Clinical trial NCT03879408
Conditions: Pain
Keywords: Analgesics Dental Pain Naproxen Acetaminophen Pain
Sponsor: Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division
Start date: 2019-05-28; Completion date: 2019-11-13
Enrollment: 290 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study assessing efficacy and safety of concomitantly dosed naproxen sodium with acetaminophen, compared with naproxen sodium, hydrocodone/acetaminophen and Placebo in a postoperative dental pain.

Detailed description:
This is a randomized, double-blind, placebo- and active-controlled, parallel-group study to evaluate the analgesic efficacy and safety of concomitantly administered naproxen sodium 440 mg with acetaminophen 1000 mg and concomitantly administered naproxen sodium 220 mg with acetaminophen 650 mg, compared with a fixed combination of hydrocodone 10 mg/acetaminophen 650 mg, naproxen sodium 440 mg, and placebo over a twelve-hour period after surgical extraction of four third molars.

Arms: arm 1: 440 mg naproxen sodium with 1000 mg acetaminophen administered as a single dose of two naproxen sodium 220 mg tablets and two acetaminophen 500 mg tablets arm 2: 220 mg naproxen sodium with 650 mg acetaminophen administered as a single dose of one naproxen sodium 220 mg tablet and two acetaminophen 325 mg tablets and one placebo tablet arm 3: 10 mg hydrocodone + 650 mg acetaminophen administered as a single dose of two hydrocodone 5 mg + acetaminophen 325 mg tablets and two placebo tablets arm 4: 440 mg naproxen sodium administered as a single dose of two naproxen sodium 220 mg tablets and two placebo tablets arm 5: Single dose of four placebo tablets
Interventions: intervention 1: 440 mg naproxen sodium with 1000 mg acetaminophen intervention 2: 220 mg naproxen sodium with 650 mg acetaminophen intervention 3: 10 mg hydrocodone + 650 mg acetaminophen intervention 4: 440 mg naproxen sodium intervention 5: Placebo tablet
Intervention descriptions: intervention 1: 440 mg naproxen sodium with 1000 mg acetaminophen administered as a single dose of two naproxen sodium 220 mg tablets and two acetaminophen 500 mg tablets intervention 2: 220 mg naproxen sodium with 650 mg acetaminophen administered as a single dose of one naproxen sodium 220 mg tablet and two acetaminophen 325 mg tablets and one placebo tablet intervention 3: 10 mg hydrocodone with 650 mg acetaminophen administered as a single dose of two hydrocodone 5 mg + acetaminophen 325 mg tablets and two placebo tablets intervention 4: 440 mg naproxen sodium administered as a single dose of two naproxen sodium 220 mg tablets and two placebo tablets intervention 5: Single dose of four placebo tablets

Protocol documents:
Prot_000.pdf: 
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COMPANY CONFIDENTIAL 
1 of 61 
 
 
CLINICAL PROTOCOL 
NAPROXEN SODIUM/ACETAMINOPHEN 
CCSPAA001068 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND ACTIVE- CONTROLLED, 
PROOF OF CONCEPT STUDY TO EVALUATE TWO STRENGTHS OF 
CONCOMITANTLY DOSED  NAPROXEN SODIUM WITH ACETAMINOPHEN, 
COMPARED WITH NAPROXEN SODIUM, HYDROCODONE/ACETAMINOPHEN 
AND PLACEBO IN POSTOPERATIVE DENTAL PAIN 
 
Investigational Product Name: 
Naproxen Sodium/Acetaminophen 
Protocol Number: 
CCSPAA001068 
IND / IDE / EudraCT number: 
141,128 
Phase: 
2 
Version (Final) Date: 
Version 1 (Final) 21 March 2019 
 
 
 
This document contains privileged and confidential information belonging to the Sponsor.  Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold the information contained herein in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for unauthorized 
purposes.  In the event information is disclosed to others, as required by applicable law, they must be informed that 
the information is privileged and confidential and may not be further disclosed by them.  These restrictions on 
disclosures will apply equally to all future information supplied to you that is indicated as privileged and 
confidential.  You agree that no unpublished information contained herein will be published or disclosed without the 
prior written approval of Sponsor.  In the event of any actual or suspected breach of this obligation, Sponsor must be 
promptly notified. 
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Test Naproxen Sodium 440 mg Tablets/Acetaminophen 1000 mg Tablets 
Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
COMPANY CONFIDENTIAL 
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1. 
SYNOPSIS 
Name and address of the Sponsor/Company of the clinical investigation: 
Johnson & Johnson Consumer, Inc., McNeil Consumer Healthcare Division 
7050 Camp Hill Road 
Fort Washington, PA 19034 
Active Ingredient(s):  
• 
440 mg of naproxen sodium with 1000 mg acetaminophen
 
 
  
• 
220 mg of naproxen sodium with 650 mg acetaminophen 
 
  
 
Title of Study:  
A Randomized, Double-Blind, Placebo- and Active- Controlled, Proof of Concept Study to Evaluate Two 
Strengths of Concomitantly Dosed Naproxen Sodium  with Acetaminophen, Compared with Naproxen 
Sodium, Hydrocodone/Acetaminophen and Placebo in Postoperative Dental Pain 
Country: USA 
Phase of development: 2 
Objective: 
Primary: 
To evaluate  relative efficacy of two strengths of concomitantly administered naproxen sodium and 
acetaminophen versus hydrocodone 10 mg + acetaminophen 650 mg, on self-assessed pain over 12 hours.  
 
Secondary: 
To evaluate  relative efficacy of two strengths of concomitantly administered naproxen sodium and 
acetaminophen versus naproxen sodium, on self-assessed pain over 12 hours. 
 
 
 
 
 
 
Overall Study Design/Methodology: 
This will be a randomized, double-blind, placebo- and active- controlled, parallel-group study to evaluate 
the analgesic efficacy, and safety profile of the following strengths of naproxen sodium (NPX) 
/acetaminophen (APAP) administered concomitantly as a single dose: 
• 
440 mg of naproxen sodium with 1000 mg acetaminophen  
• 
220 mg of naproxen sodium with 650 mg acetaminophen  
 
Subjects will undergo surgical removal  of up to four third molars, of which, two must be mandibular 
impactions. Both maxillary third molars may be removed regardless of impaction level. Supernumerary 
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Test Naproxen Sodium 440 mg Tablets/Acetaminophen 1000 mg Tablets 
Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
COMPANY CONFIDENTIAL 
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teeth may also be removed.  The mandibular third molars must meet one of the following criteria and must 
not result in an overall surgical trauma rating of severe on a mild, moderate, or severe scale: 
• 
two full bony impactions 
• 
one full bony impaction in combination with one partial bony impaction 
For the purposes of this study, a full impaction is being defined as at least 90% imbedded in the alveolar 
bone of the mandible.  The oral surgeon will make this judgement by visual examination of the panorex x-
ray. 
 
Approximately 288 subjects who meet the randomization criteria (post-surgical pain of moderate to severe 
on the four-point categorical pain scale, and at least a score of 5 on the 11-point [0-10] pain intensity 
numerical rating scale [PI-NRS] at baseline within 4.5 hours of last stitch from dental extractions) will be 
assigned to one of the following five treatment groups in a 2:2:2:2:1 allocation ratio: 
• 
440 mg of naproxen sodium with 1000 mg acetaminophen 
 
  
• 
220 mg of naproxen sodium with 650 mg acetaminophen
 
 
 
• 
10 mg hydrocodone + 650 mg acetaminophen (administered as two hydrocodone- and 
acetaminophen tablets 5 mg/325 mg  and two placebo tablets)  
• 
naproxen sodium 440 mg 
 
  
• 
Placebo (administered as four placebo tablets) 
All treatments will be administered as a single dose.  Rescue analgesic medication (tramadol 50 mg, 1-2 
tablets every 6 hours as needed for pain) will be available for subjects as needed.   Subjects who do not 
experience pain relief after dosing will be encouraged but not required to wait at least 1.5 hours before 
using rescue medication. 
 
No less than approximately 30% of randomized subjects will be either male or female. In addition, no more 
than approximately 30% of subjects will be 17 years of age at the time of screening.  To maintain the 
double-blind nature of the study, an independent third party will administer study drug to blindfolded 
subjects. 
 
Self-reported pain intensity will be collected using a 0-10 NRS at baseline (time 0). Pain intensity and pain 
relief will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly from 2 through 12 hours (± 5 minutes) 
post dose as well as at the time of rescue (if applicable)  
 
 
 
.  
 
Subject global evaluation of the investigational product will be collected at 12 hours or at the time of first 
rescue medication (whichever occurs first), or at the time of subject withdrawal with a 0-4 rating scale: (0) 
poor, (1) fair, (2) good, (3) very good, and (4) excellent. 
 
After completion of all study assessments, subjects will be discharged from the study site. Subjects will be 
interviewed by telephone to follow up on appropriate postsurgical medical care and changes in their health, 
including any emergent or existing AEs. The interview will occur between day 7 and 10.  
 
A detailed activity scheme is attached in Appendix 1.  
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Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
COMPANY CONFIDENTIAL 
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Number of subjects (planned):  
Planned for 288 subjects to be randomised, 64 per active treatment arm and 32 to receive placebo. 
Diagnosis and main criteria for inclusion in the study:  
Subjects 17 to 50 years of age who meet the inclusion and exclusion criteria, which includes surgical 
removal of up to four third molars, of which, two must be mandibular including at least one full bony 
impaction or one full bony impaction in combination with one partial bony impaction), resulting in at least 
moderate pain on the categorical scale and a pain intensity of ≥5 on a 0 to 10 scale, will be eligible for the 
study.  Subjects must have a baseline pre-dose oxygen saturation of 94% or greater based on pulse 
oximetry. 
Study product, dosage and mode of administration:  
• 
440 mg of naproxen sodium with 1000 mg acetaminophen
 
 to be taken orally with water) 
• 
220 mg of naproxen sodium with 650 mg acetaminophen
 
 
 to be taken orally with water)  
Reference therapy (comparator or placebo control), dosage and mode of administration:  
• 
10 mg hydrocodone + 650 mg acetaminophen (administered as a single dose of two hydrocodone 
and acetaminophen tablets 5 mg/325 mg and two placebo tablets, to be taken orally with water)  
• 
naproxen sodium 440 mg
 
to be taken orally with water)  
• 
Placebo (administered as a single dose of four placebo tablets, to be taken orally with water)  
Duration of treatment:  
Twelve hours: subjects will be observed at the study site for at least 12 hours after dosing with study 
medication, regardless of whether or not the subject rescues, vomits, or experiences other adverse events. 
Endpoints: 
Primary Efficacy Endpoint 
• 
Time weighted Pain Intensity Difference from 0 to 6 hours (SPID 6) 
• 
Time weighted Pain Intensity Difference from 0 to 12 hours (SPID 12) 
Secondary Efficacy Endpoint 
• 
Time weighted sum of pain relief from 0 to 6 hours (TOTPAR 6) 
• 
Time weighted sum of pain relief from 0 to 8 hours (TOTPAR 8) 
• 
Time weighted sum of pain relief from 0 to 12 hours (TOTPAR 12) 
• 
Time weighted of Pain Intensity Difference from 0 to 8 hours (SPID 8) 
• 
Pain relief (PAR) and pain intensity difference (PID) scores at individual time points 
• 
Subject Global Evaluation at 12 hours or time of rescue medication, whichever occurs first  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
COMPANY CONFIDENTIAL 
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Safety: 
Safety will be monitored and assessed by reviewing the collection, evaluation, and analysis of adverse 
events (AEs). Any causally related AE that is unresolved upon completion of the last study visit will be 
followed by the Investigator 
 
  Pulse oximetry will be monitored and recorded at each assessment while in the clinic. 
Statistical methods: 
SPID 6, SPID 8, SPID 12, 
 TOTPAR 6, TOTPAR 8, TOTPAR 12, PAR 
and PID scores and subject global evaluation will be analyzed using analysis of variance including baseline 
pain (moderative or severe) score, gender and treatment group in the model.  
 
 
 
 
 
Given the exploratory nature of the study, no multiple comparisions procedure will be applied. All 
statistical tests of hypothess will be two-sided and employ a significance level of α=0.05. 
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Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
 
COMPANY CONFIDENTIAL 
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2. 
STUDY FLOW CHART AND SCHEDULE OF ACTIVITIES 
Table 1: 
Schedule of Activities 
1 Baseline assessments collected on Electronic Case Report Form (eCRF);  
2 Blood pressure, heart rate, respiratory rate, oral temperature;  
3 Females of childbearing potential;  
4 HIV antibody, hepatitis B surface antigen (HBsAg) , hepatitis C virus antibody (anti-HCV);  
5 Scored within 4.5 hours after last stitch from dental surgery;  
6 Pain intensity and pain relief ratings collected: 0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly 2 - 12 hours (± 5 minutes) post dose. 
 
  
7 Subjects encouraged to wait at least 1.5 hours after investigational product administration before using rescue medicine;  
8 Evaluation at 12 hours or time of rescue medication (whichever occurs first), or at time of early termination; if subject is 
discontinued or withdrawn <12 hours after dosing; 
9 Collection of AEs and report of pregnancy (subject instructed to report pregnancy to PI within 30 days post dose) 
10 End of Study is at the time of follow up call or at time of subject withdrawal;  
Screening 
Baseline (Day of Surgery) 
Hours Post-Dose 
Follow-Up Call 
Procedures 
Day -30 to 1 
Day 1 
0 to 12 hours 
Days 7 - 10 
Written informed consent and/or 
assent 
X 
 
 
 
Demography (including age) 
X 
 
 
 
Inclusion / Exclusion  Assessment 
X1 
X 
 
 
Significant medical history 
X1 
X 
 
 
Vital signs2 
X1 
X 
 
 
Physical Exam (Height, weight and 
BMI) 
X 
 
 
 
Urine pregnancy test3 
X1 
X 
 
 
Urine drug screen11 
X1 
X 
 
 
Serology4 
X 
 
 
 
Dental extraction surgery 
 
X 
 
 
Categorical and Numerical Pain 
Intensity 
 
X5 
 
 
Randomization criteria 
 
X 
 
 
Investigational product administration 
 
X  
 
 
 
 
 
 
 
Pain intensity and pain relief ratings6 
 
 
X 
 
Pulse Oximetry12 
X 
X 
X 
 
  
 
 
 
 
Rescue therapy 
 
 
X7 
 
Subject Global Evaluation 
 
 
X8 
 
Prior and Concomitant Therapy 
X 
X 
X 
X 
Safety monitoring 
X 
X9 
X9 
X9 
Subject Disposition 
 
 
X10 
 
Follow up interview 
 
 
 
X 
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Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
 
COMPANY CONFIDENTIAL 
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11 Minimum requirements for urine drug testing for screening & day of surgery: cocaine, tetrahydrocannabinol, opioids (e.g., 
buprenorphine, oxycodone, methadone, and morphine), benzodiazepines, and amphetamines. 
12 Pulse oximetry will be performed at baseline and when pain ratings are collected (0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly 
2 - 12 hours (± 5 minutes) post dose). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
 
COMPANY CONFIDENTIAL 
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
1. 
SYNOPSIS ............................................................................................... 2 
2. 
STUDY FLOW CHART AND SCHEDULE OF ACTIVITIES ............. 6 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......... 12 
4. 
ETHICS .................................................................................................. 13 
4.1. 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC)
 ................................................................................................................ 13 
4.2. 
Ethical and Regulatory Considerations .................................................. 13 
4.3. 
Subject Information and Consent ........................................................... 13 
4.4. 
Subject Written Assent ........................................................................... 14 
5. 
STUDY ADMINISTRATIVE STRUCTURE ....................................... 15 
6. 
INTRODUCTION .................................................................................. 16 
7. 
STUDY OBJECTIVES AND ENDPOINTS .......................................... 17 
7.1. 
STUDY ENDPOINTS ............................................................................ 17 
7.1.1. 
Primary Efficacy Endpoint ..................................................................... 17 
7.1.2. 
Secondary Efficacy Endpoint ................................................................. 17 
 
 
7.2. 
Safety ...................................................................................................... 18 
8. 
INVESTIGATIONAL PLAN ................................................................. 19 
8.1. 
Overall Study Design and Plan ............................................................... 19 
8.2. 
End of Study for Each Subject ................................................................ 21 
8.3. 
Sponsor Discontinuation Criteria ........................................................... 21 
9. 
STUDY POPULATION ......................................................................... 22 
9.1. 
Subject Eligibility Criteria ...................................................................... 22 
9.1.1. 
Subject Inclusion Criteria ....................................................................... 22 
9.1.2. 
Exclusion Criteria ................................................................................... 23 
9.2. 
Subject Withdrawal/Termination Criteria .............................................. 24 
9.3. 
Life Style Guidelines .............................................................................. 25 
9.3.1. 
Meals and Dietary Restrictions ............................................................... 25 
9.3.2. 
Alcohol, Caffeine and Tobacco Consumption / Restrictions ................. 25 
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Test Naproxen Sodium 220 mg Tablets/Acetaminophen 650 mg Tablets 
 
Protocol: CCSPAA001068 
 
 
COMPANY CONFIDENTIAL 
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9.3.3. 
Physical Activity Requirements / Restrictions ....................................... 25 
9.3.4. 
Contraception for Females ...................................................................... 25 
9.3.5. 
Contraception for Males ......................................................................... 26 
10. 
STUDY INTERVENTION .................................................................... 27 
10.1. 
Description and Administration .............................................................. 27 
10.2. 
Packaging and Labeling .......................................................................... 27 
10.3. 
Preparation, Handling and Disposal ....................................................... 27 
10.4. 
Storage and Accountability ..................................................................... 29 
10.5. 
Randomization/Treatment Allocation .................................................... 30 
10.6. 
Blinding and Unblinding ........................................................................ 30 
10.7. 
Treatment Compliance ............................................................................ 31 
10.8. 
Previous and Concomitant Medications ................................................. 31 
10.8.1. 
Permitted Therapies ................................................................................ 31 
10.8.2. 
Prohibited Therapies ............................................................................... 31 
10.9. 
Rescue Therapy ...................................................................................... 31 
10.10. 
Product Quality Complaints ................................................................... 32 
11. 
STUDY PROCEDURES ........................................................................ 33 
11.1. 
Overview ................................................................................................. 33 
11.2. 
Screening Visit ........................................................................................ 33 
11.3. 
Baseline Visit (Day of Surgery) ............................................................. 33 
11.4. 
Randomization ........................................................................................ 34 
11.5. 
Post dose Assessments ............................................................................ 34 
11.6. 
Follow-Up Phone call ............................................................................. 35 
12. 
ASSESSMENTS..................................................................................... 36 
12.1. 
Efficacy Assessments ............................................................................. 36 
12.2. 
Safety Assessments ................................................................................. 36 
12.2.1. 
Physical Examination ............................................................................. 37 
12.2.2. 
Vital Signs .............................................................................................. 37 
12.2.3. 
Clinical Laboratory Tests ....................................................................... 37 
13. 
ADVERSE EVENTS.............................................................................. 38 
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13.1. 
Definitions .............................................................................................. 38 
13.1.1. 
Definition of Adverse Event ................................................................... 38 
13.1.2. 
Definition of Serious Adverse Events (SAE) for Drugs ......................... 39 
13.2. 
Adverse Event Assessments ................................................................... 41 
13.2.1. 
Severity Assessment ............................................................................... 41 
13.2.2. 
Causality Assessment ............................................................................. 42 
13.2.3. 
Resolution ............................................................................................... 43 
13.3. 
Adverse Event Reporting ........................................................................ 43 
13.3.1. 
Time Period ............................................................................................ 43 
13.3.2. 
Process for Reporting ............................................................................. 43 
13.4. 
Suspected Unexpected Serious Adverse Reaction ................................. 45 
13.5. 
Special Situations .................................................................................... 45 
13.5.1. 
Exposure In Utero ................................................................................... 45 
14. 
STATISTICS .......................................................................................... 47 
14.1. 
Sample Size Determination .................................................................... 47 
14.1.1. 
Efficacy Analyses Sets ........................................................................... 47 
14.1.2. 
Safety Analysis Population ..................................................................... 47 
14.2. 
Baseline and Demographics ................................................................... 47 
14.3. 
Previous and Concomitant Medications ................................................. 47 
14.4. 
Efficacy Analysis .................................................................................... 48 
14.5. 
Statistical Hypotheses and Treatment Comparisons ............................... 48 
14.6. 
Data Computations and Data Imputations .............................................. 49 
14.6.1. 
Endpoints Relating to Pain Intensity and Pain Relief ............................. 49 
 
 
 
 
14.7. 
Analysis Methods ................................................................................... 50 
14.7.1. 
SPID 6, SPID 8, SPID 12, 
 TOTPAR 
6, TOTPAR 8, TOTPAR12, PAR, PID and Subject Global Evaluation 50 
 
 
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14.7.4. 
Subgroup Analyses ................................................................................. 51 
14.8. 
Safety Analysis ....................................................................................... 51 
14.8.1. 
Adverse Events ....................................................................................... 51 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS..................... 52 
15.1. 
Study Monitoring .................................................................................... 52 
15.2. 
Audits and Inspections ............................................................................ 53 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE ..................... 54 
17. 
DATA HANDLING AND RECORDKEEPING ................................... 55 
17.1. 
Case Report Forms / Electronic Data Capture ........................................ 55 
17.2. 
Source Documents .................................................................................. 55 
17.3. 
Inspection and Retention of Records ...................................................... 55 
18. 
PUBLICATION POLICY ...................................................................... 56 
19. 
LIST OF REFERENCES ........................................................................ 57 
20. 
APPENDICES ........................................................................................ 58 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................... 6 
Table 2: 
Abbreviations and Specialist Terms ....................................................... 12 
Table 3: 
Investigational Product ........................................................................... 27 
 
LIST OF FIGURES 
Figure 1: 
Study Design ........................................................................................... 20 
 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
The following abbreviations and specialist terms are used in this study protocol.  
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation/ 
Term 
Definition 
AE 
Adverse Event 
BMI 
Body Mass Index 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EIU 
Exposure in Utero 
ICH GCP 
International Conference on Harmonization Good Clinical Practice 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IP 
Investigational Product 
JJCI 
Johnson and Johnson Consumer, Inc. 
NPX 
Naproxen Sodium 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OTC 
Over-the-Counter 
PAR 
Pain Relief 
PI 
Principal Investigator 
PID 
Pain Intensity Difference 
PQC 
Product Quality Complaint 
PI-NRS 
Pain Intensity-Numerical Rating Scale 
PR-NRS 
Pain Relief-Numerical Rating Scale 
SAE 
Serious Adverse Event 
SPID 
Time Weighted Sum of Pain Intensity Difference 
TOTPAR 
Time Weighted Total Pain Relief Scores 
 
 
 
 
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4. 
ETHICS 
4.1. 
Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) 
It is the responsibility of the Sponsor and Investigator to have prospective approval of the 
study protocol, protocol amendments, informed consent forms, and other relevant documents, 
e.g., advertisements, if applicable, from the IRB/IEC. All correspondence with the IRB/IEC 
should be retained in the Investigator File (Site Master File). Copies of IRB/IEC approvals 
obtained by the Investigator should be forwarded to the Sponsor. 
The only circumstance in which a protocol amendment may be initiated prior to IRB/IEC 
approval is where the change is necessary to eliminate apparent immediate hazards to the 
subjects. In that event, the Investigator must notify the IRB/IEC and the Sponsor in writing 
within 5 working days after implementation. 
4.2. 
Ethical and Regulatory Considerations 
The study will be performed in accordance with the protocol, International Council for 
Harmonization, Good Clinical Practice (ICH GCP) guidelines (ICH E6) and applicable local 
regulatory requirements and laws. 
Before initiating the clinical study, the Sponsor should submit any required application(s) to 
the appropriate authority (ies) for review, acceptance, and/or permission to begin the study. 
Any notification/submission should be dated and contain sufficient information to identify 
the protocol. 
Amendments to the protocol that are considered as substantial, i.e., are likely to have an 
impact on the safety of the study subjects, to change the interpretation of the scientific 
documents in support of the conduct of the study, or if they are otherwise significant, must be 
reviewed and approved by the appropriate authority(ies). 
4.3. 
Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or subject initials on any forms, reports, publications, or in any other disclosures. Each 
subject will be assigned a subject number that is used in the Case Report Form (CRF) in lieu 
of the subject’s name. In case of data transfer, the Sponsor will maintain high standards of 
confidentiality and protection of subject personal data. 
The informed consent form must be agreed to by the Sponsor and the IRB/IEC. It must be in 
compliance with current regulatory requirements (e.g., ICH E6), and legal requirements, and 
be in a language that the subject can read and understand with compliance to the 
International Standard and any regional or national regulations, as appropriate.   
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation in the study. The 
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Investigator, or a person designated by the Investigator, will obtain written informed consent 
from each subject, or legally authorized representative, before any study-specific activity is 
performed. The informed consent form used in this study, and any changes made during the 
course of the study, must be prospectively approved by both the IRB/IEC and the Sponsor 
before use. The Investigator will retain the original of each subject's signed consent form. A 
copy of the signed and dated consent form will be provided to subjects. 
Only subjects who provide informed consent will be permitted to participate in the study.  
4.4. 
Subject Written Assent 
After the informed consent form is signed and dated by the parents or legally authorized 
representatives and witnessed by a member of the investigator’s clinical team, written assent 
to participate in the study must be obtained from prospective subjects who are below the age 
of legal consent yet old enough to understand details of the study as required by the site’s 
IRB/IEC or Principal Investigator (PI), or local requirements.  During the assent process, the 
PI or designee will provide the minor with an assent document that explains, in terms 
appropriate to the child’s age, experience, maturity and condition, any discomfort and 
inconveniences the child may expect to experience if he or she agrees to participate. The 
subject should also be made aware of his or her rights to decline participation or to withdraw 
from the study at any time. The assent document will focus on the risks, benefits and 
alternatives to research participation as well as confidentiality of information obtained as a 
result of their participation. The minor should be given an opportunity to ask questions prior 
to signing the approved assent form or designated assent signature line within the Informed 
Consent Form. A witness must also sign and date the assent form. The original signed assent 
form will be retained by the investigator as part of the source documents/study files and will 
be available for review by the monitor and the Sponsor. A copy of the signed and dated 
assent form will be given to the subject. Assent by the subject acknowledges willingness to 
participate, but does not necessarily ensure a thorough understanding of the procedures, risks 
and benefits of the study. 
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5. 
STUDY ADMINISTRATIVE STRUCTURE 
Details on the administrative structure of the study (e.g., PI/study site personnel, the 
Sponsor’s study team, and the external service providers) will be included in the study 
contact list.  The study contact list will also include contact information for the Sponsor, 
Investigator(s), Monitor(s), Clinical and Bioanalytical Laboratories, and IRB/IEC(s), as well 
as the names and titles of the person(s) authorized to sign the protocol and the protocol 
amendment(s) for the Sponsor.  The complete contact list will be maintained in the trial 
master file throughout the study for inclusion in the clinical study report.  
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6. 
INTRODUCTION 
The combination of naproxen sodium and acetaminophen (paracetamol) is not marketed in 
the United States. The investigational product will involve concomitantly administered 
commercial formulations of naproxen sodium and acetaminophen.  
Naproxen sodium has been available in the US for OTC analgesic use since 1994. Naproxen 
is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic and anti-
inflammatory properties. In the US, naproxen sodium 220 mg is available as an OTC 
medication for the temporary relief of minor aches and pains due to minor pain of arthritis, 
muscular aches, backache, menstrual cramps, headache, toothache, and the common cold, 
and for the temporary reduction of fever [1]. The therapeutic effects of naproxen are 
produced through nonselective inhibition of cyclooxygenase enzymes (COX-1 and COX-2) 
resulting in inhibition of prostaglandin synthesis. Naproxen sodium salt has similar 
therapeutic properties as comparable doses of naproxen free acid based on molecular weight, 
but with more rapid systemic absorption. In this respect, 220 mg naproxen sodium is 
approximately equivalent to 200 mg naproxen [2].   .  
Acetaminophen has been available in the United States (US) for over-the-counter (OTC) 
adult analgesic use since the 1960s. In the US, adult single-ingredient OTC acetaminophen 
products are indicated for the temporary relief of minor aches and pains associated with the 
common cold, headache, toothache, muscular aches, and backache, for the minor pain of 
arthritis, for the pain of premenstrual and menstrual cramps and for the reduction of fever. 
Acetaminophen is a para-aminophenol derivative with analgesic and antipyretic properties.   
Although the precise mechanism of action has not been definitively established, it is believed 
that acetaminophen produces its analgesic and antipyretic effects by inhibiting prostaglandin 
synthesis centrally and elevating the pain threshold [3,4]. 
There are currently no fixed combination products containing acetaminophen and naproxen 
sodium available on the US market. Fixed combinations of acetaminophen and naproxen 
sodium are available in countries outside of the US, including the Dominican Republic, 
Ecuador, India, Mexico, Peru, and countries in Central America.  
The current study will evaluate the analgesic efficacy, safety, onset and duration of 
concomitantly administered naproxen sodium 440 mg with acetaminophen 1000 mg and 
naproxen sodium 220 mg with acetaminophen 650 mg, compared to a fixed combination of 
hydrocodone 10 mg + acetaminophen 650 mg, naproxen sodium 440 mg and placebo. 
 
 
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7. 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective: 
• To evaluate  relative efficacy of two strengths of concomitantly administered 
naproxen sodium and acetaminophen versus hydrocodone 10 mg + acetaminophen  
/650 mg, on self-assessed pain over 12 hours.  
Secondary Objective: 
• To evaluate  relative efficacy of two strengths of concomitantly administered 
naproxen sodium and acetaminophen versus naproxen sodium, on self-assessed pain 
over 12 hours. 
 
 
 
 
 
 
 
7.1. 
STUDY ENDPOINTS 
7.1.1. 
Primary Efficacy Endpoint 
• Time weighted Pain Intensity Difference from 0 to 6 hours (SPID 6) 
• Time weighted Pain Intensity Difference from 0 to 12 hours (SPID 12) 
7.1.2. 
Secondary Efficacy Endpoint 
• Time weighted sum of pain relief from 0 to 6 hours (TOTPAR 6) 
• Time weighted sum of pain relief from 0 to 8 hours (TOTPAR 8) 
• Time weighted sum of pain relief from 0 to 12 hours (TOTPAR 12) 
• Time weighted of Pain Intensity Difference from 0 to 8 hours (SPID 8) 
• Pain relief (PAR) and pain intensity difference (PID) scores at individual time points 
• Subject Global Evaluation at 12 hours or time of rescue medication, whichever occurs 
first  
 
 
 
 
 
 
 
 
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7.2. 
Safety 
Safety will be monitored and assessed by reviewing the collection, evaluation, and analysis 
of adverse events (AEs). Any causally related AE that is unresolved upon completion of the 
last study visit will be followed by the Investigator
 
  Pulse oximetry will be monitored and 
recorded at baseline and when pain ratings are collected. 
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8. 
INVESTIGATIONAL PLAN 
8.1. 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo- and active- controlled, parallel-group study to 
evaluate the analgesic efficacy, and safety profile of the following strengths of naproxen 
sodium (NPX) /acetaminophen (APAP) administered concomitantly as a single dose: 
• 440 mg of naproxen sodium with 1000 mg acetaminophen  
• 220 mg of naproxen sodium with 650 mg acetaminophen  
Subjects will undergo surgical removal of up to four third molars, of which, two must be 
mandibular impactions. Both maxillary third molars may be removed regardless of impaction 
level. Supernumerary teeth may also be removed.  The mandibular third molars must meet 
one of the following criteria and must not result in an overall surgical trauma rating of severe 
on a mild, moderate, or severe scale: 
• two full bony impactions 
• one full bony impaction in combination with one partial bony impaction 
For the purposes of this study, a full impaction is being defined as at least 90% imbedded in 
the alveolar bone of the mandible.  The oral surgeon will make this judgement by visual 
examination of the panorex x-ray. 
Approximately 288 subjects who meet the randomization criteria (post-surgical pain of 
moderate to severe on the four-point categorical pain scale, and at least a score of 5 on the 
11-point [0-10] pain intensity numerical rating scale [PI-NRS] at baseline within 4.5 hours of 
last stitch from dental extractions) will be assigned to one of the following five treatment 
groups in a 2:2:2:2:1 allocation ratio: 
• 440 mg of naproxen sodium with 1000 mg acetaminophen
 
 
  
• 220 mg of naproxen sodium with 650 mg acetaminophen
 
 
 
• 10 mg hydrocodone + 650 mg acetaminophen (administered as two hydrocodone 
andacetaminophen tablets 5 mg/325 mg and two placebo tablets)  
• naproxen sodium 440 mg
 
 
• Placebo (administered as four placebo tablets) 
All treatments will be administered as a single dose.  Rescue analgesic medication (tramadol 
50 mg, 1-2 tablets every 6 hours as needed for pain) will be available for subjects as needed.   
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Subjects who do not experience pain relief after dosing will be encouraged but not required 
to wait at least 1.5 hours before using rescue medication. 
No less than approximately 30% of randomized subjects will be either male or female. In 
addition, no more than approximately 30% of subjects will be 17 years of age at the time of 
screening.  To maintain the double-blind nature of the study, an independent third party will 
administer study drug to blindfolded subjects. 
Self-reported pain intensity will be collected using a 0-10 NRS at baseline (time 0). Pain 
intensity and pain relief will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly from 2 
through 12 hours (± 5 minutes) post dose as well as at the time of rescue (if applicable)
 
 
 
  
Subject global evaluation of the investigational product will be collected at 12 hours or at the 
time of rescue medication (whichever occurs first), or at the time of subject withdrawal with 
a 0-4 rating scale: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent. 
After completion of all study assessments, subjects will be discharged from the study site. 
Subjects will be interviewed by telephone to follow up on appropriate postsurgical medical 
care and changes in their health, including any emergent or existing AEs. The interview will 
occur between day 7 and 10. 
  
Figure 1: Study Design 
 
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8.2. 
End of Study for Each Subject 
End of Study for each subject is defined as the follow-up phone call or early termination.  
End of Study procedures are stated in the Schedule of Activities. For subjects whose 
participation is discontinued during this study, end of study evaluations will be completed as 
soon as possible after discontinuation.  
8.3. 
Sponsor Discontinuation Criteria 
Premature termination of this clinical study may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of the 
Sponsor. In addition, the Sponsor retains the right to discontinue development of this 
investigational compound at any time. 
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator. After notification, the investigator must contact all participating subjects within 
two weeks. All study materials must be collected and all CRFs and electronic source 
documents completed to the greatest extent possible. 
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9. 
STUDY POPULATION 
9.1. 
Subject Eligibility Criteria 
This clinical study can fulfill its objectives only if appropriate subjects are enrolled. The 
following eligibility criteria are designed to select subjects for whom protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. No 
waivers to inclusion or exclusion criteria will be permitted. 
9.1.1. 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Males or females who are 17 to 50 years of age (inclusive) at the time of screening; 
2. If female and of childbearing potential have a negative urine pregnancy at screening and at 
baseline;  
3. Weigh (100 ) pounds or greater and have a body mass index (BMI) of 18.5 to 35.4(inclusive) 
at screening; 
4. Have undergone surgical removal of up to four third molars, of which, two must be 
mandibular impactions (including at least one full bony impaction). Both maxillary third 
molars may be removed regardless of impaction level. Supernumerary teeth may also be 
removed. The mandibular extractions must meet one of the following criteria (and must not 
result in a trauma rating of ‘severe’ on a mild, moderate, or severe scale): 
• two full bony impactions 
• one full bony impaction in combination with one partial bony impaction; 
5. Indicate at least moderate pain on a categorical scale ranging from (0) none, (1) mild, (2) 
moderate, or (3) severe AND at least a score of 5 on the 11-point (0-10) pain intensity 
numerical rating scale (PI-NRS) at baseline within 4.5 hours of the last stitch from oral 
surgery; 
6. Are able to comprehend and follow the requirements of the study (including pre-surgical 
instructions provided by the site and availability on scheduled visit dates) based upon 
research site personnel’s assessment; 
7. Provide written informed consent; or for subjects who are below the age of legal consent, 
parent or legally authorized representative provides written informed consent and the 
subject provides written assent; 
8. Females of childbearing potential and males agree to the contraceptive requirements as 
outlined in section 9.3.4 and 9.3.5; 
9. Are willing for this to be the only investigational product used during the study; 
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10. Have a negative urine drug screen at screening, and on day of surgical procedure. 
9.1.2. 
Exclusion Criteria 
Subjects will be excluded if they: 
1. Are female and are pregnant, breastfeeding or currently trying to become pregnant; 
 
2. Are male with a pregnant partner or a partner who is currently trying to become 
pregnant; 
 
3. Have a known allergy or hypersensitivity to naproxen or other NSAIDs, including 
aspirin, acetaminophen, hydrocodone, tramadol or other opioids; 
 
4. Presence or history of major medical condition that in the investigator’s opinion may 
jeopardize the subject’s safety or well-being (e.g. hepatic, renal, pancreatic, 
gastrointestinal , cardiovascular, cerebrovascular, or thyroid diseases as well as a 
history of head injury (with the exception of mild or clinically non-significant at the 
judgement of the investigator) seizures, history of respiratory depression or lung 
problems such as but not limited to asthma or chronic obstructive pulmonary disease, 
psychiatric disorders, problems urinating, known or suspected gastrointestinal 
obstruction, including paralytic ileus, or a history of blockage or narrowing of the 
stomach or intestines, uncontrolled hypertension indicated as systolic blood pressure 
≥160 mm Hg or diastolic blood pressure ≥100 mm Hg, or uncontrolled diabetes in the 
last 6 months) or the integrity of the study; 
 
5. Baseline pre-dose oxygen saturation less than 94% based on pulse oximetry. 
 
6. Are not able to swallow whole large tablets or capsules; 
 
7. Routinely use oral analgesics ≥5 times per week; 
 
8. Have a history of chronic tranquilizer use, heavy drinking, or substance abuse 
(including but not limited to opioid use disorder), as judged by the investigator site 
staff, in the last 5 years. Heavy drinking is defined as the use of more than 4 standard 
drinks daily or more than 14 drinks a week for men, and more than 3 standard drinks 
daily or more than 7 standard drinks in a week for women. Standard drink refers to 14 
g (0.6 oz.) of pure alcohol, which is approximately 12 oz. of beer, 8 oz. of malt liquor, 
5 oz. of wine, 1.5 oz. or “shot” of 80-proof distilled spirits or liquor (e.g., gin, rum, 
vodka, or whiskey); 
 
9. Have a history of peptic ulcer disease or gastrointestinal bleeding in the last two years 
or hematologic bleeding 
 
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10. Used oral OTC or prescription products (except contraceptive medications and those 
required for use during the oral surgical procedure), within 5 half-lives before the oral 
surgical procedure; 
 
11. Used vitamins, dietary or herbal supplements within 5 days before the oral surgical 
procedure; 
 
12. Used any immunosuppressive drugs, corticosteroids (except for ocular, intranasal or 
topical corticosteroids), or injectable or oral anticoagulants (e.g., heparin, Lovenox, 
Xarelto, Eliquis, Pradaxa, Coumadin, Miradon) within 2 weeks of screening; 
 
13. Used alcohol within 3 days before the oral surgical procedure; 
 
14. Consumed methylxanthine-containing products (e.g., chocolate bars or chocolate 
beverages, coffee, tea, cola or caffeinated energy drinks), tobacco, or nicotine 
containing products (e.g., cigarettes, cigars, nicotine replacement therapies) < 12 
hours before the oral surgical procedure; 
 
15. Use of monoamine oxidase inhibitors within 14 days prior to surgery; 
 
16. Has a positive test for human immunodeficiency virus (HIV) antibody, hepatitis B 
surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV); 
 
17. Participated in any interventional clinical trials within 30 days before screening;  
 
18. Are related to those persons involved directly or indirectly with the conduct of this 
study (i.e., PI, sub investigators, study coordinators, other site personnel, employees 
of Johnson & Johnson subsidiaries, contractors of Johnson & Johnson, and the 
families of each). 
9.2. 
Subject Withdrawal/Termination Criteria 
Subjects have the right to withdraw from the study at any time for any reason without 
compromising their rights to receive further treatment. The Investigator and/or the Sponsor 
may terminate a subject from investigational treatment and/or study follow-up in the event of 
any of the following: 
• Medical reasons considered significant by the subject, Investigator and/or the 
Sponsor, which may include, an Adverse Event (AE), intercurrent illness or medical 
reasons unrelated to the study 
• Nonmedical reasons (e.g., subject request or noncompliance with the treatment 
procedure as determined by the Investigator, the Sponsor and/or subject) 
• Pregnancy 
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• Serious eligibility or on-study violation of the protocol 
• Administrative or other reasons (e.g., lost to follow-up, non-compliance) 
Should a subject decide to withdraw from the study at any point, all efforts should be made to 
complete all end of study assessments.  In case of questions surrounding the circumstances 
that a subject needs to be withdrawn from the study (e.g., protocol deviation), the Sponsor, or 
the Sponsor representative should be consulted. The reason for withdrawal should be 
documented in the subject’s source document and in the Subject Disposition CRF.  
If a subject is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal 
before considering the subject to be lost to follow-up. Such efforts should include repeated 
telephone calls, certified letters as described in section 11.6. The measures taken to follow up 
must be documented.  
9.3. 
Life Style Guidelines  
9.3.1. 
Meals and Dietary Restrictions  
Only clear, non-caffeinated liquids may be consumed from the time of surgery until two 
hours following administration of the investigational product. After two hours, subjects may 
consume soft foods consistent with having dental surgery. 
9.3.2. 
Alcohol, Caffeine and Tobacco Consumption / Restrictions  
Use of alcoholic beverages within three days before the oral surgical procedure and during 
the study is prohibited.  In addition, subjects must refrain from the use of any 
methylxanthine-containing products (e.g., chocolate bars or beverages, coffee, tea, colas, or 
caffeinated energy drinks) and tobacco or nicotine containing products (e.g., cigarettes, 
cigars, nicotine replacement therapies) within 12 hours before surgery and during the study 
while confined at the site.  
9.3.3. 
Physical Activity Requirements / Restrictions  
Walking at a normal pace will be permitted.  Subjects will remain sitting upright or semi- 
reclining for dosing and should remain in the study area under observation for at least 4 hours 
immediately following treatment administration, except for short durations to use the 
restroom.  
9.3.4. 
Contraception for Females 
Female subjects with reproductive potential must agree to practice a medically acceptable 
form of birth control throughout the study and for 30 days following the last dose of 
investigational product, whichever is later.  
Medically acceptable forms of birth control that may be used by the subject and/or his/her 
partner include:  
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• 
Sexually active female subjects who use hormonal contraception must have used a stable 
dose for 30 days before surgery. If hormonal contraception has been used for less than 30 
days or if the dose has changed within the past 30 days, subjects must agree to also use a 
barrier method during the study and up to 30 days after taking the investigational product. 
• Barrier methods of contraception with spermicide: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/ cream/ 
suppository;  
• Intrauterine device (IUD) or intrauterine system (IUS); 
• Surgical sterilization (e.g., vasectomy that has been confirmed effective by sperm 
count check, tubal occlusion, hysterectomy, bilateral salpingectomy); 
• Abstinence from heterosexual intercourse: When this is in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  
Female subjects are not considered of childbearing potential if they meet at least one of the 
following criteria: 
• Had a hysterectomy and/or bilateral oophorectomy at least 6 months prior to 
product administration; 
• Had sterilization surgery (e.g., hysteroscopic sterilization/tubal implants or tubal 
ligation) at least 6 months prior to screening; tubal implants must have been 
confirmed effective by medical assessment as reported by the subject; 
• Are postmenopausal (i.e., amenorrheic for at least 12 consecutive months, without 
an alternative medical cause, prior medical screening by a healthcare provider). 
9.3.5. 
Contraception for Males 
Male participants will be informed about potential risks of the study medication for embryos 
and fetuses. 
Male subjects are instructed to practice a medically acceptable form of birth control from the 
first dose of study medication until at least 30 days after the last dose of study drug in order 
to prevent their partner from becoming pregnant. Medically acceptable forms of birth control 
that may be used by the subject and/or his/her partner are described in section 9.3.4. 
Information about effective means of birth control (hormonal contraception, intrauterine 
devices, vasectomy, sexual abstinence) will be provided, and discussed as appropriate with 
individual subjects. 
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10. 
STUDY INTERVENTION 
10.1. 
Description and Administration 
A description of the investigational products are provided in Table 3.  
Table 3: 
Investigational Product 
Product 
 
(acetaminophen 
325 mg)    
 
 
(acetaminophen 
500 mg) 
 
(naproxen 
sodium 220 
mg) 
Hydrocodone  and 
acetaminophen 
tablets  CII  
(5 mg/325 mg) 
Placebo 
Dosage Form 
Tablet 
Caplet 
Tablet 
Tablet 
Tablet 
Route of Administration 
Oral 
Oral 
Oral 
Oral 
Oral 
Unit Dose 
325 mg 
500 mg 
220 mg 
5 mg/325 mg 
Not applicable 
Physical Description 
White Round 
Shaped Tablet   
White Capsule 
Shaped Caplet 
Blue Round 
Shaped 
Tablet 
White oval shaped 
tablet 
White Oval 
Shaped Tablet 
Manufacturer/Brand 
McNeil Consumer 
Healthcare,  
Fort Washington, 
PA 19034  
McNeil Consumer 
Healthcare, 
Fort Washington, 
PA 19034 
Bayer 
HealthCare 
Inc. 
Whippany, 
NJ 07981 
SpecGx LLC,  
 
Webster Groves, 
MO 63119 USA  
Patheon Inc ,  
 
Manati, PR  
00674 
10.2. 
Packaging and Labeling 
Product will be provided in High Density Polyethylene (HDPE) bottles. Each bottle will be 
labeled with a single panel sponsor study label. 
10.3. 
Preparation, Handling and Disposal 
Investigational products and placebo will be supplied by the Sponsor in bulk containers in an 
unblinded manner. In order to maintain the double-blind status of the study, the site must 
adhere to the following general storage, dispensing, and dosing procedures: 
• 
The site will delegate a qualified third party and back-up staff member(s) who will be 
responsible for dispensing and administering study medication and who will have no other 
direct or indirect role in the execution of this study. 
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Protocol: CCSPAA001068 
 
 
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• 
The Sponsor will provide a randomization schedule directly to the qualified third-party 
individual. The randomization schedule will be kept in a locked, secured area with access 
limited to only the assigned third-party individual and un-blinded monitor.  
• 
Covered dosing cups will be used by the assigned third-party dispenser to transport the 
assigned investigational product from the designated dispensing room to the subject’s room. 
Investigational product preparation and dispensing will be performed on Day 1, following 
dental surgery. For subjects who meet the randomization criteria, an independent third-party 
dispenser will administer one of the following study treatments with up to 180 ml of water at 
ambient temperature to blindfolded subjects: 
• 440 mg of naproxen sodium with 1000 mg acetaminophen
 
 
  
• 220 mg of naproxen sodium with 650 mg acetaminophen
 
 
 
• 10 mg hydrocodone + 650 mg acetaminophen (administered as two hydrocodone and 
acetaminophen tablets 5 mg/325 mg and two placebo tablets) 
• naproxen sodium 440 mg 
 
•  Placebo (administered as four placebo tablets) 
Baseline pain assessments and drug administration will be completed in the subject’s room. 
The third-party dispenser will prepare study medication for each subject in a designated 
dispensing room. Study medication will be dispensed at the time that the subject’s pain level 
is determined to be eligible by verbal assessment, just prior to the completion of the baseline 
categorical pain severity scale and the baseline 11-point [0-10] pain intensity numerical 
rating scale [PI-NRS]. The study coordinator will communicate the subject’s pain severity 
and gender to the dispenser. The dispenser will assign the next available randomization 
number from the appropriate stratum. The dispenser will dispense the appropriate study 
treatment from the appropriate bulk supply containers into two separate dosing cups. The 
double-blind label with the same randomization number will be affixed to the dosing cups 
and the tear-off portion of the label will be attached to the patient’s source documents. The 
third-party 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 un-blinded monitor. A second 
individual, with no other study involvement, will witness the preparation and dispensing 
process. No other study personnel will be present in the designated dispensing room at the 
time of study drug dispensing. The dispenser will ensure the dosing cups containing the 
randomized study treatments are covered prior to exiting the dispensing room.  
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The third-party dispenser will inform the blinded study coordinator once the study drug is 
dispensed and is ready to be administered to the subject. Following completion of the 
baseline categorical pain severity scale and baseline pain intensity numerical rating scale, the 
study coordinator will blindfold the subject and then exit the subject’s room to inform the 
dispenser that the pain assessments are completed and confirm that the pain severity has not 
changed from the verbal assessment used to determine the appropriate randomization, and 
that the pain intensity numerical rating scale score qualifies the subject for randomization. If 
the baseline categorical pain severity has changed, new study drug from the corresponding 
pain stratum will be prepared and the randomization number and study medication 
corresponding to the original pain stratum will be held in quarantine until study completion 
and will not be reused.  The dispenser will deliver the study drug from the designated 
dispensing room to the subject’s room in  covered dosing cups to ensure no other individual 
will be able to see the study drug in the bottle. No other study personnel, other than the third-
party witness, will be present in the subject’s room at the time of dosing. 
After entering the blindfolded subject’s room and while the subject is sitting up, the 
dispenser will hand the first dosing cup containing the study treatment to the blindfolded 
subject and instruct the subject to empty the contents of the dosing cup directly into his/her 
mouth and then swallow the study medication immediately with up to 180 ml of water at 
ambient temperature. The dispenser will then hand the second dosing cup containing the 
study treatment to the blindfolded subject, instruct the subject to empty the contents of the 
dosing cup directly into their mouth,  and swallow the study medication immediately with up 
to 180 ml of water at ambient temperature. The dispenser will inspect the subject’s oral 
cavity to ensure that the study treatment was swallowed. The time at which the subject 
swallows all study medication will be recorded as Time 0. Study drug will be administered to 
the subject within 5 minutes of the completion of the baseline pain assessments. In the event 
of early discontinuation, the subject is prohibited from operating a vehicle.  
If a subject vomits after dosing, the subject will not be re-dosed but will remain in the study. 
At the end of the study, the Sponsor will provide instructions as to disposition of any unused 
investigational product.  If the Sponsor authorizes destruction at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by the 
Sponsor.  Destruction must be adequately documented. 
10.4. 
Storage and Accountability 
The investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational product is stored in a secured area, at room temperature, 68 ºF to 77 ºF (20 ºC 
to 25 ºC) and in accordance with applicable regulatory requirements. 
The investigator, or assigned representative, must maintain adequate records documenting 
the receipt, use, loss, or other disposition of the investigational product on the Investigational 
Product Accountability Log supplied by the Sponsor. The log must identify the 
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investigational product and randomization number, and account for its disposition on a 
subject-by-subject basis, including specific dates administered and quantities. The log must 
be signed by the individual who dispensed the investigational product, and copies must be 
provided to the Sponsor. All Investigational Product and Investigational Product Logs are 
kept together in a secure, double-locked location with access only allowed to the third-party 
person(nel), back-up staff member and un-blinded monitor. The study site must maintain 
accurate and adequate records including shipment receipt and return of unused 
investigational product shipments. 
Storage and dispensing of all controlled substances (e.g., hydrocodone and tramadol) will be 
managed by JBR Clinical Research in accordance with the Controlled Substances Act.  
10.5. 
Randomization/Treatment Allocation 
The randomization schedule will be generated by the Sponsor to ensure treatment blinding. 
The site will keep the randomization schedule in a locked, secured area with access limited to 
only the assigned third-party person(nel), back-up staff member, and un-blinded monitor. 
After meeting the appropriate post-surgery criteria, subjects will be randomized to receive 
one of five treatments (440 mg of naproxen sodium with 1000 mg acetaminophen, 220 mg of 
naproxen sodium with 650 mg acetaminophen, 10 mg hydrocodone + 650 mg 
acetaminophen, naproxen sodium 440 mg, and Placebo in a 2:2:2:2:1  ratio. Subjects will be 
stratified by gender and baseline pain (moderate or severe). For subjects with moderate 
baseline pain, randomization numbers will be assigned to subjects in sequential order starting 
with the lowest available number within the appropriate gender stratum. Similarly, for 
subjects with severe baseline pain intensity, subjects will be assigned in sequential order 
starting with the highest available number in the appropriate gender stratum. 
10.6. 
Blinding and Unblinding  
If, in the opinion of the Investigator, it is necessary to break the treatment code for safety 
reasons and circumstances allow, the Investigator will first contact the Designated Physician 
Representative or designee for consultation about breaking the study blind. If there is a 
medical emergency and the Investigator deems it necessary to know the subject’s study 
treatment urgently for the subject’s proper medical care, the Investigator may break the 
treatment code immediately, and then contact the Designated Physician Representative or 
designee as soon as possible afterward. 
In the event of a medical emergency that necessitates breaking the code, the third-party 
person(nel) will be permitted to inform the Investigator what study drug the subject was 
given. 
When the blind is broken, the Investigator will notify the Sponsor within 24 hours after 
determining that it is necessary to unblind the treatment assignment and document the reason 
and date of the unblinding. The event will also be recorded in the CRF and in the source 
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document. Any AE or (Serious Adverse Event) SAE associated with breaking the blind must 
be recorded and reported as specified in this protocol. 
Once the treatment is unblinded, the subject must be discontinued from the study and 
followed until the event is resolved. The rationale, date, time, and attempts to contact the 
Sponsor must be documented in the source document. The study site should take the 
necessary measures to maintain the treatment blind throughout the study and prevent any 
unintended or premature unblinding. 
10.7. 
Treatment Compliance  
All subjects randomized to treatment in this study will be in compliance with treatment if 
they take the dose of study medication.  
10.8. 
Previous and Concomitant Medications  
Medications and other treatments that are taken from 30 days prior to screening until the end 
of the 12-hour assessment period will be recorded in the source documents and CRF.  
Additional postsurgical medications (e.g., antibiotics or analgesic prescriptions) and other 
treatments or therapies (e.g., ice packs) that are taken after the 12-hour assessment period  
through the follow-up interview will be captured on the source documents, but not in the 
CRF. However, concomitant medications and other treatments taken for or associated with an 
AE will be recorded on the CRF and the source documents. 
10.8.1. 
Permitted Therapies 
Female subjects taking hormonal contraceptives will be instructed to continue before, during, 
and after the study as per protocol.  All subjects will be permitted a short-acting local 
anesthetic, lidocaine with or without epinephrine, and/or nitrous oxide during dental surgery. 
Topical benzocaine is also allowed. 
10.8.2. 
Prohibited Therapies 
Long-acting anesthetics are prohibited during the dental surgery.  Other medications 
prohibited before entry into the study are listed under Exclusion Criteria. 
10.9. 
Rescue Therapy  
Subjects will be encouraged, but not required, to wait at least 1.5 hours after investigational 
product dosing before using the rescue medicine, tramadol 50 mg, if the severity of the 
subject’s pain increases to an intolerable level. Tramadol 50 mg  tablets will be used 
according to its product labeling. Use of rescue medicine will be recorded in the source 
document and CRF. Once rescue medicine has been administered,
 
 subjects will continue to record pain intensity, pain relief and their 
global assessment. 
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10.10. 
Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or oral communication, query, 
observation, or issue related to the identity, quality, durability, reliability, safety, efficacy or 
performance of investigational supplies. Any PQC discovered during the initial inventory 
should follow the instructions provided on the receipt letter; no PQC form should be filed for 
issues identified when opening or unpacking a shipment. Subsequently, any observation of a 
PQC requires immediate notification to the Sponsor’s un-blinded Study Manager via a 
completed PQC form and telephone call. The un-blinded Study Manager will then send the 
completed PQC form to the Clinical Supply Manager. During the PQC process, the un-
blinded Study Manager can assist or answer any questions the site may have. If a photograph 
is required to better understand the nature of the PQC, the site should send the photograph 
directly to the un-blinded Study Manager who will then forward it to the Clinical Supply 
Manager.  
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11. 
  STUDY PROCEDURES 
11.1. 
Overview 
The Schedule of Activities/Study Flow Chart (Section 2) summarizes dose administration 
and the timing and frequency of safety and efficacy procedures and measurements. In the 
event of abnormal safety findings during the conduct of the study, the attending physician 
may request additional safety evaluations, either immediately or subsequently at a frequency 
considered appropriate. 
11.2. 
Screening Visit 
Informed consent will be obtained from the subjects before any study related assessments are 
conducted. 
• Inclusion and exclusion criteria 
• Demography 
• Collection of age 
• Significant medical history – the condition, diagnosis, or surgical procedure 
• History of medication and other treatments (within 30 days prior to screening) 
• Vital signs: resting blood pressure, heart rate, respiratory rate, oral temperature 
• Height, weight and BMI assessment 
• A serum sample will be collected to test for HIV antibody, hepatitis B surface antigen 
(HBsAg) and hepatitis C virus antibody (anti-HCV) 
• Blood oxygen saturation 
• Urine drug screen test 
• Urine pregnancy test on females with childbearing potential 
• Safety monitoring 
• Subjects who meet all study entry requirements per the inclusion/exclusion criteria 
will be scheduled for the dental procedure within 30 days after Screening. 
11.3. 
Baseline Visit (Day of Surgery) 
The following will be re-evaluated prior to the surgical procedure, and the evaluations will be 
recorded in the source documents and the CRF. For data collected on both Screening and 
Baseline Visits, only the data collected at Baseline will be recorded on the CRF. 
• Inclusion and exclusion criteria 
• Any changes to medical and surgical history 
• Any changes to prior and concomitant therapies 
• Vital signs: resting blood pressure, heart rate, respiratory rate, oral temperature 
• Categorical and Numerical Pain Intensity 
• Blood oxygen saturation 
• Urine drug screen test.  A negative urine drug screen must be obtained on the same 
day as the surgical procedure. 
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• Urine pregnancy test on females with childbearing potential. A negative urine 
pregnancy test (for women of childbearing potential) must be obtained on the same 
day as the surgical procedure. 
11.4. 
Randomization 
After the dental procedure, subjects will be asked to rest quietly at the study center until they 
experience both post-surgical pain of moderate to severe on a four-point categorical and at 
least a score of 5 on the 11-point (0-10) PI-NRS (pain intensity numerical rating scale) within 
4.5 hours of the last stitch during oral surgery. Subjects who did not meet these criteria will 
be considered a screen failure. 
Randomization numbers will be assigned to subjects in sequential order starting with the 
lowest available number within the appropriate gender stratum for subjects with moderate 
baseline pain and starting with the highest available number in the appropriate gender 
stratum for subjects with severe baseline pain intensity. Randomized subjects will receive 
their dose of investigational product, which will be considered time 0. The administration of 
investigational product should occur as described in Section 10.3. Site staff will inspect the 
subject’s oral cavity to ensure that the investigational product was swallowed. 
11.5. 
Post dose Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the end of the 12-hour assessment, at the time of rescue, or at the time of early termination 
if a subject is discontinued or withdrawn earlier than 12 hours after dosing, subjects will be 
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asked to report their overall impression of therapy (Subject Global Evaluation) as (0) Poor, 
(1) Fair, (2) Good, (3) Very good, or (4) Excellent. Subjects who use rescue therapy will 
continue in the study and assess pain and relief through twelve hours (APPENDIX 2). 
 
 
 
 
 
 
 
11.6. 
Follow-Up Phone call 
Subjects will be interviewed by telephone to follow up on appropriate postsurgical medical 
care and changes in their health, including any emergent or existing AEs. The interview will 
occur between Day 7 – 10. At least three attempts should be made to contact the subject by 
phone. If the subject cannot be contacted by phone by Day 10, then a certified letter should 
be mailed to the subject.  Every effort will be made by the investigator or designated study 
staff to adhere to the schedule.  
 
 
   
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12. 
ASSESSMENTS  
12.1. 
Efficacy Assessments  
The investigator or designated study staff will ensure the subjects complete the pain intensity 
and pain relief assessments at 0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly from 2 through 12 
hours (± 5 minutes) after dosing as well as at the time of rescue (if applicable)
 
Subjects will record their pain intensity and pain relief directly onto the respective source 
worksheet. Evaluations will include the following parameters: 
• Pain intensity 
− Four-point categorical scale collected at baseline: (0) no pain; (1) mild pain; 
(2) moderate pain; (3) severe pain 
− 0-10 PI-NRS collected at baseline and at each time point as well as time of 
rescue (if applicable) before administration, 
 
 
• Pain relief– 0-10 PR-NRS collected at each time point as well as time of rescue (if 
applicable) before administration,  
 
 
• 
 
 
 
 
 
 
 
 
• Subject global evaluation – subject’s overall impression of the investigational 
product at 12 hours or time of rescue medication (whichever occurs first), or at 
the time of early termination if a subject is discontinued or withdrawn earlier than 
12 hours after dosing: 
(0) poor (1) fair (2) good (3) very good (4) excellent 
12.2. 
Safety Assessments 
Safety will be monitored via AE reporting. If an AE is reported, the subject will be asked to 
elaborate on the nature of the event. The investigator or designated study staff will evaluate 
and record according to the AE Reporting section of the protocol. 
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Normal consequences of dental surgery (e.g., pain, swelling, bruising) are not considered 
AEs unless the investigator believes the condition worsened or was aggravated following 
study drug therapy. 
12.2.1. 
Physical Examination 
Height and weight measurements will be collected at screening and BMI will be calculated.  
12.2.2. 
Vital Signs 
Vital signs will be collected at screening and baseline. All vital signs (blood pressure, heart 
rate respiratory rate, and oral body temperature) will be collected after at least 5 minutes of 
rest in a supine or semi-reclining position in a quiet setting without distractions (e.g., 
television, cell phones). Systolic and diastolic blood pressure and heart rate measurements 
will be assessed with a completely automated device, consisting of an inflatable cuff and an 
oscillatory detection system. All values will be registered on an automated recorder so that 
measurements are observer independent. Manual techniques will be used only if an 
automated device has malfunctioned. Respiratory rate will be measured over at least 30 
seconds. Oral body temperature will be measured using a Sponsor-approved standard 
method. Abnormal vital signs collected at screening and baseline will be assessed by the 
medically qualified investigator to confirm that the subject is medically suitable for study 
participation. A pulse oximeter will be used to monitor blood oxygen saturation levels.  
12.2.3. 
Clinical Laboratory Tests 
Females of childbearing potential will have a urine pregnancy at screening visit and at 
baseline.  Serology will be performed at screening and will include HIV antibody, hepatitis B 
surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV). A urine drug screen will 
also be performed at screening and baseline.  The minimum requirements for urine drug 
testing include cocaine, tetrahydrocannabinol, opioids (e.g., buprenorphine, oxycodone, 
methadone, and morphine), benzodiazepines, and amphetamines. 
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13. 
ADVERSE EVENTS  
Timely, accurate, and complete reporting of safety information from clinical studies are 
crucial for the protection of subjects, Investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide.  All observed or volunteered AEs regardless of suspected 
causal relationship to the Investigational Product(IP) will be reported as described in the 
following sections.  For all AEs, the Investigator or medically qualified individual 
(MD/DO/DMD/DDS) must pursue and obtain adequate information to make the appropriate 
assessments.   
13.1. 
Definitions 
13.1.1. 
Definition of Adverse Event  
An AE is any untoward medical occurrence that occurs in a subject after they have signed an 
informed consent for a study. The event does not need to have a suspected causal relationship 
with the IP. Therefore, an AE can be any unfavorable and unintended sign, symptom, disease 
or injury temporally associated with the subject’s participation in the study. Examples of AEs 
include, but are not limited to: 
• Abnormal test findings,  
• Clinically important signs and symptoms, 
• Changes in physical examination findings, 
• Hypersensitivity, and  
• Progression/worsening of underlying disease.  
Additionally, they may include the signs or symptoms resulting from: 
• Overdose,  
• Withdrawal,  
• Abuse,  
• Drug misuse,  
• Drug interactions, 
• Medication errors,  
• Product dependency, 
• Exposure in utero, and 
• Study related procedure 
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13.1.1.1. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention 
beyond ordering a repeat (confirmatory) test, and/or 
• Test result leads to a discontinuation from the study, significant additional 
concomitant treatment, or other therapy, and/or  
• Test result is considered to be an AE by the medically qualified investigator or 
designee or the Sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
13.1.2. 
Definition of Serious Adverse Events (SAE) for Drugs 
An AE or suspected adverse reaction is considered “serious” for a drug study if, in the view 
of either the medically qualified investigator or designee (MD/DO/DMD/DDS) or the 
Sponsor, it results in any of the following outcomes:  
• Results in death, 
• Is life-threatening (immediate risk of death), 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions,  
• Results in congenital anomaly/birth defect,  
• Is considered medically significant (medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not result in death, be 
life-threatening or require hospitalization but may be considered a serious adverse 
drug experience when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent 
one of the other outcomes listed above).  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an Emergency 
Room or at home, blood dyscrasia, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse, or 
malignancy), or, 
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• Is a suspected transmission of any infectious agent via a medical product 
(medically significant) and should be reported as an SAE in the category ‘Other 
medically important conditions.’ 
An AE or suspected adverse reaction is considered “serious” for a device study if, in the view 
of either the Investigator or the Sponsor, it results in any of the following outcomes:  
• Death 
• Serious injury which means an injury or illness that: 
− Is life-threatening (immediate risk of death),  
− Results in permanent impairment of a body function or permanent damage to 
a body structure, or  
− Requires inpatient hospitalization or prolongation of existing hospitalization, 
− Necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure; 
permanent means irreversible impairment or damage to a body structure or 
function, excluding trivial impairment or damage.  
• Results in congenital anomaly/birth defect 
• Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
• A malfunction that the device (or similar device marketed by the same 
manufacturer or importer) would be likely to cause death or similar injury if the 
malfunction were to recur 
• Any suspected transmission of any infectious agent via a medicinal product 
(medically significant). 
13.1.2.1. Hospitalization 
AEs reported from clinical studies associated with hospitalization or prolonging 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to 
an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit). Hospitalization does not 
include the following:  
• Rehabilitation facilities,  
• Hospice facilities,  
• Respite care (e.g., caregiver relief),  
• Skilled nursing facilities,  
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• Nursing homes,  
• Emergency room visits (unless the reason for the emergency room visit meets one 
of the other outcomes in the definition of serious), and/or  
• Same day surgeries (as outpatient/same day/ambulatory procedures), 
• Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical AE is not in itself an SAE. Examples include:  
 Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition 
(e.g., for work-up of persistent pre-treatment lab abnormality),  
 Social admission (e.g., subject has no place to sleep),  
 Administrative admission (e.g., for yearly physical exam),  
 Protocol-specified admission during a clinical study (e.g., for a procedure 
required by the study protocol),  
 Optional admission not associated with a precipitating clinical AE (e.g., or 
elective cosmetic surgery),  
Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the entire protocol and/or for the individual subject.  
• Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs. However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE. 
For example, an acute appendicitis that begins during the AE reporting period 
should be reported as the AE and the resulting appendectomy should be recorded 
as treatment of the AE. 
13.2. 
Adverse Event Assessments  
Sufficient information should be obtained for each AE to allow the Investigator or medically 
qualified individual to make assessments as described below.  
13.2.1. 
Severity Assessment 
The severity of AEs will be assessed by the medically qualified Investigator or designee 
using the following general categorical descriptors:  
MILD: 
Awareness of symptoms that are easily tolerated, causing minimal 
discomfort and not interfering with the subject's usual function or normal 
everyday activities. 
MODERATE: 
Sufficient discomfort is present to cause interference to some extent with 
the subject's usual function or normal everyday activity. 
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SEVERE:  
Extreme distress, causing significant impairment of functioning or 
incapacitation; interferes significantly with subject's usual function; 
prevents normal everyday activities. 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily a serious event.  For example, a headache may be severe (interferes significantly 
with the subject's usual function) but would not be classified as serious unless it met one of 
the criteria for SAEs listed above. 
13.2.2. 
Causality Assessment 
The medically qualified Investigator’s assessment of causality to IP (i.e., relationship to IP) 
must be provided for all AEs (serious and non-serious).  The causality assessment is the 
determination of whether there exists a reasonable possibility that the IP caused or 
contributed to an AE.  
• 
Not Related - An AE that is not related to the use of the drug  
• 
Doubtful - An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s), concomitant disease(s), or the relationship in time suggests 
that a causal relationship to IP is unlikely.  
• 
Possible - An AE that might be due to the use of the drug. An alternative 
explanation, e.g., concomitant drug(s), concomitant disease(s), is inconclusive. 
The relationship in time is reasonable; therefore, the causal relationship to IP 
cannot be excluded.  
• 
Probable - An AE that might be due to the use of the drug. The relationship in 
time is suggestive (e.g., confirmed by dechallenge) and an alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s).  
• 
Very Likely - An AE that is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant drug(s), 
concomitant disease(s). The relationship in time is very suggestive (e.g., it is 
confirmed by dechallenge and rechallenge) for a causal relationship to the drug.  
Any AE that occurs after the informed consent has been signed, until first usage of 
investigational product, will be considered non-treatment emergent and cannot (by virtue of 
time of occurrence) have a causal relationship with the IP.   
If the Investigator determines an AE is associated with study procedures, the Investigator 
must record this suspected causal relationship in the source documents and the SAE form, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
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13.2.3. 
Resolution 
The medically qualified Investigator or designee will be required to assess the outcome of the 
AE for IP as one of the following:  
• Resolved,  
• Not Resolved, 
• Fatal, 
• Resolved with sequelae,  
• Resolving, or 
• Unknown. 
Any causally-related AEs that are not resolved upon completion of the last study visit will be 
followed up by the study staff until the event or its sequelae resolve or stabilized at a level 
acceptable to the medically qualified Investigator or designee, and recorded on the CRF.  An 
event that is assessed as resolved with sequelae or resolving indicates that the subject has 
stabilized to a level acceptable to the medically qualified Investigator or designee and has 
concurrence by the Sponsor.  
13.3. 
Adverse Event Reporting  
13.3.1. 
Time Period 
All AEs, whether serious or non-serious, will be collected starting from the time a subject 
signs and dates an informed consent until the completion of the subject’s last study-related 
procedure, which may include contact for follow-up of safety. Spontaneous reports of serious 
AEs and pregnancy reporting will be collected through and including 30 calendar days after 
subject’s last dose of IP. Any SAE occurring any time after the reporting period must be 
promptly reported if a causal relationship to study product is suspected.   
13.3.2. 
Process for Reporting 
The Investigator is to report all AEs whether directly observed or spontaneously reported by 
the study subject.  In addition, each study subject will be questioned in general about any 
AEs.  
All AEs, serious or non-serious, will be recorded on the source documents; e.g., written 
documentation, electronic medical records, subject diaries or journals. AEs will be entered 
into CRFs for screen failure subjects as well as randomized subjects.  AEs should be reported 
using concise medical terminology on the CRFs and source documents. Each AE is to be 
assessed to determine if it meets the criteria for an SAE. If an SAE occurs, expedited 
reporting is required.  
 
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Emergent or existing AEs that are identified during the follow-up phone call will be recorded 
in both the source documents and CRF. 
13.3.2.1. Serious Adverse Event Reporting  
A Clinical SAE Report Form must also be completed if the event is considered to be serious. 
Where the same data are collected, the Clinical SAE Report Form and the AE CRF must be 
completed in a consistent manner. For example, the same AE term should be used on both 
forms.  
If an SAE occurs, the Sponsor or designee must be notified by telephone, email or fax 
immediately upon awareness of the event by the Investigator’s site and the SAE documented 
on the source document. Within 24 hours of the Investigator site’s awareness of the event, 
the study site must send the Sponsor the Clinical SAE Report Form (via a secure e-mail or 
fax). This timeframe also applies to additional new information (follow-up) on previously 
reported SAEs as well as to the initial and follow-up reporting of Exposure In Utero (EIU) 
cases. In the rare event that the Investigator’s site does not become aware of the occurrence 
of an SAE immediately (e.g., in a telephone contact, in a subject diary or journal, or if an 
outpatient study subject initially seeks treatment elsewhere), the Investigator’s site is to 
report the event immediately after learning of it as described, and document the date and time 
of the study site’s first awareness of the AE in the subject’s file.  
For all SAEs, the Investigator is obligated to pursue and provide information to the Sponsor 
in accordance with the timeframes for reporting specified above. In addition, an Investigator 
may be requested by the Sponsor to obtain specific additional follow-up information in an 
expedited fashion. This information may be more detailed than that captured on the AE CRF. 
In general, this will include a description of the AE in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible 
causality. Information on other possible causes of the event, such as concomitant medications 
and illnesses must be provided. In the case of a subject death, a summary of available 
autopsy findings (if available) and death certificate should be collected if permission is 
obtained from the subject’s family. For a hospitalization, a copy of the hospital discharge 
summary should be requested. If obtained, these documents (with subject’s personal 
identifiers redacted) should be submitted as soon as possible to the Sponsor or its designated 
representative.  
Appropriate SAE forms will be provided to the study site at the initiation of the study.  
13.3.2.2. Contacts for Serious Adverse Event Reporting  
Study Contacts for reporting can be found on the Study Contact List kept in the Site Master 
File.  
All nonserious AEs are to be reported on the AE CRFs and will be submitted to the Sponsor. 
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13.4. 
Suspected Unexpected Serious Adverse Reaction 
If the Sponsor judges an SAE to be a Suspected Unexpected Serious Adverse Reaction 
(SUSAR), the Sponsor will report it to the Regulatory Authority(ies) and the Investigator (or 
Sponsor) must report to the IRB/IEC as required and in accordance with the Sponsor’s 
standard operating procedures for safety reporting. 
13.5. 
Special Situations 
Special Situations are safety events that may not meet the definition of an AE; however, from 
a policy perspective, they are treated in the same manner as AE and recorded in the source 
document and CRF.  Examples include: 
• Pregnancy exposure (maternal and paternal) to a J&J product, see next section; 
• Off-label use of a J&J product.  Note: Off-label use of a product without an 
associated AE should be collected only when it is specifically and voluntarily 
brought to the attention of the company in an unsolicited manner by a reporter 
(e.g., Patient or HCP), or data obtained from databases where off-label use may 
be systematically collected (e.g., reimbursement database in US), and in 
accordance with local procedure in compliance with local laws and regulations. 
• Overdose of a J&J product; 
• Exposure to a J&J product from breastfeeding; 
• Suspected abuse/misuse of a J&J product; 
• Inadvertent, accidental exposure, or occupational exposure to a J&J product; 
• For marketed products, any failure of expected pharmacological/therapeutic 
action (i.e., lack of effect) of a J&J product.  Lack of effect/Lack of efficacy 
defined as any failure that a product did not achieve expected pharmacological 
action/therapeutic benefit when used in accordance with the Reference Safety 
Information or equivalent.  In the context of complaint intake, lack of effect shall 
be reported if there is specific evidence that the reporter did not think the product 
achieved expected pharmacological action/therapeutic benefit evidenced by 
statements such as or similar to “the product did not work/perform as expected”; 
• Medication error involving a J&J product (with or without patient exposure to the 
J&J product, e.g., product name confusion); or 
• Unexpected therapeutic or clinical benefit from use of a J&J product. 
13.5.1. 
Exposure In Utero 
An exposure in utero (EIU) occurs if:  
1. A woman is exposed to the IP at any time between her last menses prior to conception 
through the delivery of the baby.  
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2. There is a possibility of intrauterine exposure to IP via semen from the male partner 
who is taking/using the IP at the time of conception, thereby possibly exposing the 
fetus to the product.  
If an EIU occurs, the Investigator or designee should inform the Sponsor immediately. This 
must be done irrespective of whether an AE has occurred. The site must complete a 
Pregnancy Notification and Update Form and send it securely to the Sponsor within 24 hours 
of the site’s awareness. The information submitted should include the anticipated date of 
delivery (see below for information related to induced termination of pregnancy). This 
reporting requirements include environmental exposure to the IP in a pregnant woman (e.g., a 
nurse reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage).   
Follow-up should be conducted to obtain pregnancy outcome information on all EIU reports. 
The Investigator will follow the pregnancy until completion or until the pregnancy 
terminated (i.e., induced abortion) and then notify the Sponsor of the outcome. The 
Investigator will provide any updated information as a follow-up using the Pregnancy 
Notification and Update Form, and will report the outcome on the End of Pregnancy 
Collection Form. The reason(s) for an induced abortion should be specified. An EIU report is 
not created when an ectopic pregnancy report is received since this pregnancy is not usually 
viable.  Rather, an SAE case is created with the event of ectopic pregnancy.   
The medically qualified investigator or designee (MD/DO/DMD/DDS) should follow the 
procedures for reporting SAEs if the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly [including that in an aborted fetus, stillbirth, or neonatal death]).  In the 
case of a live birth, the “normality” of the newborn can be assessed at the time of birth (i.e., 
no minimum follow-up period of a presumably normal infant is required before an End of 
Pregnancy Collection Form can be completed).  The “normality” of an aborted fetus can be 
assessed by gross visual inspection, unless pre-abortion test findings are suggestive of a 
congenital anomaly.   
Additional pregnancy outcomes that are classified as SAEs and should be reported as such 
include:  
• 
“Spontaneous abortion” includes miscarriage and missed abortion.  
• 
All neonatal deaths that occur within 1 month of birth, without regard to 
causality. 
• 
Any infant death after 1 month that the Investigator assesses as possibly related 
to EIU to the IP. 
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14. 
STATISTICS 
The Sponsor will be responsible for the statistical analysis of study data. Detailed 
methodology for the statistical analysis of the data will be documented in a Statistical 
Analysis Plan finalized and approved prior to database lock and release of randomization 
codes. 
14.1. 
Sample Size Determination  
A sample size of 64 subjects per group for the active treatment arms and 32 subjects for the 
placebo arm provides 80% power to detect an effect size of 0.5 between active groups, based 
on a two-sided test at the 0.05 significance level, where effect size is defined as the 
difference between population treatment means divided by the population standard deviation.  
The effect size of 0.5 is no more than half the expected effect size for active vs. placebo 
based on previous studies.  The planned sample size also provides greater than 90% power to 
detect an effect size of 1 between active and placebo. 
14.1.1. 
Efficacy Analyses Sets 
The primary efficacy analyses will be based on the Intent-to-Treat analysis set, which will 
include all randomized subjects. As a secondary analysis, the primary endpoint will be 
analyzed based on the per-protocol analysis set, if the per-protocol analysis set differs from 
the Intent-to-Treat set by at least 5% of the subjects. The per-protocol set will exclude 
subjects who took rescue medication within 90 minutes after dosing, vomited within 60 
minutes after dosing, and those with major protocol deviations. The final per-protocol set 
will be determined before unblinding. 
14.1.2. 
Safety Analysis Population  
The Safety Set will include all subjects who are randomized and take investigational product. 
14.2. 
Baseline and Demographics 
Baseline and demographic characteristics will be presented by treatment group for each 
analysis set. For continuous variables, descriptive summaries will include number of 
subjects, mean, standard deviation, median and range (min, max). For categorical variables, 
the number and percent of subjects in each response category will be presented. 
14.3. 
Previous and Concomitant Medications 
Previous and concomitant medications will be coded. Previous medications will be those that 
were discontinued before the surgery day. Concomitant medications will be those continued 
through, or started on, the surgery day and up through the 12-hour assessment period. In 
addition, those medications taken after the 12-hour assessment period through the follow-up 
interview for an AE will be considered concomitant medications. Medications taken after the 
12-hour assessment through the follow-up call that were not taken for an AE will not be 
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collected on the CRF or summarized. Previous medications and concomitant medications 
will be summarized by treatment in separate tables. Number and percentage of subjects 
receiving each coded medication will be presented by treatment. Additionally, concomitant 
medications taken by greater than or equal to 5% of subjects in at least one treatment group 
will be presented. 
14.4. 
Efficacy Analysis 
Primary Efficacy Endpoints 
• Time weighted Pain Intensity Difference from 0 to 6 hours (SPID 6) 
• Time weighted Pain Intensity Difference from 0 to 12 hours (SPID 12) 
Secondary Efficacy Endpoints 
• Time weighted sum of pain relief from 0 to 6 hours (TOTPAR 6)  
• Time weighted sum of pain relief from 0 to 8 hours (TOTPAR 8)  
• Time weighted sum of pain relief from 0 to 12 hours (TOTPAR 12)  
• Time weighted of Pain Intensity Difference from 0 to 8 hours (SPID 8)  
• Pain relief (PAR) and pain intensity difference (PID) scores at individual time 
points  
• Subject Global Evaluation at 12 hours or time of rescue medication, whichever 
occurs first 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.5. 
Statistical Hypotheses and Treatment Comparisons 
The primary hypothesis for each of the primary endpoints is  
𝐻𝐻0∶: µ1 = µ2   
𝐻𝐻1∶: µ1 ≠ µ2   
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where µ1 and µ2 are the means for each investigational product, respectively.  These same hypotheses 
apply to other endpoints based on pain intensity scores, pain relief scores, or global evaluation. 
 
1
  
1
 
 
The following pairwise comparisions will be performed: 
• 
NPX 440 mg/APAP 1000 mg vs. placebo 
• 
NPX 220 mg/APAP 650 mg vs. placebo 
• 
Hydrocodone 10 mg/APAP 650 mg vs. placebo 
• 
NPX 440mg vs. placebo 
• 
NPX 440 mg/APAP 1000 mg vs. Hydrocodone 10 mg/APAP 650 mg 
• 
NPX 220 mg/APAP 650 mg vs. Hydrocodone 10 mg/APAP 650 mg 
• 
NPX 440 mg/APAP 1000 mg 10 mg vs. NPX 440mg  
• 
NPX 220 mg/APAP 650 mg vs. NPX 440mg 
• 
NPX 440 mg/APAP 1000 mg vs. NPX 220 mg/APAP 650 mg 
Given the exploratory nature of the study, no multiple comparisions procedure will be applied. All 
statistical tests of hypothess will be two-sided and employ a significance level of α=0.05. 
 
14.6. 
Data Computations and Data Imputations 
14.6.1. 
Endpoints Relating to Pain Intensity and Pain Relief 
The pain intensity difference (PID) at each time point will be derived by subtracting the pain 
intensity from the baseline pain intensity.  A higher value is indicative of a greater 
improvement. 
Time-weighted sum of the pain intensity difference scores (SPID) will be derived by first 
multiplying each PID score by the time from the previous time point, and adding these time-
weighted PID scores together  over the intervals from 0-6, 0-8, 0-12,
 
hours. Time-weighted total pain relief (TOTPAR) for each specified interval will be similarly 
derived. 
Pain intensity and pain relief ratings provided at times differing from the intended times by 
more than ± 5 minutes for the scores up to 90 minutes post-dose, and by more than ± 15 
minutes for the remaining measurements will be estimated by linear interpolation.  For 
subjects who use rescue medication, the last reported pain score before taking rescue 
medication or baseline pain score, whichever is worse, will be carried forward to the 
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remaining time points; pain relief scores after rescue medication will be set to zero. For 
subjects who discontinue the study early, the same imputation approach will be used. 
 
 
 
 
 
 
 
 
 
 
 
 
14.7. 
Analysis Methods 
14.7.1. 
SPID 6, SPID 8, SPID 12, 
, TOTPAR 6, 
TOTPAR 8, TOTPAR12, PAR, PID and Subject Global Evaluation 
Each will be analyzed with an analysis of variance with baseline pain (moderate or severe) 
score, gender, and treatment group in the model using imputation methods defined in Data 
Imputations Section 14.6.1. Missing data will not be imputed for subject global evaluation. 
 
 
 
 
 
 
 
 
 
 
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14.7.4. 
Subgroup Analyses 
Primary endpoints (SPID 6 and SPID 12) will be analyzed based on the following subgroups: 
age group (<18 years, ≥18 years), gender, race (white, non-white) and baseline categorical 
pain (moderate, severe). Each will be analyzed with an analysis of variance with treatment 
group in the model using imputation methods defined in Data Imputations Section 14.6.1.    
14.8. 
Safety Analysis 
The safety analysis will be based on the safety analysis set. 
14.8.1. 
Adverse Events 
Treatment-emergent AEs are those with a start date and time at or after the time of study 
drug administration. All summaries described below are for treatment-emergent AEs except 
where noted. Non- treatment-emergent AEs will be provided in a listing. 
The number and percentage of subjects experiencing AEs will be tabulated by treatment, 
system organ class and preferred term using the MedDRA coding dictionary. The number 
and percentage of subjects experiencing treatment-related AEs will also be presented by 
system organ class and preferred term. Treatment-related AEs will include events marked as 
being at least possibly related to study treatment. The number and percentage of subjects with 
AEs will be presented by severity. Subjects will be counted only once for each system organ 
class and preferred term by selecting the most severe event. The number of subjects with the 
most commonly reported adverse events (those reported by 5% or more in any one treatment 
group) will be summarized by treatment, system organ class and preferred term. The number 
of subjects with adverse events will also be summarized by demographic characteristics: age 
group (<18 years, ≥18 years), gender, and race.  
The number and percentage of subjects experiencing SAEs or who discontinued the study 
due to an AE will be presented by system organ class and preferred term. These displays will 
include all AEs, not just treatment-emergent AEs. 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator (s)/institutions(s) will permit study related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s) by providing access to the source data/documents. 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of JJCI will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities the site's 
responsibility with regard to protocol adherence as well as the study and 
monitoring responsibilities of J&J or its representatives.  These responsibilities 
will be documented in a Clinical Study Agreement between J&J and the 
investigator. 
During the study, a monitor from J&J or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are 
being accurately recorded in the CRFs, and that investigational product 
accountability checks are being performed. 
• Perform source data verification.  This includes a comparison of the data in the 
CRFs with the subject’s source documents, e.g., written medical records, 
electronic medical records at the hospital or practice, subject diaries/journals and 
other records relevant to the study.  This will require direct access to all original 
records for each subject (e.g., clinic charts). 
• Record and report all protocol deviations not previously sent to J&J.  The 
Investigator should not deviate from the Protocol except if specified by the 
Sponsor or within the Protocol.   
• Confirm AEs and SAEs have been properly documented on CRFs and confirm 
any SAEs have been forwarded to J&J and those SAEs that met criteria for 
reporting to Regulatory Authority/Competent Authority and/or IRB/IEC, as 
applicable, have been forwarded to the required authorities.  The monitor will be 
available between visits if the investigator(s) or other staff needs information or 
study-related direction. 
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15.2. 
Audits and Inspections 
Authorized representatives of J&J, a regulatory/competent authority, an IRB/IEC 
representative may visit the site to perform audits or inspections, including source data 
verification.  The purpose of a J&J audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH E6, and any applicable regulatory requirements.  The 
investigator should notify the Sponsor (e.g., Study Manager, Monitor) listed within the 
protocol or other contacts provided immediately if contacted by a regulatory agency about an 
inspection. 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements and applicable SOPs, including quality control of documents. Deviations will 
be analyzed and documented. To ensure compliance, the Sponsor may conduct one or several 
quality assurance audit(s). Please see Section 15.2 for more details regarding the audit 
process. 
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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Case Report Forms / Electronic Data Capture 
All data will be collected on source documents first and then recorded in an Electronic Data 
Capture (EDC) system. The EDC system is the database where pertinent study data are 
collected such as demography, subject randomization, efficacy assessments, adverse events, 
and subject disposition. EDC CRFs should be completed for each included subject. The 
completed pages of the EDC system are the sole property of the Sponsor and should not be 
made available in any form to third parties, except for authorized representatives of the 
Sponsor or appropriate regulatory authorities, without written permission from the Sponsor. 
It is the Investigator's responsibility to ensure completion and to review and approve all 
information captured in the EDC. The subject’s data in the EDC system must be 
electronically signed by the Investigator. These signatures serve to attest that the information 
contained in the EDC system is true. At all times, the Investigator has final personal 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered in 
the EDC. Subject source documents are the Investigator's/physician's subject records 
maintained at the study site. In cases where the source documents are the hospital or the 
physician's chart, the information collected in the EDC must match those charts. All final 
data recorded in EDC system will be copied into files and kept by the Sponsor. A copy of 
these files will also be kept at the clinical site. All data provided in the CRF must be 
supported by source document. 
17.2. 
Source Documents 
The investigator/institution should maintain adequate and accurate source documents and 
trial records that include all pertinent observations on each of the site’s trial subjects.  Source 
data should be attributable, legible, contemporaneous, original, accurate, and complete.  
Changes to source data should be traceable, should not obscure the original entry, and should 
be explained if necessary (e.g., via an audit trail). Inspection and Retention of Records 
17.3. 
Inspection and Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
investigator agrees to keep records including the identity of all participating subjects 
(sufficient information to link records, e.g., CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, SAE forms, source documents, and detailed 
records of treatment disposition.   
The PI must maintain all documentation relating to the study according to ICH guidelines or 
as specified in the Clinical Study Agreement for a period of 2 years after the last marketing 
application approval or per local requirements if longer than 2 years, or if not approved 2 
years following the discontinuance of the test article for investigation.  If it becomes 
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necessary for J&J or the Regulatory Authority to review any documentation relating to the 
study, the Investigator must permit access to such records. 
If the investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, e.g., another investigator.  The investigator must obtain Sponsor's written 
permission before disposing of any records, even if retention requirements have been met. 
18. 
PUBLICATION POLICY 
Publication of study results by the Investigator is discussed in the Clinical Study Agreement, 
as appropriate.  Results from this study may be published in the form of oral or written 
presentations at scientific meetings or as one or more peer-reviewed journal articles.  In these 
cases, no information on individual subjects will be revealed. 
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19. 
LIST OF REFERENCES 
1. 
 (Naproxen Sodium Tablets USP/Liquid Gels/Capsules 
220 mg). Bayer Inc. Consumer Care. Revised January 8th, 2015. 
2. Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin 
Pharmacokinet 1997;32:268-293. 
3. Paracetamol. In: Sweetman S, ed. Martindale - The Complete Drug Reference. 
London, UK: The Pharmaceutical Press. 37th ed. 2011:76-79. 
4. Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin 
Pharmacokinet 1982;7:93-107. 
 
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20. 
APPENDICES 
 
 
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APPENDIX 1: PAIN RATING SCALES/ CATEGORICAL PAIN INTENSITY SCALE 
 
Finish the statement “My pain at this time is” by checking the appropriate box. 
No Pain (0) Mild Pain (1) Moderate Pain (2) Severe Pain (3) 
 
0-10 PAIN INTENSITY - NUMERICAL RATING SCALE (PI-NRS) 
Circle the number that best represents your pain. 
No pain   0  1  2  3  4  5  6  7  8  9  10   Very severe pain 
 
0-10 PAIN RELIEF – NUMERICAL RATING SCALE (PR-NRS) 
Circle the number that shows your amount of pain relief. 
No relief   0  1  2  3  4  5  6  7  8  9  10   Complete relief 
  
 
 
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APPENDIX 2: SUBJECT GLOBAL EVALUATION 
 
How would you rate the study medication you received as a pain-reliever? 
Poor (0)  
Fair (1)  
Good (2) 
Very Good (3)  
Excellent (4) 
 
 
 
 
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Protocol CCSPAA001068
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND ACTIVE- CONTROLLED, 
PROOF OF CONCEPT STUDY TO EVALUATE TWO STRENGTHS OF 
CONCOMITANTLY DOSED  NAPROXEN SODIUM WITH ACETAMINOPHEN, 
COMPARED WITH NAPROXEN SODIUM, HYDROCODONE/ACETAMINOPHEN 
AND PLACEBO IN POSTOPERATIVE DENTAL PAIN
Statistical Analysis Plan
(SAP)
Version Date: December 3rd, 2019
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Protocol CCSPAA001068
Statistical Analysis Plan
Company Confidential
Page 2 of 18
CONTENTS
1
Introduction......................................................................................................3
1.1
Study Objectives ................................................................................................3
1.2
Study Design......................................................................................................4
2
Interim Analyses ..............................................................................................7
3
Analysis Sets .....................................................................................................7
3.1
Primary Analysis Set..........................................................................................7
3.2
Per-Protocol Set .................................................................................................7
3.3
Safety Analysis Set ............................................................................................7
4
Efficacy assessments and Endpoints ..............................................................7
4.1
Efficacy Assessments.........................................................................................7
4.2
Safety Assessments and Endpoints....................................................................8
4.3
Covariates ..........................................................................................................8
4.4
Data Computations and Data Imputations.........................................................8
4.4.1
Endpoints Relating to Pain Intensity and Pain Relief........................................8
5
Statistical Methodology and Statistical Analyses..........................................9
5.1
Statistical Hypotheses ........................................................................................9
5.2
Statistical Decision Rules ................................................................................10
5.3
Statistical Methods...........................................................................................10
5.3.1.
Pain Intensity Difference, Pain Relief and Subject Global Evaluation ...........10
5.3.4.
Subgroup Analyses ..........................................................................................11
         
5.4
Demographic and Baseline Characteristics .....................................................11
5.5
Previous and Concomitant Medications ..........................................................11
5.6
Safety Analysis ................................................................................................12
5.6.1
Adverse Events ................................................................................................12
5.6.2
Vital Signs........................................................................................................12
5.6.3
Pulse Oximetry.................................................................................................12
6. CHANGES FROM PROTOCOL...............................................................................12
7. References.....................................................................................................................13
APPENDICES..................................................................................................................14
APPENDIX 1: SUMMARY TABLES AND FIGURES...............................................14
APPENDIX 2: DATA LISTINGS ..................................................................................17
APPENDIX 3: DATA PATTERN AND CENSORING ...............................................18
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Protocol CCSPAA001068
Statistical Analysis Plan
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1
INTRODUCTION
As stated in the protocol:
The combination of naproxen sodium and acetaminophen (paracetamol) is not marketed 
in the United States. The investigational product will involve concomitantly administered 
commercial formulations of naproxen sodium and acetaminophen. 
Naproxen sodium has been available in the US for OTC analgesic use since 1994. 
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic 
and anti-inflammatory properties. In the US, naproxen sodium 220 mg is available as an 
OTC medication for the temporary relief of minor aches and pains due to minor pain of 
arthritis, muscular aches, backache, menstrual cramps, headache, toothache, and the 
common cold, and for the temporary reduction of fever [1]. The therapeutic effects of 
naproxen are produced through nonselective inhibition of cyclooxygenase enzymes 
(COX-1 and COX-2) resulting in inhibition of prostaglandin synthesis. Naproxen sodium 
salt has similar therapeutic properties as comparable doses of naproxen free acid based 
on molecular weight, but with more rapid systemic absorption. In this respect, 220 mg 
naproxen sodium is approximately equivalent to 200 mg naproxen [2].   
Acetaminophen has been available in the United States (US) for over-the-counter (OTC) 
adult analgesic use since the 1960s. In the US, adult single-ingredient OTC 
acetaminophen products are indicated for the temporary relief of minor aches and pains 
associated with the common cold, headache, toothache, muscular aches, and backache, 
for the minor pain of arthritis, for the pain of premenstrual and menstrual cramps and 
for the reduction of fever. Acetaminophen is a para-aminophenol derivative with 
analgesic and antipyretic properties.  Although the precise mechanism of action has not 
been definitively established, it is believed that acetaminophen produces its analgesic and 
antipyretic effects by inhibiting prostaglandin synthesis centrally and elevating the pain 
threshold [3,4].
There are currently no fixed combination products containing acetaminophen and 
naproxen sodium available on the US market. Fixed combinations of acetaminophen and 
naproxen sodium are available in countries outside of the US, including the Dominican 
Republic, Ecuador, India, Mexico, Peru, and countries in Central America. 
The current study will evaluate the analgesic efficacy, safety, onset and duration of 
concomitantly administered naproxen sodium 440 mg with acetaminophen 1000 mg and 
naproxen sodium 220 mg with acetaminophen 650 mg, compared to a fixed combination 
of hydrocodone 10 mg + acetaminophen 650 mg, naproxen sodium 440 mg and placebo.
1.1
Study Objectives
As stated in the protocol:
Primary Objective:
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Protocol CCSPAA001068
Statistical Analysis Plan
Company Confidential
Page 4 of 18

To evaluate relative efficacy of two strengths of concomitantly administered 
naproxen sodium and acetaminophen
versus hydrocodone 10 mg + 
acetaminophen / 650 mg, on self-assessed pain over 12 hours. 
Secondary Objective:

To evaluate relative efficacy of two strengths of concomitantly administered 
naproxen sodium and acetaminophen versus naproxen sodium, on self-assessed 
pain over 12 hours.
 
 
 
 
1.2
Study Design
As stated in the protocol:
This is a randomized, double-blind, placebo- and active- controlled, parallel-group study 
to evaluate the analgesic efficacy, and safety profile of the following strengths of 
naproxen sodium (NPX) /acetaminophen (APAP) administered concomitantly as a single 
dose:

440 mg of naproxen sodium with 1000 mg acetaminophen 

220 mg of naproxen sodium with 650 mg acetaminophen 
Subjects will undergo surgical removal of up to four third molars, of which, two must be 
mandibular impactions. Both maxillary third molars may be removed regardless of 
impaction level. Supernumerary teeth may also be removed.  The mandibular third 
molars must meet one of the following criteria and must not result in an overall surgical 
trauma rating of severe on a mild, moderate, or severe scale:

two full bony impactions

one full bony impaction in combination with one partial bony impaction
For the purposes of this study, a full impaction is being defined as at least 90% imbedded 
in the alveolar bone of the mandible.  The oral surgeon will make this judgement by 
visual examination of the panorex x-ray.
Approximately 288 subjects who meet the randomization criteria (post-surgical pain of 
moderate to severe on the four-point categorical pain scale, and at least a score of 5 on 
the 11-point [0-10] pain intensity numerical rating scale [PI-NRS] at baseline within 4.5 
hours of last stitch from dental extractions) will be assigned to one of the following five 
treatment groups in a 2:2:2:2:1 allocation ratio:
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
440 mg of naproxen sodium with 1000 mg acetaminophen 
 
 

220 mg of naproxen sodium with 650 mg acetaminophen 
 
 
 

10 mg hydrocodone + 650 mg acetaminophen (administered as two hydrocodone 
and acetaminophen tablets 5 mg/325 mg and two placebo tablets) 

naproxen sodium 440 mg 
 
 

Placebo (administered as four placebo tablets)
All treatments will be administered as a single dose.  Rescue analgesic medication 
(tramadol 50 mg, 1-2 tablets every 6 hours as needed for pain) will be available for 
subjects as needed.   Subjects who do not experience pain relief after dosing will be 
encouraged but not required to wait at least 1.5 hours before using rescue medication.
No less than approximately 30% of randomized subjects will be either male or female. In 
addition, no more than approximately 30% of subjects will be 17 years of age at the time 
of screening.  To maintain the double-blind nature of the study, an independent third 
party will administer study drug to blindfolded subjects.
Self-reported pain intensity will be collected using a 0-10 NRS at baseline (time 0). Pain 
intensity and pain relief will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly from 
2 through 12 hours (± 5 minutes) post dose as well as at the time of rescue 
 
 
 
 
 
Subject global evaluation of the investigational product will be collected at 12 hours or 
at the time of rescue medication (whichever occurs first), or at the time of subject 
withdrawal with a 0-4 rating scale: (0) poor, (1) fair, (2) good, (3) very good, and (4) 
excellent.
After completion of all study assessments, subjects will be discharged from the study site. 
Subjects will be interviewed by telephone to follow up on appropriate postsurgical 
medical care and changes in their health, including any emergent or existing AEs. The 
interview will occur between day 7 and 10.
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Table 1:
Schedule of Activities
1 Baseline assessments collected on Electronic Case Report Form (eCRF); 
2 Blood pressure, heart rate, respiratory rate, oral temperature; 
3 Females of childbearing potential; 
4 HIV antibody, hepatitis B surface antigen (HBsAg) , hepatitis C virus antibody (anti-HCV); 
5 Scored within 4.5 hours after last stitch from dental surgery; 
6 Pain intensity and pain relief ratings collected: 0.25, 0.5, 0.75, 1, 1.25, 1.5, and hourly 2 - 12 hours (± 5 minutes) post 
dose. If subject requests rescue medicine, ratings will be collected before administration. 
 
 
7 Subjects encouraged to wait at least 1.5 hours after investigational product administration before using rescue
medicine; 
8 Evaluation at 12 hours or time of rescue medication (whichever occurs first), or at time of early termination; if subject 
is discontinued or withdrawn <12 hours after dosing;
9 Collection of AEs and report of pregnancy (subject instructed to report pregnancy to PI within 30 days post dose)
10 End of Study is at the time of follow up call or at time of subject withdrawal; 
11 Minimum requirements for urine drug testing for screening & day of surgery: cocaine, tetrahydrocannabinol, opioids 
(e.g., buprenorphine, oxycodone, methadone, and morphine), benzodiazepines, and amphetamines.
Screening
Baseline (Day of Surgery)
Hours Post-Dose
Follow-Up Call
Procedures
Day -30 to 1
Day 1
0 to 12 hours
Days 7 - 10
Written informed consent and/or 
assent
X
Demography (including age)
X
Inclusion / Exclusion Assessment
X1
X
Significant medical history
X1
X
Vital signs2
X1
X
Physical Exam (Height, weight and
BMI)
X
Urine pregnancy test3
X1
X
Urine drug screen11
X1
X
Serology4
X
Dental extraction surgery
X
Categorical and Numerical Pain
Intensity
X5
Randomization criteria
X
Investigational product
administration
X 
Pain intensity and pain relief
ratings6
X
Pulse Oximetry12
X
X
X
 
Rescue therapy
X7
Subject Global Evaluation
X8
Prior and Concomitant Therapy
X
X
X
X
Safety monitoring
X
X9
X9
X9
Subject Disposition
X10
Follow up interview
X
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12 Pulse oximetry will be performed at baseline and when pain ratings are collected (0.25, 0.5, 0.75, 1, 1.25, 1.5, and 
hourly 2 - 12 hours (± 5 minutes) post dose).
2
INTERIM ANALYSES
No interim statistical analysis is planned for this trial.
3
ANALYSIS SETS
3.1
Primary Analysis Set
The primary analysis set will be based on the Intent-to-Treat analysis set, which will 
include all randomized subjects
3.2
Per-Protocol Set 
As a secondary analysis, the primary endpoint will be analyzed based on the per-protocol 
analysis set, if the per-protocol analysis set differs from the Intent-to-Treat set by at least 
5% of the subjects. The per-protocol set will exclude subjects who took rescue 
medication within 90 minutes after dosing, vomited within 60 minutes after dosing, and 
those with major protocol deviations. The final per-protocol set will be determined before 
unblinding.
3.3
Safety Analysis Set
The Safety Analysis Set will include all subjects who are randomized and take
investigational product. Safety analysis will be based on the actual received treatment.
4
EFFICACY ASSESSMENTS AND ENDPOINTS 
4.1
Efficacy Assessments
Primary Efficacy Endpoint

Time weighted Pain Intensity Difference from 0 to 6 hours (SPID 6)

Time weighted Pain Intensity Difference from 0 to 12 hours (SPID 12)
Secondary Efficacy Endpoint

Time weighted sum of pain relief from 0 to 6 hours (TOTPAR 6)

Time weighted sum of pain relief from 0 to 8 hours (TOTPAR 8)

Time weighted sum of pain relief from 0 to 12 hours (TOTPAR 12)

Time weighted of Pain Intensity Difference from 0 to 8 hours (SPID 8)

Pain relief (PAR) and pain intensity difference (PID) scores at individual time 
points

Subject Global Evaluation at 12 hours or time of rescue medication, whichever 
occurs first 
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4.2
Safety Assessments and Endpoints
Safety will be monitored and assessed by reviewing the collection, evaluation, and 
analysis of adverse events (AEs). Any causally related AE that is unresolved upon 
completion of the last study visit will be ollowed by the Investigator 
 
.  Pulse 
oximetry will be monitored and recorded at baseline and when pain ratings are collected.

Number and percentage of subjects with treatment-emergent adverse event (AE)

Number and percentage of subjects who discontinued the study due to an AE

Number and percentage of subjects experiencing a serious AE

Number and percentage of subjects with treatment-related AEs

Number and percentage of subjects with treatment-emergent AE by severity and 
relationship to treatment
4.3
Covariates
Baseline pain (moderative or severe) score, gender and treatment group will be used as 
covariates in the model for analysis related to SPID 6, SPID 8, SPID 12, 
 
 TOTPAR 6, TOTPAR 8, TOTPAR 12, PAR and PID scores and 
subject global evaluation.
4.4
DATA COMPUTATIONS AND DATA IMPUTATIONS
4.4.1
Endpoints Relating to Pain Intensity and Pain Relief
The pain intensity difference (PID) at each time point will be derived by subtracting the
pain intensity from the baseline pain intensity.  A higher value is indicative of a greater 
improvement.
Time-weighted sum of the pain intensity difference scores (SPID) will be derived by first 
multiplying each PID score by the time from the previous time point and adding these 
time-weighted PID scores together over the intervals from 0-6, 0-8, 0-12
 hours. Time-weighted total pain relief (TOTPAR) for each specified interval will be 
similarly derived.
Pain intensity and pain relief ratings provided at times differing from the intended times 
by more than ± 5 minutes for the scores up to 90 minutes post-dose, and by more than ± 
15 minutes for the remaining measurements will be estimated by linear interpolation.  For 
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subjects who use rescue medication, the last reported pain score before taking rescue 
medication or baseline pain score, whichever is worse, will be carried forward to the 
remaining time points; pain relief scores after rescue medication will be set to zero. For 
subjects who discontinue the study early, the same imputation approach will be used.
 
 
 
 
 
 
 
  
 
 
5
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
5.1
Statistical Hypotheses
The primary hypothesis for each of the primary endpoints is 
∶: μ	 = μ  
	∶: μ	 ≠ μ  
where μ	 and μ are the means for each investigational product, respectively.  These 
same hypotheses apply to other endpoints based on pain intensity scores, pain relief 
scores, or global evaluation.
 
 
 
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5.2
Statistical Decision Rules
For each of the endpoints, the following pairwise comparisons will be performed:
1. NPX 440 mg/APAP 1000 mg vs. placebo
2. NPX 220 mg/APAP 650 mg vs. placebo
3. Hydrocodone 10 mg/APAP 650 mg vs. placebo
4. NPX 440mg vs. placebo
5. NPX 440 mg/APAP 1000 mg vs. Hydrocodone 10 mg/APAP 650 mg
6. NPX 220 mg/APAP 650 mg vs. Hydrocodone 10 mg/APAP 650 mg
7. NPX 440 mg/APAP 1000 mg vs. NPX 440mg 
8. NPX 220 mg/APAP 650 mg vs. NPX 440mg
9. NPX 440 mg/APAP 1000 mg vs. NPX 220 mg/APAP 650 mg
Given the exploratory nature of the study, no multiple comparisons procedure will be 
applied. All statistical tests of hypotheses will be two-sided and employ a significance 
level of α=0.05.
5.3
STATISTICAL METHODS
5.3.1. Pain Intensity Difference, Pain Relief and Subject Global Evaluation
For pain intensity difference, analysis will be performed for SPID 6, SPID 8, SPID 12, 
and pain intensity difference (PID) at each time-point. 
For pain relief scores, analysis will be performed for TOTPAR 6, TOTPAR 8, TOTPAR
12, 
and pain relief scores (PAR) at each 
time point.
Each of these variables (SPID 6, SPID 8, SPID 12, 
 
TOTPAR 6, TOTPAR 8, TOTPAR12,
PID, PAR and subject global evaluation) will be analyzed with an analysis of variance 
with baseline pain (moderate or severe) score, gender, and treatment group in the model 
using imputation methods defined in Data Imputations Section 4.4. Missing data will not 
be imputed for subject global evaluation.
The following is sample SAS code for analysis of variance: 
proc glm data=DATASET;
  class pain gender trt;
  model outcome = pain gender trt;
  lsmeans trt;
run;
 
 
  
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5.3.4. Subgroup Analyses
Primary endpoints (SPID 6 and SPID 12) will be analysed based on the following 
subgroups: age group (<18 years, ≥18 years), gender, race (white, non-white) and 
baseline categorical pain (moderate, severe). Each will be analysed with an analysis of 
variance with treatment group in the model using imputation methods defined in Data 
Imputations Section 4.4.1. 
 
 
 
 
  
5.4
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Baseline and demographic characteristics will be presented by treatment group for each 
analysis set. For continuous variables, descriptive summaries will include number of 
subjects, mean, standard deviation, median and range (min, max). For categorical 
variables, the number and percent of subjects in each response category will be presented.
5.5
PREVIOUS AND CONCOMITANT MEDICATIONS
Previous and concomitant medications will be summarized. Previous medications will be 
those that were discontinued before the surgery day. Concomitant medications will be 
those continued through, or started on, the surgery day and up through the 12-hour 
assessment period. In addition, those medications taken after the 12-hour assessment 
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period through the follow-up interview for an AE will be considered concomitant 
medications. 
Medications taken after the 12-hour assessment through the follow-up call that were not 
taken for an AE will not be collected on the CRF or summarized. Previous medications 
and concomitant medications will be summarized by treatment in separate tables. 
Number and percentage of subjects receiving each coded medication will be presented by 
treatment. Additionally, concomitant medications taken by greater than or equal to 5% of 
subjects in at least one treatment group will be presented.
5.6
SAFETY ANALYSIS 
5.6.1
Adverse Events 
Treatment-emergent AEs are those with a start date and time at or after the time of study 
drug administration. All summaries described below are for treatment-emergent AEs 
except where noted. Non- treatment-emergent AEs will be provided in a listing.
The number and percentage of subjects experiencing AEs will be tabulated by treatment, 
system organ class and preferred term using the MedDRA coding dictionary. The number 
and percentage of subjects experiencing treatment-related AEs will also be presented by 
system organ class and preferred term. Treatment-related AEs will include events marked 
as being at least possibly related to study treatment. The number and percentage of 
subjects with AEs will be presented by severity. Subjects will be counted only once for
each system organ class and preferred term by selecting the most severe event. The 
number of subjects with the most commonly reported adverse events (those reported by 
5% or more in any one treatment group) will be summarized by treatment, system organ 
class and preferred term. The number of subjects with adverse events will also be 
summarized by demographic characteristics: age group (<18 years, ≥18 years), gender, 
and race. 
The number and percentage of subjects experiencing SAEs or who discontinued the study 
due to an AE will be presented by system organ class and preferred term. These displays 
will include all AEs, not just treatment-emergent AEs.
5.6.2
Vital Signs 
Vital signs (temperature, pulse, respiratory rate, and blood pressure) collected at baseline 
will be summarized (number of subjects, mean, standard deviation, median, minimum 
and maximum) by treatment group.
5.6.3
Pulse Oximetry
Pulse oximetry (oxygen saturation) collected at baseline and post-baseline will be 
summarized (number of subjects, mean, standard deviation, median, minimum and 
maximum) by treatment group.
6. CHANGES FROM PROTOCOL
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For secondary efficacy endpoints based on TOTPAR, analysis will also be performed for 
TOTPAR 4-12, 6-12 and 8-12.
7. REFERENCES
None. 
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APPENDICES
APPENDIX 1: SUMMARY TABLES AND FIGURES
The following tables and figures are planned for the Clinical Study Report. The 
numbering and titles of tables and figures in this document serves as guidance; the exact 
numbers and titles may be modified as appropriate. 
Section /
Table No
Title
Population / Analysis Sets
14.1 Subject Disposition, Demographics, and Baseline Information
Table 14.1.1
Subjects Disposition and Analysis Sets
All Enrolled Subjects
Table 14.1.2
Summary of Protocol Deviations 
All Randomized Subjects
Table 14.1.2.1
Summary of Major Protocol Deviations 
All Randomized Subjects
Table 14.1.2.2
Summary of Minor Protocol Deviations 
All Randomized Subjects
Table 14.1.3.1
Demographic and Baseline Characteristics
All Randomized Subjects
Table 14.1.3.2
Demographic and Baseline Characteristics
Safety Analysis Subjects
Table 14.1.3.3
Demographic and Baseline Characteristics  
Per-Protocol Subjects
Table 14.1.4
Previous Medications
All Randomized Subjects
Table 14.1.5
Concomitant Medications
All Randomized Subjects
Table 14.1.5.1
Concomitant Medications Taken By >= 5% of
Subjects in One or More Treatment Groups
All Randomized Subjects
Table 14.1.6
Vital Signs at Baseline
All Randomized Subjects
14.2 Efficacy 
Table 14.2.1
Time weighted Pain Intensity Difference 
(SPID)
All Randomized Subjects
Table 14.2.2
Time Weighted Total Pain Relief Scores 
(TOTPAR)
All Randomized Subjects
Table 14.2.3
Pain Intensity Difference (PID) from baseline At 
Each Time Point 
All Randomized Subjects
Table 14.2.4
Pain Relief Score (PAR) At Each Time Point 
All Randomized Subjects
Table 14.2.5
Subject Global Evaluation of Study Medication
All Randomized Subjects
 
 
Table 14.2.9
Time weighted Pain Intensity Difference 
(SPID) – Age < 18 Years Old
All Randomized Subjects
Table 14.2.10
Time weighted Pain Intensity Difference 
(SPID) – Age >= 18 Years Old
All Randomized Subjects
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Table 14.2.11
Time weighted Pain Intensity Difference 
(SPID) – Female
All Randomized Subjects
Table 14.2.12
Time weighted Pain Intensity Difference 
(SPID) – Male
All Randomized Subjects
Table 14.2.13
Time weighted Pain Intensity Difference 
(SPID) – Whites
All Randomized Subjects
Table 14.2.14
Time weighted Pain Intensity Difference 
(SPID) – Non-Whites
All Randomized Subjects
Table 14.2.15
Time weighted Pain Intensity Difference 
(SPID) – Moderate Baseline Pain
All Randomized Subjects
Table 14.2.16
Time weighted Pain Intensity Difference 
(SPID) – Severe Baseline Pain
All Randomized Subjects
Table 14.2.17
Time weighted Pain Intensity Difference 
(SPID)a
Per Protocol Analysis Set
 
a.
Provided if the per-protocol analysis set differs from the Intent-to-Treat set by at least 
5% of the randomized subjects. 
14.3 Safety
Section /
Table No
Title
Population / Analysis Sets
Table 14.3.1
Summary of Adverse Events 
Safety Analysis Subjects
Table 14.3.2
Summary of Treatment-Emergent Adverse 
Events by System Organ Class and MedDRA 
Preferred Term
Safety Analysis Subjects
Table 14.3.3
Summary of Treatment-Emergent Adverse 
Events by Demographic Characteristics
Safety Analysis Subjects
Table 14.3.4
Summary of Treatment-Emergent Adverse 
Events by Severity
Safety Analysis Subjects
Table 14.3.5
Most Commonly Reported (>=5% of Subjects in 
One or More Treatment Groups) Treatment-
Emergent Adverse Events
Safety Analysis Subjects
Table 14.3.6
Summary of Treatment-Related Adverse Events
Safety Analysis Subjects
Table 14.3.7
Most Commonly Reported (>=5% of Subjects in 
One or More Treatment Groups) Treatment-
Related Adverse Events
Safety Analysis Subjects
Table 14.3.8
Summary of Treatment-Related Adverse Events 
By System Organ Class and MedDRA Preferred 
Term 
Safety Analysis Subjects
Table 14.3.9
Summary of Treatment-Related Adverse Events 
By Severity
Safety Analysis Subjects
Table 14.3.10
Summary of Serious Adverse Events By System 
Organ Class and MedDRA Preferred Term 
Safety Analysis Subjects
Table 14.3.11
Summary of Subject Discontinuation from Study 
Due to Adverse Events By System Organ Class 
and MedDRA Preferred Term
Safety Analysis Subjects
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Table 14.3.12
Summary of Pulse Oximetry 
Safety Analysis Subjects
FIGURES:
Figure 14.1
SPID by Treatment
All Randomized Subjects
Figure 14.2
TOTPAR by Treatment
All Randomized Subjects
Figure 14.3
Pain Intensity Difference (PID) from Baseline at 
Each Time Point
All Randomized Subjects
Figure 14.4
Pain Relief Score (PAR) at Each Time Point
All Randomized Subjects
 
 
 
 
 
 
 
 
 
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APPENDIX 2: DATA LISTINGS
The following listings are planned for Clinical Study Report.  The numbering and titles of data 
listings in this document serve as guidance; the exact numbers and titles may be modified as 
appropriate. 
Listing No.
Title
Population
16.1.7
Randomization Schedule
All Randomized
16.2.1
Subject Disposition
All Randomized
16.2.2.1
Discontinued Subjects
All Randomized
16.2.2.2
Subjects with Protocol Deviations
All Randomized
16.2.2.3
Subjects Excluded from Per Protocol Population
All Randomized
16.2.3.1
Demographic and Baseline Characteristics
All Randomized
16.2.3.2
Significant Medical History
All Randomized
16.2.3.3
Previous and Concomitant Medications
All Randomized
16.2.3.4
Non-Drug Therapy/Procedure
All Randomized
16.2.4.1
Surgery Information and Baseline Pain Measurement 
All Randomized
16.2.4.2
Tooth Extractions
All Randomized
16.2.4.3
Dosing Time of Study Medication
All Randomized
 
16.2.5.2
Pain Intensity and Pain Relief Assessments
All Randomized
16.2.5.3
Pain Intensity and Pain Relief Assessments Out of 
Assessment Window and Imputed Values 
All Randomized
 
 
 
 
16.2.6.1
Subjects with Treatment-Emergent Adverse Events
All Randomized
16.2.6.2
Subjects with Non-Treatment-Emergent Adverse Events
All Randomized
16.2.6.3
Subjects with Adverse Events that Resulted in Subject 
Discontinuation From Study
All Randomized 
16.2.6.4
Subjects with Serious Adverse Events
All Randomized
16.2.6.5
MedDRA Preferred Terms for Adverse Events
All Randomized
16.2.6.6
Self-Reported Pregnancy
All Randomized
16.2.6.7
Vital Signs
All Randomized
16.2.6.8
Pulse Oximetry 
All Randomized
16.2.7
Follow-up Interview
All Randomized
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