The Safety Population will include all randomized patients who received the study medication. 
This population will be used for all safety summaries. 
6.5.2. 
Evaluable Population 
The Evaluable Population will include all randomized patients who, as documented prior to the 
breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were 
administered Dose 1.  
The efficacy analyses will be performed using this population. 
6.5.3. 
PK Evaluable Population 
The PK Evaluable Population will include all randomized subject who, as documented prior to 
the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were 
administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate 
pharmacokinetic parameters. 
6.6. 
Baseline Definition 
A baseline assessment is defined as the last non-missing result prior to administration of the first 
dose of study medication.   


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6.7. 
Derived and Transformed Data 
6.7.1. 
Baseline Age  
following formula: 
Age (year) = FLOOR((date of informed consent  date of birth)/365.25*12) 
where FLOOR( ) function returns the integer part of the result. 
6.7.2. 
Study Day 
If the date of interest occurs on or after the first dose/randomization date, then study day will be 
calculated as (date of interest  date of first dose/randomization) + 1. If the date of interest occurs 
prior to the first dose/randomization date, then study day will be calculated as (date of interest  
date of first dose/randomization). There is no study day 0.  Duration of event in hours will be 
calculated as: [stop date/time of the event minus the start date/time] and displayed with one 
decimal (e.g., 6.1 hours). 
6.7.3. 
Change from Baseline 
Change from baseline will be calculated as (post-baseline result  baseline result). If used, 
percent change from baseline will be calculated as (change from baseline/baseline result * 100). 
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percentage change from baseline is set to missing as well. 
6.7.4. 
Visit Windows 
Summaries and data listings will be presented by nominal protocol timepoint and no visit 
windowing will be used for data presentations.  Unscheduled visit will be excluded from the 
summary tables but will be included in the listings.  As discussed in Section 6.4, if multiple visits 
or assessments occur within the same nominal timepoint, the latest will be used for 
analyses/presentations. The protocol-defined visits with the allowed visit windows are presented 
in Table 2. 
 
Table 2: 
Visit Windows (Days) 
Visit 
Relative Target Day 
Visit Window 
Visit 1 (Screening) 
-7 
-30  0 
Day of Surgery/Dosing 
1 
n/a 
Post-Op 
2 
n/a 
Follow Up Post-Surgery Call 
7 
±2 day 


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6.7.5. 
Multiple Assessments and Uninterpretable values 
If duplicate values are obtained at a given visit (e.g., repeated vital sign measurements), the last 
value will be used unless it is noted that the measurement was in error for that value. Values that 
compromise interpretation will not be used in summaries (e.g., values that were obtained post-
dose will not be summarized as pre-dose values). 
6.8. 
Handling of Missing Data 
6.8.1. 
Missing Efficacy Endpoints 
Prior to each dose of rescue medication, 11-Point Pain Intensity (via 0-10 Numerical Rating Scale) 
and Pain Relief (via 5-Point Categorical Pain Relief Assessment) measurements will be performed. 
For statistical purposes, pain assessments performed after any dose of rescue will be censored and 
imputed in the following manner. For subjects who take rescue medication, a windowed last pain 
score carried forward (wLOCF) will be used for all PI and PR endpoints. The pre-rescue pain 
score will be used to impute scheduled assessments for 4hrs following the rescue use. Note: if a 
pre-rescue NRS assessment occurs at the same time as a scheduled NRS assessment, the 
scheduled assessment will be assumed to happen first, and then the pre-rescue NRS will be 
assumed to occur afterwards. If a scheduled NRS assessment occurs at the same time as the time 
of taking a rescue medication, the NRS assessment will be assumed to be a Pre-rescue 
medication result. For subjects who drop out of the study early, scheduled pain assessments will 
first be imputed using the worst prior pain score carried forward (WOCF). 
For time to treatment failure, if a subject does not qualify for treatment failure, but prematurely 
discontinues from the study before 24 hours, then the subject will be censored at the time of 
discontinuation.  If a subject never qualifies as a treatment failure and completes the treatment 
phase of the study, then the subject will be considered censored at 24 hours. 
For the other time to event analyses (FPR-C, MPR) if a subject does not record 
perceptible/meaningful pain relief and prematurely discontinues from the study prior to 24 hours, 
then the subject will be censored at 24 hours. If a subject does not record perceptible/meaningful 
pain relief prior to taking rescue medication, the subject will again be censored at 24 hours. 
Imputation of non-numerical values reported in the plasma PK data set for acetaminophen will 
be dealt with, in both PK parameter calculation and calculation of descriptive statistics of the 
concentration data, as follows:   
 
Day 1 pre dose sample times will be set equal to zero; 
 
Values that are below the limit of quantification (BLQ) obtained prior to the first 
quantifiable concentration post-dose administration will be set equal to zero; 
 
Values that are BLQ after the first quantifiable concentration post dose administration will 
be treated as missing for the calculation of PK parameters  
 
Concentrations that are treated as missing (non-numerical values) will be ignored in the 
calculation of descriptive statistics for serum concentrations. 
No other missing data will be imputed.  


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6.8.2. 
Missing Start and Stop Dates for Adverse Events 
If a Treatment-emergent AEs (TEAE) is reported as ongoing at the time of database lock, the AE 
will be shown as ongoing in listings, and the stop date will be imputed for calculations as the 
date of the last visit or the last date of any event for the subject in the database, whichever is 
later. 
If a TEAE is considered resolved, but the stop date is missing, the last day of the month will be 
imputed if the month and year are available. If only the year is available, and the year is the same 
as the year of the last visit, the stop date will be the latest of the last visit date or latest event for 
the subject in the database. 
If the year of the event is prior to the year of the last treatment, the end day and month will be set 
to 31 December. 
For missing or partial start and stop dates/times, the most conservative imputation will be used 
(AEs will be assumed to be temporally related to the study medication). The original incomplete 
or missing dates will be presented in the listings, not the imputed dates. Table 4 will be used to 
impute any missing dates/times: 
 
Table 3:  
Table of Imputation Rules for Missing AE Start Dates 
Missing Date 
Portion 
Prior to 
Treatment 
Same as Treatment Start 
Date 
After Treatment Start 
Date 
Day 
Month and Year < Month 
and Year of Study 
treatment: 
 
Start Day = 1 
Stop Day=last day of the 
month 
Month and Year = Month 
and Year of Study 
treatment: 
 
Start Day = Day of first 
treatment 
Stop Day= last day of the 
month 
Month and Year > Month 
and Year of Study 
Treatment: 
 
Start Day = 1 
Stop Day=last day of the 
month 
Day and Month 
Define Day as 
above, then: 
Year < Year of first 
treatment: 
 
Start Month = July 
Stop Month = Dec 
Year = Year of study 
treatment: 
Start Month = Month of 
study treatment 
Stop Month = Dec 
Year > Year of study 
treatment: 
 
Start Month = January 
Stop Month = Dec 
 
Day, Month, 
and Year 
 
To be conservative, completely missing start dates will be imputed using the date of 
study treatment, Missing end dates will be imputed using date of last study contact 
with the subject 
 
Time 
Missing start times will be imputed as 00:01 
Missing stop times will be imputed as 23:59 
6.8.3. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Partially missing dates for medications and procedures will be imputed as described in Section 
6.8.2 for adverse events. 


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7. 
STUDY POPULATION 
7.1. 
Subjects Disposition 
All subjects and the populations for which they qualify will be listed. Subjects who are screened 
and who fail screening, are randomization failures or withdraw consent prior to randomization or 
are randomized but not treated will be listed and summarized in the disposition summary table. 
Subjects who are randomized, subject inclusion into each study population, subjects who are 
treated, subjects who complete follow-up as well as subjects who withdraw early from the study 
and the reason for withdrawal will be summarized by treatment group and overall in the subject 
disposition summary table. 
7.2. 
Protocol Deviations 
Deviations are categorized as informed consent procedures, inclusion/exclusion criteria, study 
medication, prohibited medications, study procedures, study drug assignment/treatment, visit or 
assessment time window, missed visit or assessment and/or other. All protocol deviations will be 
captured on case report forms (CRFs) and/or documented in site-specific logs throughout the 
study. Deviations will be categorized and classified as major or minor by the project team and 
the medical monitor after database lock but before unblinding and will be discussed in the CSR. 
Subjects with protocol deviations, both minor and major, will be presented in a data listing and 
will be summarized by type of deviation and major/minor classification for all randomized 
subjects. 
7.3. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized overall and by treatment group 
using the Safety and Evaluable Populations. 
7.4. 
Listing of Subject Inclusion and Exclusion Criteria 
Listing showing subject inclusion/exclusion status (inclusion criteria not met and exclusion 
criteria met) will be provided. 
7.5. 
Medical History and Medical Conditions Present at Entry 
Medical histories will be presented in a by-subject listing. Any events that occur prior to surgical 
removal of molars will be categorized as medical history . 
7.6. 
Prior Medication History and Medications Present at Entry 
All medications and non-medical therapies captured in CRFs will appear in data listings. 


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8. 
EFFICACY  
8.1. 
Statement of the Hypothesis 
The hypotheses of this study are that 
 APAP 
 dosed three times daily and 
 APAP 
 dosed four times daily have similar safety, tolerability, and efficacy profiles when 
compared to placebo. 
8.2. 
Subgroup Analyses 
Time Weighted Sum of Pain Intensity Difference from 0 to 24 hours (SPID24) and Time 
Weighted Sum of Pain Relief from 0 to 24 hours (TOTPAR24) will be analyzed by age group 
(<median, >=median) and by sex, using an analysis of covariance (ANCOVA) model with 
treatment group as a fixed effect and baseline pain intensity PI-NPRS as a covariate.  Descriptive 
summaries, including least square means (lsmeans) and standard errors for each treatment group 
and confidence intervals will be presented. 
8.3. 
Multiple Comparisons and Multiplicity 
No adjustments for multiple comparisons/end points will be performed. 
8.4. 
Analysis of the Efficacy Endpoints 
8.4.1. 
Time Weighted Sum of Pain Intensity Difference from 0 to 24 hours (SPID24) 
Pain intensity (PI) is collected at various scheduled timepoints and also prior to each use of 
rescue medication.  SPID is calculated as 
(i) T(i-1)] x (PID(i-1) + PID(i))/2, where T(0)=0, 
T(i) is the scheduled time, and PID(i) is the pain intensity difference (PID) score at time i.   At 
any timepoint, SPID will include all assessments from T0 to the nominal time point. Thus, 
SPID24 will include all nominal timepoints from T0 to T24.25. The last PI score prior to the use 
of any rescue medication will be used to impute subsequent PI scores for the subsequent 
protocol-specified time points for measurement of pain intensity through 4 hours after the time of 
the dosing of the rescue medication (wLOCF).  If a pre-rescue PI assessment occurs at the same 
time as a scheduled assessment, the schedule PI will be assumed to happen first, and then the 
pre-rescue PI will be assumed to occur. If a PI assessment occurs at the same time as the time of 
taking a rescue medication, the PI will be assumed to be a Pre-rescue medication result. If the PI 
time is the same as the end of time window after taking the rescue medication (end of imputation 
period), then PI score will be considered as occurring before the 4 hours assessment and will be 
imputed. Intermittent missing pain scores will not be imputed, and SPID24 will be calculated 
based on non-missing values. For subjects who drop out of the study early, scheduled 
assessments will first be imputed using the worst prior pain score carried forward (WOCF). 
For calculations of SPID24, the actual dates/times of assessments will be used in calculations. 
While the PI scores are intended to be collected at the pre-defined protocol scheduled time 
points, it is recognized that operationally the scores are collected as close to the target times as 
possible but there is some flexibility in terms of the actual times the scores are collected. Thus, to 
account for this inherent aspect of data collection, the ACTUAL TIMES will be used for the 


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calculation of SPID24. The actual times will be based relative to the time of completion of study 
drug administration. 
This will be analyzed using an analysis of covariance (ANCOVA) model with treatment group as 
a fixed effect and baseline PI-NPRS as a covariate. Descriptive summaries including least square 
means and standard errors for each treatment group, confidence intervals, and p-values will be 
presented. 
8.4.2. 
Time Weighted Sum of Pain Relief from 0 to 24 hours (TOTPAR24) 
Pain Relief Rating (PR) is scored on a 5-point scale (0=no-, 1= a little-, 2= some-, 3= a lot of-, 
and 4=complete- PR) at each observation time after Dose 1 administration, TOTPAR24 is 
derived similarly as SPID24 above, with pain relief at time i (PR(i)) replacing PID(i) in the 
formula. 
This will be analyzed using an analysis of covariance (ANCOVA) model with treatment group as 
a fixed effect and baseline PI-NPRS as a covariate. Descriptive summaries including least square 
means and standard errors for each treatment group, confidence intervals, and p-values will be 
presented. 
8.4.3. 
Time to Perceptible Pain Relief Confirmed (FPR-C) and Cumulative % of 
patients with onset of First Perceptible Relief Confirmed after Dose 1 
administration  
This will be analyzed using a log-rank test; the log rank test may be stratified by baseline 
categorical pain intensity score (moderate / severe) if there are sufficient subjects in each 
stratum.  Number of subjects in the population (N), number of subjects with FPR-C event, 
number of subjects censored, median time to FPR-C, and p-values from log-rank test will be 
displayed in a summary table. 
In addition, the cumulative percent of subjects achieving perceptible pain relief confirmed after 
Dose 1 will be presented in Kaplan-Meier curves by treatment group. 
If a subject does not record perceptible pain relief and prematurely discontinues from the study 
prior to 24 hours, then the subject will be censored at time of drop out. If a subject does not 
record perceptible pain relief prior to taking rescue medication, the subject will be censored at 24 
hours.  
8.4.4. 
Time to Meaningful Pain Relief (MPR) and Cumulative % of patients with onset 
of Meaningful Pain Relief after Dose 1 administration 
This will be analyzed using a log-rank test; the log rank test may be stratified by baseline 
categorical pain intensity score (moderate / severe).  Number of subjects in the population (N), 
number of subjects with MPR event, number of subjects censored, median time to MPR, and p-
values from stratified log-rank test will be displayed in a summary table. 
In addition, the cumulative percent of subjects achieving meaningful pain relief after Dose 1 will 
be presented in Kaplan-Meier curves by treatment group. 


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If a subject does not record meaningful pain relief and prematurely discontinues from the study 
prior to 24 hours, then the subject will be censored at time of drop out. If a subject does not 
record meaningful pain relief prior to taking rescue medication, the subject will also be censored 
at 24 hours. 
8.4.5. 
Cumulative proportion of patients with pain half gone over time 
percent PID, defined as PPID(i) =(PID(i) / PI(T0) *100, at that assessment time point is less than 
50%.  
The endpoint will be analyzed using a Kaplan Meier approach to summarize time to first 
occurrence of 50% improvement.  This will count a subject as an event when they first hit 50% 
pain half gone.  If a subject does not record 50% improvement and prematurely discontinues 
from the study prior to 24 hours, then the subject will be censored at time of drop out. If a subject 
does not record 50% improvement prior to taking rescue medication, the subject will be censored 
at 24 hours. 
Number of subjects in the population (N), number of subjects that achieve 50% improvement, 
number of subjects censored, median time to achieving 50% improvement, and p-values from 
stratified log-rank test will be displayed in a summary table. 
In addition, Kaplan-Meier curves will be presented by treatment group. 
8.4.6. 
Patient Global Evaluation of the study medication 
The Patient Global Evaluation will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group as a fixed effect and baseline PI-NPRS as a covariate. Descriptive 
summaries including least square means and standard errors by treatment group, confidence 
intervals, and p-values will be presented. 
8.4.7. 
Pain Intensity Difference (PID) Rating at each observation time after Dose 1 
administration 
This will be summarized descriptively and plotted over time by treatment group. 
8.4.8. 
Pain Intensity (PI) Ratings at each observation time after Dose 1 administration 
This will be summarized descriptively and plotted over time by treatment group. 
Compliance with recording NRS is calculated as the number of non-missing NRS scores divided 
by the number of expected NRS scores. NRS scores recorded prior to rescue medication use are 
excluded from the calculation.  Compliance with recording NRS will also be summarized 
descriptively by treatment group. 
8.4.9. 
Pain Relief (PR) Ratings at each observation time after Dose 1 administration 
This will be summarized descriptively and plotted over time by treatment group. 
Compliance with recording PR is calculated as the number of non-missing PR scores divided by 
the number of expected PR scores. PR scores recorded prior to rescue medication use are 


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excluded from the calculation.  Compliance with recording PR will also be summarized 
descriptively by treatment group. 
8.4.10. 
Time to treatment failure and Cumulative % of patients with treatment failure 
Time to treatment failure is defined in the protocol as the earlier of the time to first dose of 
rescue medication after Dose 1 or time to withdrawal from the study due to lack of efficacy (if 
prior to any rescue). Since withdrawal from the study due to lack of efficacy was not collected in 
the study, this SAP redefines Time to treatment failure as the earlier of the time to first dose of 
rescue medication after Dose 1 or withdrawal from the study for any reason.  
This will be analyzed using a log-rank test; the log rank test may be stratified by baseline 
categorical pain intensity score (moderate / severe).  Number of subjects in the population (N), 
number of subjects with treatment failure, number of subjects censored, median time to treatment 
failure, and p-values from stratified log-rank test will be displayed in a summary table. 
In addition, the cumulative percent of subjects that fail treatment will be presented in Kaplan-
Meier curves by treatment group. 
If a subject does not take rescue medication or withdraw from the study prior to 24 hours, the 
subject will be censored at 24 hours. 
8.4.11. 
Sensitivity Analyses of the Primary Efficacy Results 
Interaction between baseline PI-NPRS and treatment group will be tested for statistical 
significance for SPID24 and TOTPAR24 by including the interaction term in the ANCOVA 
model utilized for the primary efficacy analyses.  


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9. 
SAFETY AND TOLERABILITY 
9.1. 
Overall Summary of Tolerability 
All AEs will be listed, but only TEAEs will be summarized. Treatment-emergent AEs are 
defined as all AEs which initially occurred or worsened following first dose of treatment (T0). 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
9.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects 
For evaluation of causal relatedness to treatment, the categories are definitely related, probably 
related, possibly related, unlikely related, or not related. For categorization in the summary 
tables, AEs designated as definitely, probably, or possibly related will be considered related. 
For the evaluation of event severity terms, the criteria are mild, moderate, or severe. In addition 
to a listing of all AEs, treatment associated TEAEs, serious TEAEs, Deaths, and TEAEs leading 
to premature discontinuation from the study will be provided. 
An overall summary will be prepared giving for each treatment group and overall, both the 
number of TEAEs, and the number of subjects with at least one TEAEs.  SAEs, TEAEs 
associated with treatment and TEAEs leading to premature discontinuation from study will also 
be included in this overall summary.  
The number of subjects with AEs will be summarized for each treatment group and overall by 
System Organ Class (SOC) and Preferred Term (PT) sorted alphabetically by SOC, and then by 
PT within SOC. Separate tables will be presented for each of the following TEAE event sets: 
All events 
Treatment-related events 
Serious events 
Events leading to premature discontinuation from study 
Events by maximum severity 
Events by relationship to study drug 
If a given subject experiences a TEAE that maps to the same PT/SOC more than once, the 
subject will be counted only once for the SOC/PT at the greatest severity (i.e., mild, moderate, or 
severe) and causality (i.e., related). 
 
Duration of a TEAE lasting more than 24 hours will be computed in days as the stop date of the 
event minus the start date plus 1 and will be reported in days. TEAEs lasting less than 24 hours 
will be computed as stop date/time minus start date/time and reported in hours. If reported as 
ongoing at the time of database lock, the date used to calculate duration will be defined as the 
date/time of the last visit or the last date/time of any event for the subject in the database, 
whichever is later. 


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9.2.2. 
Missing and Partial AE Onset Dates 
Missing and partial AE onset dates will be handled as described in Section 6.8.3: Missing Start 
and Stop Dates for Adverse Events. 
9.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication, and Compliance 
A listing of study drug administration and exposure data will be provided. 
 
 of drug administered is 1300 (10x130) ml. Percentage of intended dose that was 
taken by each subject is defined as 100 x 10 x (actual volume administered at each timepoint) / 
intended volume. A summary table by treatment group of percentage of intended dose that was 
taken by each subject will be provided. 
9.4. 
Concomitant and Other Medications 
9.4.1. 
All medications and non-medical therapies captured in CRFs will appear in data 
listings. 
Missing and partial concomitant and other medication start and stop dates will be handled as 
described in Section 6.8.2: Missing Start and Stop Dates for Prior and Concomitant Medication. 
9.5. 
Rescue Medications, and Compliance for Pre-Rescue NRS and Pain 
Relief    
Rescue medication will consist of one ibuprofen 200 mg tablet taken orally with at least 4 ounces 
of water. Total dose in mg will be derived as number of tablets taken multiplied by 200. 
Summary statistics will be presented for total dose of rescue medication used, by treatment 
group. 
NPRS and PR assessments should be completed prior to each rescue dose.  
Compliance with recording NPRS prior to rescue = 100 x (number of times NPRS are recorded 
prior to rescue)/(number of rescue doses taken).  
Compliance with recording PR prior to rescue = 100 x (number of times PR are recorded prior to 
rescue)/(number of rescue doses taken).   
9.6. 
Routine Clinical Laboratory Data 
Serology test is done at Screening only, while Liver Function Panel is done at Screening and 
Hour 24. All results will be listed. For each lab test, the raw value will be summarized by 
treatment group and timepoint. 
The number and percentage of subjects who have clinically significant laboratory results will be 
summarized for overall, and by treatment group. 


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9.7. 
Vital Signs 
Vital signs results including blood pressure (systolic and diastolic; mmHg), heart rate (beats per 
minute), respiration rate (breaths/min), and temperature will be listed for individual subjects.  
Baseline for vital signs measurements will be defined as the last evaluation before dosing with 
study medication. Summary statistics, including change from baseline, will be presented for each 
measure and will be summarized by treatment group and time point. 
9.8. 
Physical Examination 
A complete physical examination including all major body systems will be performed at 
Screening. 
Physical examination results will be listed for individual subjects. 
9.9. 
Study Termination Status 
A post-text table will be provided that categorizes the status of the subjects at the end of the 
study by treatment group.  The completion status will be summarized with respect to the number 
of subjects: 
1. Completing the entire course of treatment. 
2. Discontinuing the trial prematurely. 
3. Reason for premature study termination. 
The reasons for early study termination are adverse event, protocol violation, screen failure, 
administrative, lack of efficacy, lost to follow-up, death, subject non-compliance, withdrawal of 
consent by subject, prohibited medication, sponsor decision, investigator decision, and other. 


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10. 
PHAMACOKINETIC EVALUATION 
10.1. 
Pharmacokinetic Objectives  
The PK objectives/questions to be addressed in this study are as follows : 
1. 
Is the daily drug exposure from the 
 APAP 
 q6h dose like that from the 
 
APAP 
 q8h dose? 
2. 
Is there any change in the PK of acetaminophen in going from a single dose of 
 APAP 
 to a single dose of 
 APAP 
 ?  
3. 
Is there drug accumulation on multiple dosing with either regimen? If yes, how much? 
4. 
Do we achieve a steady state with either regimen? 
10.2. 
Pharmacokinetic Sample Analysis and Modeling Process  
Sampling for Pharmacokinetic (PK) assessments will be done following the schedule discussed 
in Section 4.5.17 (Pharmacokinetic (PK) Assessment). Samples will be sent to a 
 
who will measure the concentration of APAP in each sample and return those 
concentration results to the project team.   
Seventh Wave will use the concentration data to perform a Non-Compartmental Analysis (NCA) 
of the concentrations and produce PK parameters and a stand-alone PK report.  PK parameters to 
be used in evaluating the above objectives will be provided by Seventh Wave, to include: 
 
For the 
 q8h regimen:  
 
Dose 1: 
1. AUC(0-8) 
2. AUC(0-inf) 
3. Cmax 
4. Ctrough 
5. Half-life (t1/2) 
 
 
Dose 2: 
1. Cmax 
2. Ctrough 
3. RA_Cmax_Dose 2 
 
Dose 3: 
1. Cmax 
2. Ctrough 
3. RA_Cmax_Dose 3 
 
Daily Drug Exposure 


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1. AUC(0-24)  
 
 
For the 
 q6h regimen: 
 
Dose 1: 
 
1. AUC(0-6) 
2. AUC(0-inf) 
3. Cmax  
4. Ctrough 
5. Half-life (t1/2) 
 
Dose 2: 
 
1. Cmax 
2. Ctrough 
3. RA_Cmax_Dose 2 
 
Dose 3: 
 
1. Cmax 
2. Ctrough 
3. RA_Cmax_Dose 3 
 
Dose 4: 
 
1. Cmax 
2. Ctrough 
3. RA_Cmax_Dose 4 
 
Daily Drug Exposure 
1. AUC(0-24) 
 
10.3. 
Summary of Pharmacokinetic Concentrations 
 will receive the PK concentrations as provided by 
.  PK 
concentrations will be summarized using descriptive statistics (number of non-missing and 
missing observations, arithmetic mean, geometric mean, standard deviation (SD), percent 
coefficient of variation (CV%), minimum , median, and maximum for each treatment group and 
nominal time point.  Figures of the PK concentrations over time for each subject and the mean 
concentration over time for each treatment group will be presented in both standard and log 
scale. 


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10.4. 
Statistical Analysis of Pharmacokinetic Parameters 
 will receive the PK parameters as derived by Seventh Wave. All 
analyses that involve 
will be back-transformed.    PK parameters except Tmax will be summarized using descriptive 
statistics [N, Mean, SD, CV%, minimum, median, maximum, geometric mean (Geom Mean), 
and geometric CV% (Geom CV%)] for each treatment group, nominal time point and study day. 
Minimum, median and maximum will be presented for Tmax. 
All PK parameters will be summarized with the same number of significant figures as reported.  
In addition, the following statistical analysis will be performed to support each of the PK 
objectives.    
10.4.1. 
Differences in Daily Drug Exposure by Dose Regimen 
To evaluate PK objective 1, AUC(0-24) after the 
 q8h will be compared with the 
AUC(0-24) after the 
 q6h using an analysis of variance (ANOVA) model with daily 
drug exposure (AUC(0-24)) as the dependent variable and treatment group as a fixed effect 
independent variable. The null hypothesis here is that there is no difference between the AUC(0-
24) of the two active treatment groups. 
Because the overall study is being performed at the 0.10 (one sided) confidence level, eighty 
percent (80%) confidence intervals, standard errors, lsmeans, and geometric mean ratios (GMR) 
will be presented. 
10.4.2. 
Differences in Pharmacokinetics by Dose Regimen 
Evaluation of PK objective 2 will be accomplished by comparing the dose normalized AUC(0-
inf) of the two active treatment groups using an ANOVA model and summarized as described in 
section 10.4.1 above. The null hypothesis here is that there is no difference between the dose 
normalized AUC(0-inf) of the two active treatment groups. 
10.4.3. 
Drug Accumulation by Dose 
To evaluate PK objective 3, the accumulation for each active treatment group will be evaluated 
to see if it is significantly different from 1.0.  
For the 
 q8h regimen, the null hypothesis that RA_Cmax_Dose 3 = 1 will be analyzed 
using a one sample t-test. For the 
 q6h regimen RA_Cmax_Dose 4 will be tested under a 
similar hypothesis and analysis method. P-values will be presented and are considered significant 
if < 0.10 (one-sided). 
10.4.4. 
Steady State by Dose 
To evaluate PK objective 4 (achievement of a steady state with either active treatment group), 
differences between absolute values of Cmax (last dose) and Cmax (previous Dose) will be 
compared for each subject for the last dose. T-test will be used to test the null hypotheses that 
these differences equal 0 within each treatment regimen.  For the 
 q8h regimen, the null 
hypothesis that Cmax from Dose 3 will be comparable to Cmax from Dose 2 will be done using 


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a one sample t-test of the difference. For the 
 q6h regimen Cmax from Dose 4 will be 
similarly compared to Cmax from Dose 3.  P-values will be presented and are considered 
significant if < 0.10 (one sided).  Helmert contrasts may be performed if warranted. 


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11. 
REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry:  
Statistical Principles for Clinical Trials. Department of Health and Human Services:  Food and 
Drug Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry:  
Structure and Content of Clinical Study Reports. Department of Health and Human Services:  
Food and Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320.  
Guidance for Industry (2014) Analgesic Indications:  Developing Drug and Biological Products -  
Draft Guidance.  Department of Health and Human Services:  Food and Drug Administration.  
Center for Drug Evaluation and Research (CDER) February 2014 Clinical/Medical. 


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12. 
APPENDIX 
12.1. 
Table of Contents for Data Display Specifications 
Tables  
Table 
Number 
Title 
Analysis 
Population  
Comments 
Study Population Section 
14.1.1 
Summary of Subject Disposition 
All Subjects  
Unique 
14.1.2 
Summary of Analysis Populations 
Randomized 
Unique 
14.1.3 
Summary of Reasons for Efficacy Non-
Evaluability/Exclusion from Evaluable Population 
Safety 
Unique 
14.1.4.1 
Summary of Demographic Characteristics 
Safety 
Unique 
14.1.4.2 
Summary of Demographic Characteristics 
Evaluable 
Repeat 14.1.3.1 
14.1.5 
Summary of Protocol Deviations 
Safety  
Unique 
14.1.6 
Summary of Baseline Vital Signs 
Safety  
Unique 
14.1.7.1 
Summary of Subject Compliance for: NRS Diary, 
Dosing, and Pre-Rescue NRS 
Safety 
Unique 
14.1.7.2 
Summary of Subject Compliance for: Pain Relief and 
Pain Relief at Rescue 
Safety 
Unique 
14.1.8 
Incidence and Total Dose of Rescue Medication Use 
by Treatment Group 
Safety 
Unique 
Efficacy Section  
 
 
Figures 
 
 
14.2.1 
Kaplan-Meier Plot of Time to Perceptible Pain 
Relief Confirmed (FPR-C) 
Evaluable 
Unique 
14.2.2 
Kaplan-Meier Plot of Time to Meaningful Pain 
Relief (MPR) 
Evaluable 
Repeat 12.2.3 
14.2.3 
Kaplan-Meier Plot of Time to Treatment Failure 
Evaluable 
Repeat 12.2.4 
14.2.4 
Kaplan-Meier Plot of Time to Pain Half Gone 
Evaluable 
Repeat 12.2.4 
14.2.5 
Plot of % Subjects with Pain Half Gone at Each 
Time Point  
Evaluable 
Unique 
Tables 
 
 
14.2.1.1 
ANCOVA Analysis of Time Weighted Sum of Pain 
Intensity Difference from 0 to 24 hours (SPID24)  
WOCF 
Evaluable 
Unique 
14.2.1.2 
Sensitivity Analysis of Time Weighted Sum of Pain 
Intensity Difference from 0 to 24 hours (SPID24)  
WOCF 
Evaluable 
Unique 


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14.2.2.1 
ANCOVA Analysis of Time Weighted Sum of Pain 
Relief from 0 to 24 hours (TOTPAR24)  WOCF 
Evaluable 
 Repeat 14.2.1 
12.2.2.2 
Sensitivity Analysis of Time Weighted Sum of Pain 
Relief from 0 to 24 hours (TOTPAR24)  WOCF 
Evaluable 
Unique 
14.2.3 
Log-Rank Analysis of Time to Perceptible Pain Relief 
Confirmed (FPR-C) 
Evaluable 
Unique 
14.2.4 
Log-Rank Analysis of Time to Meaningful Pain Relief 
(MPR) 
Evaluable 
Repeat 14.2.3 
14.2.5 
Cumulative Proportion of Patients with Pain Half Gone 
over Time 
Evaluable 
Unique 
14.2.6 
ANCOVA Analysis of Patient Global Evaluation (PGE) 
of Study Medication 
Evaluable 
Unique 
14.2.7 
Summary of Pain Intensity Difference (PID) Rating at 
Each Observation Time after Dose 1 Administration 
Evaluable 
Unique 
14.2.8 
Summary of Pain Intensity (PI) Ratings at Each 
Observation Time after Dose 1 Administration 
Evaluable 
Repeat 14.2.7 
14.2.9 
Summary of Pain Relief (PR) Ratings at Each 
Observation Time after Dose 1 Administration 
Evaluable 
 Repeat 14.2.7 
14.2.10 
Log-Rank Analysis of Time to Treatment Failure 
Evaluable 
Unique 
Safety Section 
14.3.1 
Overall Summary of Treatment-emergent Adverse Events 
(TEAEs) 
Safety 
Unique 
14.3.2.1 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety 
Unique 
14.3.2.2 
Summary of Treatment Related Treatment-Emergent 
Adverse Events (TEAEs) by System Organ Class and 
Preferred Term 
Safety 
Unique 
14.3.2.3 
Summary of Death and Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety 
Unique 
14.3.2.4 
Summary of Treatment-Emergent Adverse Events 
(TEAEs) Leading to Study Discontinuation by System 
Organ Class and Preferred Term 
Safety 
Unique 
14.3.2.5 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term and Maximum 
Severity 
Safety 
Unique 
14.3.2.6 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term and Relationship to 
Study Drug 
Safety 
Unique 
14.3.3 
Summary of Clinical Chemistry Data by Treatment 
Group and Study Time 
Safety 
Unique 
14.3.4 
Summary of Actual Values and Changes from Baseline in 
Vital Signs by Treatment Group and Study Time 
Safety 
Unique 


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PK Section 
Tables 
14.4.1 
Summary of PK Concentration Data  
PK Evaluable 
Population 
Unique 
14.4.2 
Summary of PK Parameters  
PK Evaluable 
Population 
Unique 
14.4.3 
ANOVA Analysis of Daily Drug Exposure 
PK Evaluable 
Population 
Unique 
14.4.4 
ANOVA Analysis of Dose Normalized AUC 
PK Evaluable 
Population 
Unique 
14.4.5 
One Sample T-Test of Dose Accumulation 
PK Evaluable 
Population 
Unique 
14.4.6 
Analysis of Cmax values to Evaluate Steady State 
PK Evaluable 
Population 
Unique 
Figures 
14.4.1 
PK Concentration-over time by Subject 
PK Evaluable 
Population 
Unique 
14.4.2 
PK Concentration-over time by Subject (Log scale)  
PK Evaluable 
Population 
Unique 
14.4.3 
Mean PK Concentration-over time by Treatment 
PK Evaluable 
Population 
Unique 
14.4.4 
Mean PK Concentration-over time by Treatment 
(log scale)  
PK Evaluable 
Population 
Unique 
14.4.5 
Mean (SD) trough concentrations vs time by 
Treatment 
PK Evaluable 
Population 
Unique 


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Listings 
 
 
 
Listing Number 
Title 
Population 
Comment 
16.2.1.1 
Subject Enrollment Information 
Enrolled 
Unique  
16.2.1.2 
Subject Disposition 
Safety 
Unique 
16.2.2.1 
Subjects who did not Satisfy Inclusion/Exclusion Criteria 
All Subjects 
Unique 
16.2.2.2 
Protocol Deviations 
Safety 
Unique 
16.2.2.3 
Subject Demographic and Baseline Characteristics 
Safety 
Unique 
16.2.2.4 
Listing of Medical/Surgical History 
Safety 
Unique  
16.2.2.5 
Listing of Physical Exam 
Safety 
Repeat  
16.2.2.6.1 
Listing of Concomitant Medications  
Safety 
Unique  
16.2.2.6.2 
Listing of Non-Medication Therapies 
Safety 
Unique  
16.2.2.7 
Listing of Drug Administration and Compliance  
Safety 
Unique  
16.2.2.8 
Listing of Pain Assessment Training  
Safety 
Unique 
16.2.3.1a 
 Listing of Subject NPRS and NPRS at Rescue Compliance 
Safety 
Unique 
16.2.3.1b 
Listing of Subject PR and PR at Rescue Compliance 
Safety 
Unique 
16.2.3.2 
Listing of Pain Intensity as measured on 11  Point Numeric Pain Rating 
Scale (NPRS) 
Safety 
Unique 
16.2.3.3 
Listing of 5-Point Categorical Pain Relief Assessment (PR) 
Safety 
Unique 
16.2.3.4 
Listing of Efficacy Endpoints 
Safety 
Unique 
 
 
 
 
16.2.6.1 
Listing of Relationship of Adverse Event Body System, Group Terms, and 
Verbatim Text 
Safety 
Unique 
16.2.6.2 
Listing of All Adverse Events 
Safety 
Unique 
16.2.6.3 
Listing of Subjects Withdrawn Due to AEs 
Safety 
Repeat  
16.2.6.4 
Listing of Deaths or SAEs 
Safety 
Repeat 


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16.2.7.1 
Listing of Chemistry Data 
Safety 
Unique  
16.2.7.2 
Listing of Hematology Data 
 Safety 
Repeat 16.2.7.1 
16.2.7.4 
Listing of Serology 
Safety 
Repeat 16.2.7.1 
16.2.8 
Listing of Vital Sign Data  
Safety 
Unique 
16.2.9 
Listing of Rescue Medication Administration 
Safety 
Unique 
16.2.10 
Listing of Pregnancy Test 
Safety 
Unique 
16.2.11 
Listing of Surgery 
Safety 
Unique 
16.2.12 
Listing of Pharmacokinetic (PK) Concentration (unit) Data 
Evaluable 
Unique 
16.2.13 
Listing of Pharmacokinetic (PK) Parameters 
Evaluable 
Unique 
 
12.2. 
7th wave 17-RS-610CL PKAP