Clinical trial NCT03566979
Conditions: Post-operative Dental Pain
Sponsor: Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division
Start date: 2018-08-13; Completion date: 2019-04-15
Enrollment: 501 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate analgesic onset, efficacy, and safety of a single dose of 440 mg of naproxen sodium administered as two Test Naproxen Sodium 220 mg tablets compared with two commercial naproxen sodium products (two naproxen sodium 220 mg tablets and two naproxen sodium 220 mg liquid gels capsules) and placebo in the dental pain model following third-molar extractions.

Detailed description:
This is a single-dose, randomized, double-blind, placebo- and active- controlled, parallel-group study to evaluate the analgesic onset, efficacy, and safety profile of 440 mg of naproxen sodium administered as two Test NPX 220 mg tablets compared with two commercial products and placebo over a twelve-hour period after third-molar extractions. Subjects will undergo dental extraction of three or four third molars.

Arms: arm 1: Single dose of 440 mg of naproxen sodium administered as two Test Naproxen Sodium 220 mg tablets (Test NPX) arm 2: Single dose of 440 mg of naproxen sodium administered as two commercial naproxen sodium 220 mg tablets arm 3: Single dose of 440 mg of naproxen sodium administered as two 220 mg commercial liquid gels capsules arm 4: Single dose of two Placebo tablets
Interventions: intervention 1: Test naproxen sodium tablet intervention 2: Commercial naproxen sodium tablet intervention 3: Commercial naproxen sodium liquid gels capsule intervention 4: Placebo tablet
Intervention descriptions: intervention 1: Single dose of 2 test naproxen sodium 220 mg tablets intervention 2: Single dose of 2 naproxen sodium 220 mg tablets intervention 3: Single dose of 2 naproxen sodium 220 mg liquid gel capsules intervention 4: 2 placebo tablets

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL
NAPROXEN SODIUM
CCSPAA000457
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND ACTIVE-
CONTROLLED, EFFICACY AND SAFETY STUDY OF A TEST 
NAPROXEN SODIUM 220 MG TABLET IN POSTOPERATIVE 
DENTAL PAIN
Investigational Product Name:
Naproxen Sodium
Protocol Number:
CCSPAA000457
IND / IDE / EudraCT number:
135,012
Phase:
3
Version (Final) Date:
Version 1 (Final): 11 May 2018
Version 2: Administrative Change/Non-
substantial Amendment 1 - 19 July 2018
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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1.
SYNOPSIS
Name and address of the Sponsor/Company of the clinical investigation:
Johnson & Johnson Consumer, Inc., McNeil Consumer Healthcare Division
Active Ingredient(s):
Test Naproxen Sodium, 220 mg Tablet (440 mg dose as two 220 mg tablets) (Test NPX)
Title of Study: 
A Randomized, Double-Blind, Placebo- and Active- Controlled, Efficacy and Safety Study of a 
Test Naproxen Sodium 220 mg Tablet in Postoperative Dental Pain
Country: USA
Phase of development: 3
Objective:
To evaluate analgesic onset, efficacy, and safety of a single dose of 440 mg of naproxen sodium 
administered as two Test Naproxen Sodium 220 mg tablets (Test NPX) compared with two 
commercial naproxen sodium products (two 
220 mg tablets and two 
 220 mg 
 capsules) and placebo in the dental pain model following third-molar extractions.
Methodology:
This will be a single-dose, randomized, double-blind, placebo- and active- controlled, parallel-
group study to evaluate the analgesic onset, efficacy, and safety profile of 440 mg of naproxen 
sodium administered as two Test NPX 220 mg tablets compared with two commercial products 
and placebo over a twelve-hour period after third-molar extractions. Subjects will undergo dental 
extraction of three or four third molars. Maxillary third molars may be removed regardless of 
impaction level. The mandibular extractions must meet one of the following scenarios and must 
not result in a trauma rating of severe on a mild, moderate, or severe scale:
•
two full bony impactions
•
two partial bony impactions
•
one full bony impaction in combination with one partial bony impaction
Pain assessments will be based on subject self-report.  Subjects who meet the randomization 
criteria (post-surgical pain of moderate to severe on the four-point categorical pain scale [0-no 
pain, 1-mild pain, 2-moderate pain, 3-severe pain], 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 four treatment groups.  This PI-NRS will be within 
5 minutes prior to study medication dosing and will be considered the time 0 pain intensity 
assessment.
Approximately 500 subjects will receive a single 440 mg dose of either Test NPX, 
 


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tablets, 
 capsules, or placebo in a 3:3:3:1 allocation ratio, and will be 
stratified according to gender and baseline pain rating (moderate or severe). To maintain the 
double-blind nature of the study, an independent third party will administer study drug to 
blindfolded subjects. 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.
 
. Perceptible pain relief and meaningful pain 
relief will be collected using two separate stopwatches. 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.
 
 
.
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 adverse events (AEs). The 
interview will occur between Day 6 through 10. 
Number of subjects (planned): 
Approximately 500
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 extraction of three or four third molars 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.
Study product, dosage and mode of administration: 
Depending on randomization, to maintain the double-blind nature of the study, an independent 
third party will administer a single 440-mg dose of naproxen sodium as two Test NPX 220 mg 
tablets to blindfolded subjects. Subjects will swallow the dose with up to 180 mL water at 
ambient temperature.
Reference therapy (comparator or placebo control), dosage and mode of administration: 
Depending on randomization, an independent third party will administer one of the following 
reference products with up to180 ml water at ambient temperature to blindfolded subjects:
•
a single 440-mg dose of naproxen sodium as two 
 220 mg tablets;
•
a single 440-mg dose of naproxen sodium as two 
 220 mg 
 capsules; or
•
a single dose of two placebo tablets.
Duration of treatment: 
One dose: subjects will remain at the study site for 12 hours after dosing whether or not the 
subject rescues, vomits, or experiences other AEs.
Endpoints:


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Primary Efficacy Endpoint
•
Time to confirmed perceptible pain relief (TCPR)
Secondary Efficacy Endpoint
•
Percentage of subjects with confirmed perceptible pain relief from 45 minutes to successively
earlier minutes in one-minute increments (Test NPX versus PBO)
 
 
Safety:
Safety will be monitored and assessed by reviewing the collection, evaluation, and analysis of 
AEs. Any causally related AE that is unresolved upon completion of the last study visit will be 
followed by the Investigator until the event, or its sequelae, resolves or stabilizes at a level 
acceptable to the Investigator.
Statistical methods:
 
. The survival 
function (cumulative proportions of subjects with pain relief at each time point) and the median 
survival time will be estimated by the Kaplan-Meier method for each treatment. The survival 
functions will be compared using the Wilcoxon test. 
The earliest time of separation of confirmed perceptible pain relief between Test NPX and 
placebo will be established by comparing the percentage of subjects with confirmed perceptible 
pain relief starting from 45 minutes to successively earlier minutes in one-minute increments, 
until statistical significance is no longer achieved. The dichotomized response will be analyzed 
using logistic regression analysis. 
 
 
To control the family-wise Type I error rate at 0.05 for the primary endpoint (TCPR) and the 
secondary endpoint of percentage of subjects with confirmed perceptible pain relief from 45 
minutes to successively earlier minutes, a fixed sequence testing with fallback method will be 
used. Table 1 presents the order of the tests and the assigned α values for each ordered test. 
Testing will commence with an assigned alpha = 0.049 and an alpha value of 0.001 will be 
reserved for the comparison of Test NPX and placebo on the percentage of subjects with 
confirmed perceptible relief from 45 minutes to successively earlier minutes in one-minute 


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increments.
Table 1
Order of Tests and Assigned Alpha Values
Pre-Assigned 
α
α available if 
previous test 
positive
α available if 
previous test 
negative
TCPR: Test NPX vs Placebo
0.049
Not Applicable
Not Applicable
TCPR: Test NPX vs 
None
0.049
None
TCPR: Test NPX vs 
None
0.049
None
Percentage subjects with confirmed 
perceptible pain relief from 45 to 
successively earlier minutes: Test NPX 
vs Placebo
0.001
0.05
0.001


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2.
STUDY FLOW CHART AND SCHEDULE OF ACTIVITIES
Table 2:
Schedule of Activities
1Scored within 4.5 hours after last stitch from dental surgery; 2
 
 3Subjects encouraged to wait at least 1.5 hours after investigational product administration before using rescue
medicine; 
; 5 Medications and other treatments 
taken after 12-hour assessment period through follow-up interview will be captured on source documents and only those taken for or associated with an AE will be recorded in the CRF; 6 Collection of
AEs and report of pregnancy; 7 End of Study for each subject is defined as the follow-up phone call or early termination.
Screening
Baseline (Day of Surgery)
Hours Post-Dose
Follow-Up Call/End of Study
Procedures
Day -30 to 1
Day 1
0 to 12 hours
Day 6 - 10
Written informed consent and/or assent
X
Demography (including age)
X
Inclusion / Exclusion Assessment
X
X
Significant medical history
X
X
Vital signs
X
X
Physical Exam (Height, weight and BMI)
X
Urine pregnancy test (Females of childbearing potential)
X
X
Urine drug screen
X
X
Serology
X
Dental extraction surgery
X
Baseline Pain Assessments (Categorical and PI-NRS)
X1
Randomization criteria
X
Investigational product administration
X
Stopwatch Assessments (perceptible & meaningful pain 
relief)
X
X
Rescue therapy
X3
X4
Prior and Concomitant Therapy
X
X
X
X5
Safety monitoring6
X
X
X
X
Subject Disposition
X7


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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
7.1.3.
........................................................................................17
7.2.
Safety..........................................................................................................................17
8.
INVESTIGATIONAL PLAN.....................................................................................18
8.1.
Overall Study Design and Plan...................................................................................18
8.2.
End of Study for Each Subject....................................................................................19
8.3.
Sponsor Discontinuation Criteria ...............................................................................19
9.
STUDY POPULATION.............................................................................................21
9.1.
Subject Eligibility Criteria..........................................................................................21
9.1.1.
Subject Inclusion Criteria ...........................................................................................21
9.1.2.
Exclusion Criteria.......................................................................................................22
9.2.
Subject Withdrawal/Termination Criteria ..................................................................23
9.3.
Life Style Guidelines ..................................................................................................24
9.3.1.
Meals and Dietary Restrictions...................................................................................24
9.3.2.
Alcohol, Caffeine and Tobacco Consumption / Restrictions .....................................24


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9.3.3.
Physical Activity Requirements / Restrictions ...........................................................24
9.3.4.
Contraception for Females..........................................................................................24
9.3.5.
Contraception for Males .............................................................................................25
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................................................................................................30
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 .......................................................................................31
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


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13.
ADVERSE EVENTS..................................................................................................38
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.....................................................................48
14.4.
Efficacy Analysis........................................................................................................48
14.5.
Statistical Hypotheses and Treatment Comparisons...................................................48
14.6.
Data Computations and Data Imputations..................................................................49
14.6.1.
Time to 
 Confirmed Perceptible, 
 Pain Relief 
(
 TCPR
) ...............................................................................................49
14.6.2.
................................................50
14.7.
Analysis Methods .......................................................................................................50
14.7.1.
 
...............................................................50


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14.7.2.
Earliest Statistically Significant Separation of Test NPX and Placebo on 
Percentage of Subjects with Confirmed Perceptible Relief........................................51
14.7.3.
 
................................................................................................51
14.7.4.
...........................................51
14.7.5.
.........................................................................................51
14.7.6.
...........................................................................................................51
14.7.7.
..........................................................................................51
14.7.8.
Subgroup Analyses .....................................................................................................51
14.8.
Safety Analysis ...........................................................................................................52
14.8.1.
Adverse Events ...........................................................................................................52
15.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................53
15.1.
Study Monitoring........................................................................................................53
15.2.
Audits and Inspections................................................................................................54
16.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55
17.
DATA HANDLING AND RECORDKEEPING.......................................................56
17.1.
Case Report Forms / Electronic Data Capture............................................................56
17.2.
Source Documents......................................................................................................56
17.3.
Inspection and Retention of Records..........................................................................56
18.
PUBLICATION POLICY ..........................................................................................57
19.
LIST OF REFERENCES............................................................................................58
20.
APPENDICES ............................................................................................................59
LIST OF TABLES
Table 1
Order of Tests and Assigned Alpha Values..................................................................5
Table 2:
Schedule of Activities...................................................................................................6
Table 3:
Abbreviations and Specialist Terms...........................................................................12
Table 4:
Investigational Product ...............................................................................................27
Table 5: 
Order of Tests and Assigned Alpha Values................................................................49


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LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................19


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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 3:
Abbreviations and Specialist Terms
Abbreviation/ 
Term
Definition
AE
Adverse event
BMI
Body Mass Index
CRF
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
PI
Principal Investigator
PQC
Product Quality Complaint
PI-NRS
Pain intensity-numerical rating scale
SAE
Serious adverse event
TCPR
Time to confirmed perceptible pain relief


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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 


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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 
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
Naproxen is a propionic acid derivative and nonsteroidal anti-inflammatory drug (NSAID) 
with analgesic and antipyretic properties. The mechanism of action of naproxen involves 
inhibition of cyclooxygenase enzymes resulting in decreased prostaglandin synthesis. The 
sodium salt of naproxen has been developed as a more rapidly absorbed formulation of 
naproxen.  Naproxen sodium products have been available over-the-counter (OTC) for the 
indications of fever reduction and relief of minor aches and pains in several countries for 
many years. 
In the United States, naproxen sodium has been available as an OTC analgesic and 
antipyretic since 1994. It is indicated for OTC use 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 temporary reduction of fever.  According 
to the Drug Facts for 
 
, dosing for adults and children 12 years of age and older 
is one 220 mg dosage unit (e.g., tablet, caplet, capsule) every 8-12 hours, and for the first 
dose, may take two 220 mg units within the first hour.
 
 
 
 
 
 
Clinical efficacy and safety studies have not yet been conducted on the 
 formulation 
of naproxen sodium. The current study will evaluate the analgesic onset, efficacy and safety 
of a single 440 mg dose of 
 naproxen sodium (administered as two 
220 mg tablets) compared to two currently marketed 
 formulations of naproxen 
sodium and placebo after third molar dental extractions. The postoperative dental pain model 
is a validated model of acute pain that is widely used to study analgesic efficacy of
compounds [1] [2].


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7.
STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
To evaluate analgesic onset, efficacy, and safety of a single dose of 440 mg of naproxen 
sodium administered as two Test Naproxen Sodium 220 mg tablets (Test NPX) compared 
with two commercial naproxen sodium products (two 
 220 mg tablets and two 
 
220 mg 
 capsules) and placebo in the dental pain model following third-molar 
extractions.
7.1.
STUDY ENDPOINTS
7.1.1.
Primary Efficacy Endpoint

Time to confirmed perceptible pain relief (TCPR) 
7.1.2.
Secondary Efficacy Endpoint

Percentage of subjects with confirmed perceptible pain relief from 45 minutes to 
successively earlier minutes in one-minute increments (Test NPX versus PBO) 
7.1.3.
Tertiary Efficacy Endpoints

 
 
7.2.
Safety
Safety will be monitored and assessed by reviewing the collection, evaluation, and analysis 
of AEs.


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8.
INVESTIGATIONAL PLAN
8.1.
Overall Study Design and Plan
This is a single-dose, randomized, double-blind, placebo- and active- controlled, parallel-
group study to evaluate the analgesic onset, efficacy, and safety profile of 440 mg of 
naproxen sodium administered as two Test NPX 220 mg tablets compared with two 
commercial products and placebo over a 12-hour period after third-molar extractions (Figure
1). Subjects will undergo dental extraction of three or four third molars. Maxillary third 
molars may be removed regardless of impaction level.  The mandibular extractions must 
meet one of the following scenarios and must not result in a trauma rating of severe in a mild, 
moderate, or severe scale:

two full bony impactions

two partial bony impactions

one full bony impaction in combination with one partial bony impaction
Pain assessments will be based on subject self-report.  Subjects who meet the randomization 
criteria (post-surgical pain of moderate to severe on the four-point categorical pain scale [0-
no pain, 1-mild pain,2-moderate pain, 3-severe pain], 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 four treatment groups.  This PI-NRS 
will be within 5 minutes prior to study medication dosing and will be considered the time 0 
pain intensity assessment. 
Approximately 500 subjects will receive a single 440 mg dose of either Test NPX, 
 
tablets, 
capsules, or placebo in a 3:3:3:1 allocation ratio, and will be 
stratified according to gender and baseline pain rating (moderate or severe). To maintain the 
double-blind nature of the study, an independent third party will administer study drug to 
blindfolded subjects. 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. 
Pain intensity (PI-NRS) 
 (using the 11-point [0-10] pain relief numerical rating 
scale [PR-NRS]) will be collected at ee post dose as well as at the time of rescue (if 
applicable) before administration 
. 
Perceptible pain relief and meaningful pain relief will be collected using two separate 
stopwatches. 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. 
 


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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 6 – 10 of the study.
Figure 1:
Study Design
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


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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 17.5 to 30.4
(inclusive) at screening;
4. Have undergone dental extraction of three or four third molars. 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 scenarios (and must
not result in a trauma rating of ‘severe’ on a mild, moderate, or severe scale):

two full bony impactions

two partial 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 
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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;
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, or to acetaminophen, hydrocodone 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 or seizures, history of respiratory depression or lung problems such as but 
not limited to asthma or chronic obstructive pulmonary disease, psychiatric disorders, 
problems urinating, 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. Are not able to swallow whole large tablets or capsules;
6. Routinely use oral analgesics ≥5 times per week;
7. Have a history of chronic tranquilizer use, heavy drinking, or substance abuse, 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);
8. Have a history of endoscopically documented peptic ulcer disease or bleeding disorder in 
the last 2 years;


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9. 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;
10. Used vitamins, dietary or herbal supplements within 5 days before the oral surgical 
procedure;
11. Used any immunosuppressive drugs, corticosteroids (except for topical corticosteroids), 
or injectable or oral anticoagulants (e.g., heparin, Lovenox, Xarelto, Eliquis, Pradaxa, 
Coumadin, Miradon) within 2 weeks of screening;
12. Used alcohol within 3 days before the oral surgical procedure;
13. 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;
14. Use of monoamine oxidase inhibitors within 14 days prior to surgery;
15. Has a positive test for human immunodeficiency virus (HIV) antibody, hepatitis B 
surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV);
16. Participated in any interventional clinical trials within 30 days before screening;
17. 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 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. Females must have used such birth control for at 
least three months prior to the Baseline visit. 


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Medically acceptable forms of birth control that may be used by the subject and/or his/her 
partner include: 

Established use of hormonal methods of contraception (oral, injected, implanted, 
patch or vaginal ring).  Sexually active female subjects (or female partners of 
male subjects) who use hormonal contraception must have used a stable dose for 
at least 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 at least 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 screening).
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 prevent their partner from becoming pregnant from the first 
dose of study medication until at least 30 days after the last dose of study drug. Information 
about effective means of birth control (hormonal contraception, intrauterine devices, 


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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 test naproxen, reference naproxen and placebo investigational products 
are provided in Table 4. 
Table 4:
Investigational Product
Product
Test NPX
(440 mg)
 Tablets
(440 mg)
 
Capsules
(440 mg)
Placebo
Dosage Form
Tablet
Tablet
Liquid-filled
Capsule
Tablet
Route of Administration
Oral
Oral
Oral
Oral
Unit Dose
220 mg
220 mg
220 mg
Not applicable
Physical Description
 
 
 
 
Manufacturer/Brand
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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•
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:

a single 440-mg dose of naproxen sodium as two Test NPX 220 mg tablets

a single 440-mg dose of naproxen sodium as two commercial 
220 mg tablets

a single 440-mg dose of naproxen sodium as two commercial 
 220 
mg capsules, or

a single dose of two 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 an individual dosing cup. The 
double-blind label with the same randomization number will be affixed to the dosing cup 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 cup containing the randomized study 
treatment is covered prior to exiting the dispensing room. 
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 


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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 not be reused. The dispenser will deliver the 
study drug from the designated dispensing room to the subject’s room in a covered dosing 
cup 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 dosing cup containing the study treatment to the blindfolded subject 
and instruct the subject to empty the contents of the dosing cup directly into their mouth and 
then 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 the 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.
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 
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.


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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 four treatments (Test NPX 440 mg, 
 tablet 440 mg, 
 440 mg 
or placebo) in a 3:3:3:1 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 
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 if they take the dose
of study medication. 


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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. 
Medications and other treatments taken after the 12-hour assessment period through the 
follow-up interview will be captured on the source documents and only those taken for or 
associated with an AE will also be recorded in the CRF.
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.
The use of any oral OTC or prescription products (except contraceptive medications and 
those required for use during oral surgical procedure such as short-acting local anesthetics) 
are prohibited within 5 half-lives before the surgical procedure and during the on-site portion 
of the study.  In addition, vitamins, dietary or herbal supplements are prohibited within 5 
days before the oral surgical procedure and during the on-site portion of the study.
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, hydrocodone bitartrate 5 mg / 
acetaminophen 325 mg, if the severity of the subject’s pain increases to an intolerable level. 
Hydrocodone bitartrate 5 mg / acetaminophen 325 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, the stopwatch(s) will be collected from the 
subject. No stopwatch data will be recorded after use of rescue medication; 
 
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 


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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)
· Urine drug screen test
· Urine pregnancy test on females with childbearing potential
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


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· Any changes to prior and concomitant therapies
· Vital signs: resting blood pressure, heart rate, respiratory rate, oral temperature
· Urine drug screen test
· Urine pregnancy test on females with childbearing potential
A negative urine drug screen and 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 at least moderate pain on a categorical scale ranging 
from (0) none to (3) severe and at least a score of 5 on the 11-point (0-10) PI-NRS 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
Two stopwatches labeled as perceptible and as meaningful will be used to measure 
“perceptible pain relief” and “meaningful pain relief”, respectively. The face of each 
stopwatch will be covered to prevent the subject from seeing the running clock. Upon dosing, 
the investigator or the designated site staff will start both stopwatches at the same time. 
Subjects will only be given the second stopwatch after they stop the first one.
Site personnel will instruct “I would like you to stop the first stopwatch (perceptible) when 
you first begin to feel any pain relieving effect whatsoever of the drug, that is, when you first 
feel any pain relief. This does not necessarily mean you feel completely better, although you 
might, but when you first feel any difference in the pain you have now. As soon as you stop 
the stopwatch please press your call light to notify the study coordinator. I would like you to 
stop the second stopwatch (meaningful) when you have meaningful pain relief, that is, when 
the relief from the starting pain is meaningful to you. As soon as you stop the stopwatch, 
please press your call light to notify the study coordinator.” Upon dosing, the investigator or 
the designated site staff will start both stopwatches at the same time. Once the stopwatch has 
been stopped, the investigator or designated study staff will retrieve the stopwatch and record 
the time in the source documents and CRF. 
 


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(APPENDIX 1) 
 
 
 
Subjects who use rescue therapy will 
continue in the study 
(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 6 – 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. Additional postsurgical medicines (e.g., antibiotics or 
analgesic prescriptions) or therapies (e.g., ice packs) that are taken after the 12-hour 
 
 will be recorded on the subject’s 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. Emergent or existing AEs will 
be recorded in both the source documents and CRF.


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12.
ASSESSMENTS
12.1.
Efficacy Assessments
 
. 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 
 

 

Time to perceptible pain relief – recorded using stopwatch perceptible

Time to confirmed perceptible pain relief is defined as the time to perceptible pain 
relief, provided that the subject subsequently stopped the second stopwatch 
indicating meaningful pain relief.



 
 
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.
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.


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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, pulse, 
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 pulse 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.
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 
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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), 


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
Skilled nursing facilities, 

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.


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MODERATE:
Sufficient discomfort is present to cause interference to some extent with
the subject's usual function or normal everyday activity.
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 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. 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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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: 


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1. A woman is exposed to the IP at any time between her last menses prior to conception 
through the delivery of the baby. 
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 150 per group for the active treatment arms was chosen based on 
pharmacokinetic/pharmacodynamics modeling and simulation using data from previous 
studies[3]. Based on the modeling, it was determined that 150 subjects per active treatment 
arm would be needed to provide 90% power to reject the null hypothesis of equal 
distributions for time to confirmed perceptible relief, when comparing Test NPX tablets with 
 tablets, using a two-sided test at the 0.05 significance level. A sample size of at least 
50 subjects per treatment arm provides greater than 90% power to reject the null hypothesis 
of equal distributions for time to confirmed perceptible relief when comparing Test NPX 
tablet and placebo assuming median times to relief of 17 minutes for Test NPX and at least 2 
hours for 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.


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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 
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 Endpoint

Time to confirmed perceptible pain relief (TCPR)
Secondary Efficacy Endpoint

Percentage of subjects with confirmed perceptible pain relief from 45 minutes to 
successively earlier minutes in one-minute increments (Test NPX versus PBO)
Tertiary Efficacy Endpoints

 
 
 
14.5.
Statistical Hypotheses and Treatment Comparisons
The primary hypothesis for the primary endpoint is 
)
(
)
(
:
2
1
0
t
S
t
S
H

(all t) 


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)
(
)
(
:
2
1
t
S
t
S
H A

(at least some t)
where S1(t) and S2(t) are the survival functions of each compared treatment, respectively.
To control the family-wise Type I error rate at 0.05 for primary and secondary endpoints, the fixed 
sequence testing with fallback method will be used [4]. Table 5 presents the order of the tests and the 
assigned α values for each ordered test. Testing will commence with an assigned alpha = 0.049 and an 
alpha value of 0.001 will be reserved for the comparison of Test NPX and placebo on the percentage 
of subjects with confirmed perceptible relief from 45 minutes to successively earlier minutes in one-
minute increments.
Table 5: 
Order of Tests and Assigned Alpha Values
Pre-Assigned 
α-value
α-value available 
if previous test 
positive
α-value available if 
previous test(s) 
negative
TCPR: Test NPX vs PLACEBO 
0.049
Not Applicable
Not Applicable
TCPR: Test NPX vs 
 
None
0.049
None
TCPR: Test NPX vs 
 
None
0.049
None
Percentage of subjects with
confirmed perceptible pain relief 
from 45 minutes to successively 
earlier minutes in one-minute 
increments: Test NPX vs Placebo
0.001
0.05
0.001
14.6.
Data Computations and Data Imputations
14.6.1.
Time to 
 Confirmed Perceptible
 Pain Relief 
(
TCPR
)
 
  Time to confirmed perceptible pain relief is 
defined as the time (in minutes) to perceptible pain relief as indicated on the first stopwatch, 
provided that the subject also stopped the second stopwatch indicating meaningful pain 
relief.  
 


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.
subjects who do not have relief by 12 hours, who 
take rescue medication before having relief, or who discontinue before having relief will 
have time to relief set to 12 hours and be censored at 12 hours
14.6.2.
 
 
 
 
 
 
 
 
 
 
 
14.7.
Analysis Methods
14.7.1.
 Time to Confirmed Perceptible Pain Relief
 time to confirmed perceptible pain relief (TCPR),
 
 will be analyzed using survival data analysis. The survival function 
(cumulative proportions of subjects with pain relief at each time point) and the median survival time 
will be estimated by the Kaplan-Meier method for each treatment. The survival functions will be 
compared using the Wilcoxon test. 
Sensitivity analyses will be conducted for TCPR assessing the impact of censoring at the time of 
rescue medication for subjects not having meaningful relief, and also the impact of censoring at the 
time of perceptible relief for subjects not having meaningful relief. Further details regarding these 
analyses will be provided in the statistical analysis plan.     


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14.7.2.
Earliest Statistically Significant Separation of Test NPX and Placebo on 
Percentage of Subjects with Confirmed Perceptible Relief
The earliest time of separation between Test NPX and placebo will be established by comparing the 
percentage of subjects with confirmed perceptible pain relief starting from 45 minutes to successively
earlier minutes in one-minute increments, until statistical significance is no longer achieved. The 
dichotomized response will be analyzed using logistic regression analysis.
14.7.3.
 
 
14.7.4.
 
Section 14.6.2. 
14.7.5.
 
14.7.6.
 
 
 
 
 
14.7.7.
 
 Section 14.6
.
14.7.8.
Subgroup Analyses
Time to confirmed perceptible relief will be analyzed based on the following subgroups: age 
group (<18 years, ≥18 years), gender, race (white, non-white) and baseline categorical pain 


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(moderate, severe). The survival function and the median survival time will be estimated by 
the Kaplan-Meier method within each subgroup. 
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 


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years following the discontinuance of the test article for investigation.  If it becomes 
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. Averbuch M, Katzper M. Baseline pain and response to analgesic medications in the 
postsurgery dental pain model. J  Clin Pharmacol 2000;40:133-137.
2. Cooper SA. Single-dose analgesic studies: the upside and downside of assay sensitivity. 
In: Max M, Portenoy R, Laska E, eds. Advances in pain research and therapy. Vol 18. New 
York, NY: Raven Press, Ltd., 1991:117-24.
3. Data on file for “PKPD Model-Based Meta-Analysis of the Comparative Onset of Relief 
from Acute Pain for Naproxen Sodium Bicarbonate”, McNeil Consumer Healthcare, Fort 
Washington, PA, 2017.
4. Wiens, BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceutical Statistics 2003; 2:211-215.


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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


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APPENDIX 2: 
 
 
 

SAP_001.pdf: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND 
ACTIVE-CONTROLLED, EFFICACY AND SAFETY 
STUDY OF A TEST NAPROXEN SODIUM 220 MG 
TABLET IN POSTOPERATIVE DENTAL PAIN 
CCSPAA000457
Statistical Analysis Plan
(SAP)
Version Date: April 3, 2019


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CONTENTS
1
Introduction......................................................................................................3
1.1
Study Objectives ................................................................................................3
1.2
Study Design......................................................................................................3
2
Interim Analyses ..............................................................................................5
3
Analysis Sets .....................................................................................................5
3.1
Primary Analysis Set..........................................................................................5
3.2
Per-Protocol Set .................................................................................................6
3.3
Safety Analysis Set ............................................................................................6
4
Efficacy assessments and Endpoints ..............................................................6
4.1
Efficacy Assessments.........................................................................................6
4.2
Efficacy Endpoints.............................................................................................7
4.3
Safety Assessments 
....................................................................8
4.4
Covariates ..........................................................................................................8
5
Statistical Methodology and Statistical Analyses..........................................8
5.1
Statistical Hypotheses ........................................................................................8
5.2
Statistical Decision Rules ..................................................................................8
5.3
Statistical Methods.............................................................................................9
5.3.1
Time to Confirmed Perceptible Pain Relief (TCPR), 
 
............................................................9
5.3.2
Earliest Statistically Significant Separation of Test NPX and Placebo on Percentage 
of Subjects with Confirmed Perceptible Relief ...............................................10
5.3.3
 
11
5.3.4
............................11
5.3.5
11
5.3.6
.............................................................................12
5.3.7
...............................................................................12
5.3.8
Subgroup Analyses ..........................................................................................12
5.4
Demographic and Baseline Characristics ........................................................12
5.5
Previous and Concomitant Medications ..........................................................12
5.6
Safety Analysis ................................................................................................13
5.6.1
Adverse Events ................................................................................................13
5.6.2
Vital Signs........................................................................................................13
6. References.....................................................................................................................13
APPENDICES..................................................................................................................14
APPENDIX 1: SUMMARY TABLES AND FIGURES...............................................14
APPENDIX 2: DATA LISTINGS ..................................................................................18
APPENDIX 3: DATA PATTERN AND CENSORING ...............................................19


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1
INTRODUCTION
Naproxen is a propionic acid derivative and nonsteroidal anti-inflammatory drug 
(NSAID) with analgesic and antipyretic properties. The mechanism of action of naproxen 
involves inhibition of cyclooxygenase enzymes resulting in decreased prostaglandin 
synthesis. The sodium salt of naproxen has been developed as a more rapidly absorbed 
formulation of naproxen. Naproxen sodium products have been available over-the-
counter (OTC) for the indications of fever reduction and relief of minor aches and pains 
in several countries for many years. According to the Drug Facts for 
, dosing 
for adults and children 12 years of age and older is one 220 mg dosage unit (e.g., tablet, 
caplet, capsule) every 8-12 hours, and for the first dose, may take two 220 mg units 
within the first hour. 
 
.
 
 
Clinical efficacy and safety studies have not yet been conducted on the 
 
formulation of naproxen sodium. The current study will evaluate the analgesic onset, 
efficacy and safety of a single 440 mg dose of 
 naproxen sodium 
(administered as two 220 mg tablets) compared to two currently marketed 
 
formulations of naproxen sodium and placebo after third molar dental extractions. The 
postoperative dental pain model is a validated model of acute pain that is widely used to 
study analgesic efficacy of compounds.
1.1
Study Objectives
To evaluate analgesic onset, efficacy, and safety of a single dose of 440 mg of naproxen 
sodium administered as two Test Naproxen Sodium 220 mg tablets (Test NPX) compared 
with two commercial naproxen sodium products (two 
220 mg tablets and two 
 220 mg 
 capsules) and placebo in the dental pain model following 
third-molar extractions.
1.2
Study Design
This is a single-dose, randomized, double-blind, placebo- and active- controlled, parallel-
group study to evaluate the analgesic onset, efficacy, and safety profile of 440 mg of 
naproxen sodium administered as two Test NPX 220 mg tablets compared with two 
commercial products and placebo over a 12-hour period after third-molar extractions. 
Subjects will undergo dental extraction of three or four third molars.  Maxillary third 
molars may be removed regardless of impaction level.  The mandibular extractions must 
meet one of the following scenarios and must not result in a trauma rating of severe in a 
mild, moderate, or severe scale:
•
two full bony impactions
•
two partial bony impactions


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•
one full bony impaction in combination with one partial bony impaction
Pain assessments will be based on subject self-report.  Subjects who meet the 
randomization criteria (post-surgical pain of moderate to severe on the four-point 
categorical pain scale [0-no pain, 1-mild pain,2-moderate pain, 3-severe pain], 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 
four treatment groups.  This PI-NRS will be within 5 minutes prior to study medication 
dosing and will be considered the time 0 pain intensity assessment. 
Approximately 500 subjects will receive a single 440 mg dose of either Test NPX, 
 
tablets, 
 capsules, or placebo in a 3:3:3:1 allocation ratio and will be 
stratified according to gender and baseline pain rating (moderate or severe). To maintain 
the double-blind nature of the study, an independent third party will administer study 
drug to blindfolded subjects. 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. 
Self-reported pain intensity will be collected at baseline (time 0). 
 
 
  Perceptible pain relief and meaningful pain relief will be 
collected using two separate stopwatches.  Subjects who do not experience any pain relief 
after dosing will be encouraged, but not required, to wait at least 1.5 hour before using 
rescue therapy.
 
 
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 6 – 10 of the study.


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Table 1:Schedule of Activities
1Scored within 4.5 hours after last stitch from dental surgery; 
 
 
; 3Subjects encouraged to wait at least 1.5 hours after investigational product administration before using rescue
medicine;
 
 5 Medications and other treatments taken after 12-hour assessment period through follow-up 
interview will be captured on source documents and only those taken for or associated with an AE will be recorded in the CRF; 6 
Collection of AEs and report of pregnancy; 7 End of Study for each subject is defined as the follow-up phone call or early termination.
2
INTERIM ANALYSES
No interim statistical analysis is planned for this trial.
3
ANALYSIS SETS
3.1
Primary Analysis Set
The primary analysis set for the efficacy analyses will be all randomized subjects.  
Screening
Baseline (Day of 
Surgery)
Hours Post-
Dose
Follow-Up Call/End 
of Study
Procedures
Day -30 to
1
Day 1
0 to 12 
hours
Day 6 - 10
Written informed consent and/or assent
X
Demography (including age)
X
Inclusion / Exclusion Assessment
X
X
Significant medical history
X
X
Vital signs
X
X
Physical Exam (Height, weight and
BMI)
X
Urine pregnancy test (Females of 
childbearing potential)
X
X
Urine drug screen
X
X
Serology
X
Dental extraction surgery
X
Baseline Pain Assessments 
(Categorical and PI-NRS)
X1
Randomization criteria
X
Investigational product administration
X
Stopwatch Assessments (perceptible & 
meaningful pain relief)
X
X
Rescue therapy
X3
X4
Prior and Concomitant Therapy
X
X
X
X5
Safety monitoring6
X
X
X
X
Subject Disposition
X7


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Subjects who received different treatment from their assigned treatment according to the 
sponsor-intended treatment decodes will be analyzed based on the actual received 
treatment. 
 
 
 
  
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 primary analysis 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 having potential substantial impact on the efficacy evaluation. The 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

Time to perceptible pain relief (TPPR)– recorded using perceptible pain relief
stopwatch

 

Time to confirmed perceptible pain relief (TCPR) – defined as the time to 
perceptible pain relief provided that the subject subsequently stopped the 
meaningful pain relief stopwatch

Pain intensity  


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Categorical 4-point scale: 0 – no pain, 1 – mild pain, 2 – moderate pain and 3 –
severe pain, collected at baseline.
Numerical 0 – 10 scale (PI): 0 – no pain to 10 – very severe pain, collected at 
Baseline
 

 
 


 
 
4.2
Efficacy Endpoints
Primary efficacy endpoint

Time to confirmed perceptible pain relief (TCPR)
Secondary efficacy endpoints

Percentage of subjects with confirmed perceptible pain relief from 45 minutes to 
successively earlier minutes in one-minute increments (Test NPX versus PBO)
Tertiary efficacy endpoints

 
 
 
 


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4.3
Safety Assessments and Endpoints

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
4.4
Covariates
No covariate variable will be adjusted in the analyses.
5
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
5.1
Statistical Hypotheses
The primary hypothesis is 
)
(
)
(
:
2
1
0
t
S
t
S
H

(all t) 
)
(
)
(
:
2
1
t
S
t
S
H A

(at least some t)
where S1(t) and S2(t) are the survival functions of each compared treatment, respectively.   
For the primary endpoint TCPR
 
survival functions will be compared between Test NPX and 
, between 
Test NPX and 
 Tablet, and between each naproxen product and placebo.   
5.2
Statistical Decision Rules
To control the family-wise Type I error rate at 0.05 for primary and secondary endpoints, 
the fixed sequence testing with fallback method will be used [Wiens 2003]. Table 2
presents the order of the tests and the assigned α values for each ordered test. Testing will 
commence with an assigned alpha = 0.049 and an alpha value of 0.001 will be reserved 
for the comparison of Test NPX and placebo on the percentage of subjects with 
confirmed perceptible relief from 45 minutes to successively earlier minutes in one-
minute increments.
Table 2: 
Order of Tests and Assigned Alpha Values


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Pre-Assigned 
α-value
α-value available 
if previous test 
positive
α-value available if 
previous test(s) 
negative
TCPR: Test NPX vs PLACEBO 
0.049
Not Applicable
Not Applicable
TCPR: Test NPX vs 
 
None
0.049
None
TCPR: Test NPX vs 
None
0.049
None
Percentage of subjects with
confirmed perceptible pain relief 
from 45 minutes to successively 
earlier minutes in one-minute 
increments: Test NPX vs Placebo
0.001
0.05
0.001
The four tests in the above family will be conducted as follows: The survival functions 
for TCPR will be compared between Test NPX and PBO. If it is non-significant at the 
0.049 level, then the first test and the following two tests will be failed and the last test 
(the percentage of subjects with CPR) will be tested at the 0.001 level.  If the first test is 
significant at the 0.049 level, then the second test, the comparison of survival functions 
for TCPR between Test NPX and
, will be compared at the 0.049 level
and the following tests will follow the same pattern as for the first test. If the first 3 tests 
are significant at the 0.049 level, the last test, the percentage of subjects with CPR, will 
be tested at the 0.05 level.
5.3
Statistical Methods
5.3.1
Time to Confirmed Perceptible Pain Relief (TCPR)
 
 Time to confirmed perceptible 
pain relief is defined as the time (in minutes) to perceptible pain relief as indicated on 
the first stopwatch, provided that the subject also stopped the second stopwatch 
indicating meaningful pain relief.
 subjects who do not have relief by 12 hours, 
who take any type of rescue medication before having relief, or who discontinue before 
having relief will have time to relief set to 12 hours and be censored at 12 hours.
Subjects who take rescue medication after confirmed perceptible pain relief will not be 
censored Subjects who received lidocaine 2% after dosing will be treated as subjects 
taking rescue medication. 


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 TCPR
 will be analysed using survival data analysis. The survival 
function (cumulative proportions of subjects with pain relief at each time point) and the 
median survival time will be estimated by the Kaplan-Meier method for each treatment. 
The survival functions will be compared using the Wilcoxon test. 
The estimation of the survival functions and the comparison of the survival functions 
between treatments will be performed by the following SAS codes
proc lifetest data=DATASET method=KM outsurv=predict;
  strata trt;
  time TIME*censor(x);
  ods output Quartiles=output1(where=(percent=50));
run;
Sensitivity analyses will be conducted for TCPR to assess the impact of different 
censoring.  

To assess the impact of censoring at the time of rescue medication for subjects not 
having meaningful relief, the following approach will be used: For subjects
taking rescue medication before having confirmed perceptible pain relief, TCPR 
will be censored at the time of rescue medication. For those subjects who 
discontinue before having confirmed perceptible pain relief, TCPR will be 
censored at the time of discontinuation, approximated using the last observed 
timepoint 
.  For subjects having perceptible relief but not 
meaningful relief, TCPR will be censored at 12 hours.

To assess the impact of censoring at the time of perceptible relief for subjects not 
having meaningful relief, the following approach will be used:  For subjects 
having perceptible relief but not meaningful relief, TCPR will be censored at the 
time of perceptible relief.  For subjects not experiencing TCPR who discontinue 
before 12 hours, TCPR will be censored at the time of discontinuation,
.  For subjects 
not experiencing TCPR who receiving rescue medication, TCPR will be censored 
at 12 hours.
5.3.2
Earliest Statistically Significant Separation of Test NPX and Placebo on 
Percentage of Subjects with Confirmed Perceptible Relief
The earliest time of separation between Test 
 and PBO will be established by 
comparing the percentage of subjects with confirmed perceptible pain relief starting from 
45 minutes to successive earlier minutes in one-minute increments, until statistical 
significance is no longer achieved. At each one-minute increment, each subject will be 
categorized as either having experienced confirmed perceptible pain relief by that time or 
not.  The resulting binary response at each time point will be analyzed using logistic 
regression analysis.
The following is sample SAS code for the logistic regression analyses: 
proc GENMOD data=DATASET ;
  class trt;


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  model responder = trt / dist=BIN link=LOGIT;
  lsmeans trt / diff cl exp;
run;
5.3.3
 
 
 
 
 
 
 
 
 
 
 
5.3.5
 
 
 
 
 
 
 
 
  
 


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5.3.6
 
 
 
 
 
 
5.3.7
 
 
5.3.8
Subgroup Analyses 
Time to confirmed perceptible relief 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). The survival function and the median survival time 
will be estimated by the Kaplan-Meier method within each subgroup. 
5.4
DEMOGRAPHIC AND BASELINE CHARACRISTICS 
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 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 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 


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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 summarised (number of subjects, mean, standard deviation, median, minimum 
and maximum) by treatment group.
6. REFERENCES
1. Wiens, BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceutical Statistics 2003; 2:211-215.


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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
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief 
All Randomized Subjects
Table 14.2.1.1
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief
Per-Protocol Subjects
Table 14.2.1.2
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Moderate Baseline Pain
All Randomized Subjects
Table 14.2.1.3
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Severe Baseline Pain
All Randomized Subjects
Table 14.2.1.4
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Male
All Randomized Subjects
Table 14.2.1.5
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Female
All Randomized Subjects
Table 14.2.1.6
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Age < 18 Years Old
All Randomized Subjects
Table 14.2.1.7
Kaplan-Meier Estimates of The Cumulative All Randomized Subjects


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Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Age >= 18 Years Old
Table 14.2.1.8
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – White Subjects
All Randomized Subjects
Table 14.2.1.9
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Non-White Subjects
All Randomized Subjects
Table 14.2.1.10
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Sensitivity Analysis 1
All Randomized Subjects
Table 14.2.1.11
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Sensitivity Analysis 2
All Randomized Subjects
Table 14.2.1.12
 
 
 
All Randomized Subjects
Table 14.2.2
 
 
All Randomized Subjects
Table 14.2.3
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief at Specified Times – Test 
NPX vs Placebo
All Randomized Subjects
Table 14.2.4
 
 
 
 
 
All Randomized Subjects
Table 14.2.5
 All Randomized Subjects
Table 14.2.6
 All Randomized Subjects
Table 14.2.7
 All Randomized Subjects
Table 14.2.8
 All Randomized Subjects
Table 14.2.9
All Randomized Subjects
Table 14.2.10
 All Randomized Subjects
Table 14.2.11
All 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 
Safety Analysis Subjects


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One or More Treatment Groups) Treatment-
Emergent Adverse Events
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 Withdrawals Due to Adverse Events 
By System Organ Class and MedDRA Preferred 
Term
Safety Analysis Subjects
FIGURES:
Figure 14.1
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief
All Randomized Subjects
Figure 14.1.1
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Moderate Baseline Pain
All Randomized Subjects
Figure 14.1.2
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Severe Baseline Pain
All Randomized Subjects
Figure 14.1.3
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Male
All Randomized Subjects
Figure 14.1.4
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Female
All Randomized Subjects
Figure 14.1.5
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Age < 18 Years Old
All Randomized Subjects
Figure 14.1.6
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Age >= 18 Years Old
All Randomized Subjects
Figure 14.1.7
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – White Subjects
All Randomized Subjects
Figure 14.1.8
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Non-White Subjects
All Randomized Subjects
Figure 14.2
 
All Randomized Subjects


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Figure 14.3
All Randomized Subjects
Figure 14.4
t
All Randomized Subjects
Figure 14.5
 
All Randomized Subjects
Figure 14.6
All Randomized Subjects
Figure 14.7
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
16.2.5.1
 
All Randomized
16.2.5.2
All Randomized
16.2.5.3
 
 
All Randomized
16.2.5.4
 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 Study 
Discontinuation
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
16.2.7
Follow-up Interview
All Randomized


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APPENDIX 3: DATA PATTERN AND CENSORING
Pattern
TCPR
(Primary 
analysis)
TCPR 
(Sensitivity 
analysis 1)
TCPR 
(Sensitivity 
analysis 2)
 
1.
AB
A
A
A
2.
ABR
A
A
A
3.
ABD
A
A
A
4.
A
*12hr
*12hrs
*A
5.
AR
*12hr
*R
*A
6.
AD
*12hr
*D 
*A
7.
R 
(or 
BR)
*12hr 
*R
*12hr
 
8.
D 
(or 
BD)
*12hr
*D
*D
9.
None 
*12hr
*12hr
*12hr
Notation:  Time of Stopwatch 1-A  ;Time of Stopwatch 2- B ;Time to Rescue - R  ;Time to 
Discontinue: D (last observed time point)
*censored