Conditions: Post-operative Dental Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 664
Healthy volunteers: no

Brief summary:
To evaluate analgesic onset, efficacy, and safety of 1000 mg acetaminophen administered as two Test Acetaminophen 500 mg tablets (Test ACM) compared with 1000 mg acetaminophen administered as two commercial acetaminophen 500 mg caplets (ACM) and 400 mg ibuprofen administered as two commercial ibuprofen 200 mg liquid-filled capsules (IBU) 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 Test ACM 1000 mg compared with two commercial products over a four-hour period after third-molar extractions. Subjects will undergo dental extraction of three or four third molars.

Arms:
arm 1: Test acetaminophen 1000 mg dose arm 2: Commercial acetaminophen 1000 mg dose arm 3: Commercial ibuprofen, 400 mg dose arm 4: Placebo

Interventions: intervention 1: Test acetaminophen intervention 2: Commercial acetaminophen intervention 3: Commercial ibuprofen intervention 4: Placebo
Intervention descriptions: intervention 1: single dose of 2 Test acetaminophen 500 mg tablets intervention 2: single dose of 2 acetaminophen 500 mg caplets intervention 3: Single dose of 2 ibuprofen 200 mg Liquid-filled Capsules intervention 4: 2 placebo caplets

Protocol document:
Prot_000.pdf: 
, 
Protocol:CO-170317095828-PACT
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CO-170317095828-PACT
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND 
ACTIVE- CONTROLLED, SINGLE-DOSE, EFFICACY 
AND SAFETY STUDY OF A 
 IN POSTOPERATIVE DENTAL PAIN
Study Product Name
Protocol Number
CO-170317095828-PACT
IND / IDE / EudraCT number
Not Applicable
Phase
3
Version and Date
FINAL 16May2017
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 of Sponsor/Company:
Johnson & Johnson Consumer, Inc., McNeil Consumer Healthcare Division
7050 Camp Hill Road
Fort Washington, PA 19034
Name of Investigational Product:
Tablet
Name of Active Ingredient:
Acetaminophen 
Title of Study: A Randomized, Double-Blind, Placebo- and Active- Controlled, 
Single-Dose, Efficacy and Safety Study of a 
 in 
Postoperative Dental Pain
Study center:
Jean Brown Research
1045 East 3900 South
Salt Lake City, UT   84124
Principal Investigator:
Study period:
Estimated date first subject enrolled: July 
2017
Estimated date last subject completed:
May 2018
Phase of development: 3
Objectives:
To evaluate analgesic onset, efficacy, and safety of 
 
compared with 
1000 mg acetaminophen administered as two commercial acetaminophen 500 mg 
caplets (ACM) and 400 mg ibuprofen administered as two commercial ibuprofen 200 
mg liquid-filled capsules (IBU) in the dental pain model following third-molar 
extractions.


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Methodology:
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 
 
 compared with two commercial products over a four-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
Subjects who meet the randomization criteria (post-surgical pain of moderate to severe on 
the four-point categorical pain scale, and at least a score of 5 on the 11-point [0-10] pain 
intensity numerical rating scale [PI-NRS] at baseline within 4.5 hours of last stitch from 
dental extractions) will be assigned to one of four treatment groups.
Approximately 660 subjects will receive a single dose of either 
, ACM 
1000 mg, IBU 400 mg, or placebo in a 4:4:2:1 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). Pain intensity and pain 
relief will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, and 4 hours (± 5 minutes) post 
dose as well as at the time of rescue (if applicable) and time of meaningful pain relief (if 
applicable). 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 hour before using rescue therapy. Subject 
global evaluation of the investigational product will be collected at hour 4, at the time of 
rescue medication, or at the time of subject withdrawal, whichever comes first, with a 0-4 
categorical rating scale: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent.


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Number of subjects (planned): Approximately 660 subjects
Diagnosis and main criteria for inclusion:
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 and a pain 
intensity of ≥5 on a 0 to 10 scale, will be eligible for the study.
Investigational product, dosage and mode of administration:
To maintain the double-blind nature of the study, an independent third party will administer 
a 
 tablets to blindfolded 
subjects depending on randomization  Subjects will swallow the dose with up to 180 mL of 
water at ambient temperature.
Duration of treatment: One dose, four hours


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Reference treatments, dosage and mode of administration:
Depending on randomization, an independent third party will administer one of the 
following reference products with up to 180 ml of water at ambient temperature to 
blindfolded subjects:

a single 1000-mg dose of acetaminophen as two commercial ACM 500 mg caplets,

a single 400-mg dose of ibuprofen as two commercial IBU 200 mg liquid-filled 
capsules,

a single dose of two placebo caplets
Criteria for evaluation:
Primary Efficacy Endpoint

Time to confirmed perceptible pain relief (TCPR)
Secondary Efficacy Endpoints

Time to meaningful pain relief (TMPR);

Percentage of subjects with confirmed perceptible pain relief from 30 minutes to 
successively earlier minutes in one-minute increments (
 versus PLACEBO);
Tertiary Efficacy Endpoints:

Percentage of subjects with meaningful pain relief at 35, 40, and 45 minutes (
 
versus ACM)

Percentage of subjects with confirmed perceptible relief at 15, 20, and 25 minutes

Time weighted sum of pain intensity difference from 0 to 4 hours (SPID 0-4);

Time weighted sum of pain relief from 0 to 4 hours (TOTPAR 0-4);

Pain relief (PAR) and pain intensity difference (PID) scores at individual time points;

Time to rescue analgesic (duration of relief after dosing);

Subject Global Evaluation.


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Safety:
Safety will be monitored and assessed by reviewing the collection, evaluation, and analysis 
of subject-reported spontaneous adverse events (AEs).
Statistical Methods:
Time to confirmed perceptible pain relief (TCPR) and time to meaningful pain relief 
(TMPR) 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 median survival times for 
the active treatments will be compared using the bootstrap re-sampling method and the 
survival functions of the active treatments will be compared with the survival function of 
placebo using the Wilcoxon test.  The earliest time of separation between 
 and 
placebo will be established by comparing the percentage of subjects with confirmed 
perceptible pain relief starting from 30 minutes to successive earlier minutes in one minute 
increments, until statistical significance is no longer achieved. The dichotomized response 
will be analyzed using logistic regression analysis.
2.
STUDY FLOWCHART
Table 1:
Schedule of Activities
Screening
Baseline
(Day of Surgery)
Hours
Post-Dose
Follow-Up
Call
Procedures
Day -30 to 1
Day 1
0 to 4 hours
Day 6 (±1 day)
Written informed consent and/or assent
X
Demography
X
Collection of age
X
Inclusion / Exclusion assessment
X1
X
Significant medical history
X1
X
Vital signs2
X1
X
Height, weight, and BMI
X
Urine pregnancy test3
X1
X
Urine drug screen11
X1
X
Serology4
X


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Screening
Baseline
(Day of Surgery)
Hours
Post-Dose
Follow-Up
Call
Procedures
Day -30 to 1
Day 1
0 to 4 hours
Day 6 (±1 day)
Dental extraction surgery
X
Categorical and Numerical Pain Intensity
X5
Randomization criteria
X
Investigational product administration
X
Stopwatch assessments (pain relief)
X
Pain intensity and pain relief ratings6
X
Rescue therapy
X7
Subject Global Evaluation
X8
Prior and Concomitant Therapy
X
X
X
X
Safety monitoring
X
X9
X9
X9
Subject Disposition
X10
Follow up interview
X
1:
Only baseline assessments will be collected on the CRF
2:
Blood pressure, heart rate, respiratory rate, and oral temperature
3:
Women of childbearing potential
4:
HIV antibody, hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV)
5:
Scored within 4.5 hours after last stitch from dental surgery
6:
Subjects will record pain ratings on worksheets that will be entered into the CRF by designated site staff. Ratings 
will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, and 4 hours (± 5 minutes) post dose. If a subject requests
rescue medicine, ratings will be collected before administration. Ratings will also be collected at the time of 
meaningful pain relief (if applicable).
7:
Subjects will be encouraged to wait at least 1 hour after investigational product administration before using rescue
medicine.
8:
At Hour 4, at time immediately before use of rescue medication, or at the time of early termination if a subject is      
discontinued or withdrawn earlier than four hours after dosing.
9:
Includes collection of AEs and any report of pregnancy
10: End of Study is when all 4-Hour assessments are complete or at the time of subject withdrawal
11: Minimum requirements for urine drug testing at screening and on the day of surgery include cocaine, 
tetrahydrocannibinol, opioids (e.g., buprenorphine, oxycodone, methadone, and morphine), benzodiazepines, and 
amphetamines


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TABLE OF CONTENTS
1.
SYNOPSIS ...................................................................................................................2
2.
STUDY FLOWCHART...............................................................................................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 Conduct of the Study......................................................................................13
4.3.
Subject Information and Consent...............................................................................13
4.4.
Subject Written Assent...............................................................................................14
5.
STUDY ADMINISTRATIVE STRUCTURE...........................................................15
6.
INTRODUCTION......................................................................................................15
7.
STUDY OBJECTIVES AND ENDPOINTS .............................................................16
7.1.
STUDY OBJECTIVES ..............................................................................................16
7.2.
STUDY ENDPOINTS ...............................................................................................16
7.2.1.
Primary Efficacy Endpoint.........................................................................................16
7.2.2.
Secondary Efficacy Endpoint.....................................................................................16
7.2.3.
Tertiary Efficacy Endpoint.........................................................................................16
7.3.
Safety..........................................................................................................................17
8.
INVESTIGATIONAL PLAN ....................................................................................18
8.1.
Overall Study Design and Plan ..................................................................................18
8.2.
Selection of Study Population ....................................................................................19
8.2.1.
Inclusion Criteria........................................................................................................19
8.2.2.
Exclusion Criteria.......................................................................................................20
8.3.
Subject Withdrawal Criteria.......................................................................................22
9.
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT.............23
9.1.
Investigational Product...............................................................................................23
9.2.
Description of Study Product .....................................................................................23
9.3.
Investigational Product Packaging and Labeling.......................................................24
9.4.
Investigator Unblinding..............................................................................................24
9.5.
Method of Assigning Subjects to Treatment Groups.................................................24
9.6.
Study Product Storage, Accountability and Disposal ................................................25


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9.7.
Preparation, Dispensing and Administration of Investigational Product...................25
9.8.
Product Quality Complaints.......................................................................................27
10.
STUDY PROCEDURES............................................................................................28
10.1.
Overview ....................................................................................................................28
10.2.
Screening Visit ...........................................................................................................28
10.3.
Baseline Visit (Day of Surgery) .................................................................................28
10.3.1.
Randomization............................................................................................................29
10.3.2.
Postdose Assessments ................................................................................................29
10.3.3.
End of Study...............................................................................................................30
10.4.
Follow-Up Phone call.................................................................................................30
10.5.
Life Style Guidelines..................................................................................................31
10.5.1.
Meals and Dietary Restrictions ..................................................................................31
10.5.2.
Alcohol, Caffeine and Tobacco Consumption / Restrictions.....................................31
10.5.3.
Physical Activity Requirements / Restrictions...........................................................31
10.5.4.
Contraception for Females .........................................................................................31
10.5.5.
Contraception for Males.............................................................................................32
10.6.
Prior and Concomitant Medications and Therapies ...................................................32
10.6.1.
Permitted Therapies....................................................................................................32
10.6.2.
Prohibited Therapies...................................................................................................32
10.7.
Rescue Medicine ........................................................................................................33
11.
ASSESSMENTS ........................................................................................................34
11.1.
Efficacy Assessments.................................................................................................34
11.2.
Safety Assessments ....................................................................................................34
11.3.
Vital Signs ..................................................................................................................35
12.
ADVERSE EVENT REPORTING............................................................................36
12.1.
Introduction ................................................................................................................36
12.2.
Reporting Period.........................................................................................................36
12.3.
Definition of an Adverse Event..................................................................................36
12.4            Abnormal Test Findings.............................................................................................37
12.5.
Serious Adverse Events (SAE)...................................................................................38
12.6
Hospitalization............................................................................................................38
12.7.
Resolution...................................................................................................................39


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12.8.
Severity Assessment...................................................................................................40
12.9.
Causality Assessment.................................................................................................40
12.10.
Exposure In Utero ......................................................................................................41
12.10.1.
Withdrawal Due to Adverse Events ...........................................................................42
12.10.2.
Eliciting Adverse Event Information .........................................................................42
12.10.3.
Reporting Requirements.............................................................................................42
12.10.3.1.  Serious Adverse Event Reporting Requirements ........................................................43
13.
STATISTICS..............................................................................................................45
13.1.
Sample Size Determination........................................................................................45
13.2.
Analysis Sets ..............................................................................................................45
13.2.1.
Efficacy Analysis Sets................................................................................................45
13.2.2.
Safety Analysis Population ........................................................................................45
13.2.3.
Subject Disposition and Protocol Violations..............................................................45
13.3.
Baseline and Demographics.......................................................................................46
13.4.
Previous and Concomitant Medications.....................................................................46
13.5.
Efficacy Analysis .......................................................................................................46
13.6.
Statistical Hypotheses and Treatment Comparisons ..................................................47
13.7.
Data Computations and Data Imputations..................................................................48
13.7.1.
Time to Confirmed Perceptible and Meaningful Pain Relief.....................................48
13.7.2.
Endpoints Relating to Pain Intensity and Pain Relief ................................................48
13.8.
Analysis Methods.......................................................................................................49
13.8.1.
Time to Confirmed Perceptible and Meaningful Relief.............................................49
13.8.2.
Earliest Statistically Significant Separation of 
 and Placebo on 
Percentage of Subjects with Confirmed Perceptible Relief .......................................49
13.8.3.
Percentage of Subjects with Meaningful Pain Relief at 35, 40, and 45 
minutes .......................................................................................................................49
13.8.4.
Percentage of Subjects with Confirmed Perceptible Pain Relief at 15, 20, 
and 25 minutes............................................................................................................49
13.8.5.
SPID0-4 and TOTPAR0-4 .........................................................................................49
13.8.6.
PID and PAR at each Time ........................................................................................49
13.8.7.
Time to Rescue...........................................................................................................50
13.8.8.
Subject Global Evaluation..........................................................................................50
13.8.9.
Subgroup Analyses.....................................................................................................50


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13.9.
Safety Analysis...........................................................................................................50
13.9.1.
Adverse Events...........................................................................................................50
14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................51
14.1.
Study Monitoring .......................................................................................................51
14.2.
Audits and Inspections ...............................................................................................52
14.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)..................52
15.
QUALITY CONTROL AND QUALITY ASSURANCE.........................................52
16.
DATA HANDLING AND RECORDKEEPING.......................................................53
16.1.
Case Report Forms/ Electronic Data Record .............................................................53
16.2.
Record Retention........................................................................................................53
17.
SPONSOR DISCONTINUATION CRITERIA.........................................................53
18.
PUBLICATION POLICY..........................................................................................54
19.
LIST OF REFERENCES ...........................................................................................54
20.
APPENDICES............................................................................................................55
LIST OF TABLES
Table 1:
Schedule of Activities ..................................................................................................6
Table 2:
Abbreviations and Specialist Terms...........................................................................12
Table 3:
Investigational Product...............................................................................................23
Table 4:
Sponsor Contact Information .....................................................................................44
Table 5: 
Order of Tests and Assigned Alpha Values ...............................................................47
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 2:
Abbreviations and Specialist Terms
Abbreviation/ 
Term
Definition
AE
Adverse event
ACM
Acetaminophen
BMI
Body Mass Index
CRF
Case report form
EDC
Electronic data capture
EIU
Exposure in Utero
IBU
Ibuprofen
ICH GCP
International Conference on Harmonization Good Clinical Practice
IRB/IEC
Institutional Review Board/Independent Ethics Committee
NSAID
Nonsteroidal anti-inflammatory drug
OTC
Over the counter
PAR
Pain relief
PI
Principle Investigator
PID
Pain intensity difference
PQC
Product Quality Complaint
PI-NRS
Pain intensity-numerical rating scale
PR-NRS
Pain relief-numerical rating scale
RSI
Reference Safety Information
SAE
Serious adverse event
SPID
Time weighted sum of pain intensity difference
TOTPAR
Time weighted total pain relief scores


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4. ETHICS
4.1.
Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC)
It is the responsibility of the 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 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 Conduct of the Study
The study will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice (GCP) guidelines (ICH E6) and applicable local 
regulatory requirements and laws.
4.3.
Subject Information and Consent
Only subjects who provide informed consent will continue in the study.  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 study 
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 and must be 
in compliance with ICH E6, GCP, local regulatory requirements, and legal requirements.
The Principal Investigator (PI) must ensure that each study subject is fully informed about the 
nature and objectives of the study and possible risks associated with participation.  The 
Investigator, or a person designated by the Investigator, will obtain written informed consent 
from each subject 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.


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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.  During the assent process, the
PI or designee will provide the minor with an assent document that explains, in concrete and 
age-appropriate terms, the purpose of the research, what they will be asked to do and what 
procedures they will undergo.  The assent document will focus on the risks, benefits, and 
alternatives to research participation as well as the confidentiality of any information obtained 
as a result of their participation.  The PI or designee will explain the information, give the 
minor a chance to ask questions and ask the minor to indicate their assent by signing the assent 
document.  The prospective subject will do this by signing an IRB/IEC-approved assent form 
or designated assent section of the informed consent, depending on individual institutional 
regulations.  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 and will be available 
for review by 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 constitute an understanding of the procedures and hazards of the study.


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5.
STUDY ADMINISTRATIVE STRUCTURE
Details on the administrative structure of the study (e.g., Principal Investigator (PI)/study site 
personnel, the Sponsor study team, and the external service providers) will be included in a 
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/IECs, as well as 
the names and titles of the person(s) authorized to sign the protocol and the protocol 
amendment(s) for the sponsor. This list will be maintained in the study and site master files 
throughout the study for inclusion in the clinical study report.
6.
INTRODUCTION
Acetaminophen is a para-aminophenol derivative with analgesic and antipyretic properties, and 
is thought to produce analgesia by inhibiting prostaglandin synthesis centrally and elevating the 
pain threshold.  Acetaminophen is available as an over-the-counter (OTC) analgesic and 
antipyretic in many global markets. In the US, TYLENOL® is commercially available in extra 
strength (500 mg) and regular strength (325 mg) dosage forms marketed under the Internal 
Analgesic, Antipyretic and Antirheumatic Drug Products for OTC Human Use Tentative Final 
Monograph.  TYLENOL® Regular Strength 325 mg is dosed 2 dosage units every 4 to 6 hours 
and TYLENOL® Extra Strength 500 mg is dosed 2 dosage units every 6 hours. It is labeled for 
the temporary relief of minor aches and pains due to the common cold, headache, backache, 
toothache, premenstrual and menstrual cramps, minor pain of arthritis, muscular aches and for 
the temporary relief of fever.
The overall purpose of this study is to evaluate the analgesic onset, efficacy, and safety of a 
single dose of 1000 mg acetaminophen administered as
 tablets 
compared with a single dose of 1000 mg acetaminophen administered as two commercial 
acetaminophen 500 mg caplets (ACM), a single dose of 400 mg ibuprofen administered as two 
commercial ibuprofen 200 mg liquid-filled capsules (IBU), and placebo over 4 hours. 
 
The dental pain model, a validated model of acute pain widely used to
study analgesic efficacy of compounds, will be used in this study [1, 2]. Reference Safety
Information (RSI) for the 
 and ACM commercial product is the Drug Facts labeling 
for the ACM commercial product in the US, and the RSI for the IBU commercial product is the 
associated Drug Facts Label in the US.


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7.
STUDY OBJECTIVES AND ENDPOINTS
7.1.
STUDY OBJECTIVES
To evaluate analgesic onset, efficacy, and safety of 1000 mg acetaminophen administered as 
 compared with 1000 mg acetaminophen 
administered as two commercial acetaminophen 500 mg caplets (ACM) and 400 mg ibuprofen 
administered as two commercial ibuprofen 200 mg liquid-filled capsules (IBU) in the dental 
pain model following third-molar extractions.
7.2.
STUDY ENDPOINTS
7.2.1.
Primary Efficacy Endpoint

Time to confirmed perceptible pain relief
7.2.2.
Secondary Efficacy Endpoint

Time to meaningful pain relief

Percentage of subjects with confirmed perceptible relief from 30 minutes to 
successively earlier minutes in one-minute increments (
 versus 
PLACEBO);
7.2.3.
Tertiary Efficacy Endpoint

Percentage of subjects with meaningful relief at 35, 40, and 45 minutes 
 versus ACM);

Percentage of subjects with confirmed perceptible relief at 15, 20, and 25 minutes

Time weighted sum of pain intensity difference from 0 to 4 hours (SPID 0-4);

Time weighted sum of pain relief from 0 to 4 hours (TOTPAR 0-4);

Pain relief (PAR) and pain intensity difference (PID) scores at individual time points;

Time to rescue analgesic (duration of relief after dosing);

Subject Global Evaluation.


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7.3.
Safety
Safety will be monitored and assessed by reviewing the collection, evaluation, and analysis of 
subject-reported spontaneous adverse events (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 
 
compared with two commercial products over a four-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
Subjects who meet the randomization criteria (post-surgical pain of moderate to severe on the 
four-point categorical pain scale, and at least a score of 5 on the 11-point [0-10] pain intensity
numerical rating scale [PI-NRS] at baseline within 4.5 hours of last stitch from dental 
extractions) will be assigned to one of four treatment groups.  Approximately 660 subjects will 
receive a single dose of either 
, ACM 1000 mg, IBU 400 mg, or placebo in 
a 4:4:2:1 allocation ratio, and will be stratified according to gender and baseline pain rating 
(moderate or severe).  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).  
Pain intensity and pain relief will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, and 4 hours 
(± 5 minutes) after the dose.  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 hour before using rescue therapy.


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Figure 1:
Study Design
8.2.
Selection of Study Population
The following eligibility criteria are designed to select subjects for whom study treatment is 
considered appropriate. All relevant medical and nonmedical conditions should be considered
when deciding whether this protocol is suitable for a particular subject. No waivers to inclusion
or exclusion criteria will be permitted.
8.2.1.
Inclusion Criteria
Subjects are eligible for enrollment if they:
1. Are 17 to 50 years of age (inclusive) at the time of screening;
2. Weigh 100 lbs. or greater and have a body mass index (BMI) of 18 to 30 (inclusive) at 
screening;
3. 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


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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;
4.   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;
5.   Are able to comprehend and follow the requirements of the study (including availability on 
scheduled visit dates) based upon research site personnel’s assessment;
6.   Are able to provide written informed consent;
7.   Females of childbearing potential and males who are sexually active must be willing to use
a medically acceptable method of birth control during the study. In addition, females of 
childbearing potential who are sexually active must be willing to use a medically 
acceptable method of birth control for up to 30 days after the last dose of investigational 
product;  
8.   Are willing for this to be the only investigational product used during the study.
8.2.2.
Exclusion Criteria
Subjects will be excluded if they:
1.   Are female and are pregnant or breastfeeding;
2.   Are male with a pregnant partner or a partner who is currently trying to become pregnant;
3.   Have a known allergy to acetaminophen or nonsteroidal anti-inflammatory drugs
(NSAIDs), including aspirin as well as hypersensitivity to 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, or the integrity of the study (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);


t
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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 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;
9.  Used oral OTC or prescription products (except contraceptive medications and those 
required for use during the oral surgical procedure), vitamins, or herbal supplements within 
5 days or 5 half-lives (whichever is longer) before the oral surgical procedure;
10. 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;
11. Used alcohol within 3 days before the oral surgical procedure;
12. Have a positive urine drug screen, including a test for buprenorphine. However, if tested 
positive for amphetamine/methamphetamine due to treatment for Attention Deficit 
Hyperactivity Disorder, the subject will not be excluded;
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 or had 
participated in this current trial previously;
17. Are related to those persons involved directly or indirectly with the conduct of this study
(i.e., principal investigator, sub investigators, study coordinators, other site personnel, 
employees of Johnson & Johnson subsidiaries, contractors of Johnson & Johnson, and the 
families of each).


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8.3.
Subject Withdrawal 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 product and/or study follow-up in the event of any
of the following:

Serious eligibility or on-study violation of the protocol

Medical reasons that are considered significant by the subject, investigator, or Sponsor

AEs

Intercurrent illness

Medical reason unrelated to the study

Non-medical reasons
o
Compliance problems
o
Subject withdrew consent

Pregnancy

Treatment was unblinded

Administrative or other reasons
Should a subject decide to withdraw from the study after beginning Day 1 Baseline procedures, 
he or she will be strongly encouraged to complete all end-of-study assessments and the follow-
up telephone call.  In case of questions surrounding the circumstances that a subject needs to be 
withdrawn from the study (e.g., protocol deviation), the Sponsor or its designated 
representative should be consulted.  The reason for withdrawal will be documented in the 
source document and CRF.
If a subject does not return for a scheduled visit or cannot be reached for the follow-up phone 
call, the staff will attempt to contact the subject at least three times by telephone, and lastly, by
certified letter.  The outcome for each attempt will be recorded in the source document. The 
investigator should inquire about the reason for withdrawal and follow-up with the subject 
regarding any unresolved AEs.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations will be performed and no additional data will be collected.  
The Sponsor may retain and continue to use any data collected before such withdrawal of 
consent.


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9.
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT
9.1.
Investigational Product
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.

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.
Detailed dosing procedures to ensure maintenance of the double-blind status of the study are 
provided in Section 9.7.
9.2.
Description of Study Product
A description of the 
, acetaminophen, ibuprofen, and placebo investigational 
products are provided in Table 3. 
Table 3:
Investigational Product
Product
ACM 
(1000 mg)
IBUb
(400 mg)
Placebo
Dosage Form
Caplet
Liquid-filled Capsule
Caplet
Route of Administration
Oral
Oral
Oral
Unit Dose
500 mg
200 mg
Not applicable
Physical Description
White caplet
Teal liquid- filled
capsule
White caplet


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Table 3:
Investigational Product
Product
ACM 
(1000 mg)
IBUb
(400 mg)
Placebo
Manufacturer/Brand
J&J Consumer 
Inc., McNeil
Consumer Health 
Division/ Tylenol
Pfizer/Advil         
Liqui-Gel®
Catalent
b: Ibuprofen is solubilized as the free acid and potassium salt.
9.3.
Investigational Product Packaging and Labeling
 
9.4.
Investigator 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 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.
9.5.
Method of Assigning Subjects to Treatment Groups
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 


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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 (
 
 ACM 1000 mg, IBU 400 mg or placebo) in a 4:4:2:1 
ratio.  Subjects will be stratified by gender and baseline pain (moderate or severe). For subjects 
with moderate baseline pain, randomization numbers will be assigned to subjects in sequential 
order starting with the lowest available number within the appropriate gender stratum. 
Similarly for subjects with severe baseline pain intensity, subjects will be assigned in 
sequential order starting with the highest available number in the appropriate gender stratum.
9.6.
Study Product Storage, Accountability and Disposal
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 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. At the end of the study, the Sponsor will provide instructions regarding the disposition 
of any unused and exhausted investigational product.  The study site must maintain accurate 
and adequate records including shipment receipt and return of unused investigational product 
shipments.
9.7.
Preparation, Dispensing and Administration of Investigational 
Product
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 1000-mg dose of acetaminophen as two commercial ACM 500 mg caplets,

a single 400-mg dose of ibuprofen as two commercial IBU 200 mg liquid-filled 
capsules, or

a single dose of two placebo caplets.


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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 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 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. 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 the 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.


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9.8.
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 Clinical Supply Manager via a 
completed PQC form and telephone call.  The PI or designee should also complete, sign, and
forward a copy of the PQC form to the Clinical Supply Manager.
In addition, PQC information must be included on the Investigational Product Dispensing and 
Accountability Log or equivalent in the comments field and completed by the third-party
dispenser.  The Clinical Supply Manager listed can assist you or answer questions related to 
this process. To aid in the initial conversation and understanding of a PQC, the site staff may
be asked to photograph the issue and send it to the Clinical Supply Manager.


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10.
STUDY PROCEDURES
10.1.
Overview
Collection of adverse events and concomitant medications will start after the study-specific 
informed consent document has been signed and continue until completion of the follow-up 
procedures.  The Schedule of Activities (Table 1) 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.
10.2.
Screening Visit
Informed consent should be obtained from the subjects before any study related assessments 
are conducted.

Inclusion and exclusion criteria

Demography

Significant medical history – the condition, diagnosis, or surgical procedure

History of medication and other treatments (within 30 days)

Vital signs:  resting blood pressure, heart rate, respiratory rate, oral temperature

Height, weight and body mass index (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, including a test for buprenorphine

Urine pregnancy test on females with childbearing potential
Subjects who meet all inclusion/exclusion criteria will be scheduled for the dental procedure 
within 30 days after Screening.
10.3.
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 


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Baseline Visits with the exception of age, only the data collected at Baseline will be recorded 
on the CRF.

Inclusion and exclusion criteria

Any changes to medical and surgical history

      Collection of age

Any changes to prior and concomitant therapies

Vital signs: resting blood pressure, heart rate, respiratory rate, oral temperature

Urine drug screen test, including a test for buprenorphine

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.
10.3.1.
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 9.7. Site staff will inspect the subject’s oral 
cavity to ensure that the investigational product was swallowed.
10.3.2.
Postdose 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. Subjects will only be given the 
second stopwatch after they stop the first one.


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Site personnel will instruct the subject: “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.
Pain relief and pain intensity will be assessed using the NRS (see APPENDIX 1) at 0.25, 0.5,
0.75, 1, 1.25, 1.5, 2, 3, and 4 hours (± 5 minutes) after the dose, at the time of rescue (if 
applicable), and at the time of meaningful relief (if applicable).
At the end of the 4-hour assessment, at the time of rescue, or at the time of early termination if 
a subject is discontinued or withdrawn earlier than four hours after dosing, subjects will be 
asked to report their overall impression of therapy (Subject Global Evaluation) as (0) Poor, (1) 
Fair, (2) Good, (3) Very good, or (4) Excellent. Subjects who use rescue therapy will continue
in the study and assess pain and relief through four hours.
10.3.3.
End of Study
End of study is defined as completion of the 4-hour assessments or at the time of early 
termination if a subject is discontinued or withdrawn earlier than four hours after the dose. 
Subjects who rescue are to remain at the study site through the 4-hour assessments, which is 
their time of end of study.
10.4.
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 the 5th -7th day after the dental surgery unless the 5th day occurs on a Friday in 
which case the interview period can be extended to the next business day. Three attempts should 
be made to contact the subject by phone. If the subject cannot be contacted by phone by the 7th
day after the dental surgery or the next business day if the 5th day after dental surgery occurs on 
a Friday, then a certified letter should be mailed to the subject on the 7th day after the dental 
surgery or the next business day if the 5th day after surgery occurs on a Friday. 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 4-hour and Subject Global assessments will be recorded on the subject’s 
source documents, but not in the CRF; however concomitant medications taken for an adverse 
event will be recorded on the CRF.  Emergent or existing AEs will be recorded in both the 
source documents and CRF.


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10.5.
Life Style Guidelines
10.5.1.
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.
10.5.2.
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.
10.5.3.
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.
10.5.4.
Contraception for Females
Female subjects are considered not of childbearing potential if they meet at least one of the 
following criteria:

Had a hysterectomy and/or bilateral oophorectomy

Had sterilization surgery

Are post-menopausal (i.e., amenorrheic for at least 12 months prior to the Baseline 
visit)
Females with childbearing potential who are sexually active must agree to continue using a 
medically acceptable form of birth control during the study and for 30 days after taking the 
investigational product.  
Medically acceptable methods of birth control for this study include:
a.
Established use of hormonal methods of contraception (oral, injected, implanted, patch 
or vaginal ring)
b. Barrier methods of contraception with spermicide: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, or 
suppository.


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c.
Intrauterine device (IUD) or intrauterine system (IUS)
d. Surgical sterilization (e.g., vasectomy that has been confirmed effective by sperm count 
check, tubal occlusion, hysterectomy, bilateral salpingectomy)
e.
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. 
Sexually active female subjects who use hormonal contraception must have used a stable dose 
for 30 days before surgery.  If hormonal contraception has been used for less than 30 days or if 
the dose has changed within the past 30 days, subjects must agree to also use a barrier method 
during the study and up to 30 days after taking the investigational product.
10.5.5.
Contraception for Males
If a male subject is sexually active with a woman of childbearing potential and has not had a 
vasectomy with confirmation of azoospermia, he must either agree to use a condom with 
spermicidal foam/gel/film/cream during the study or must confirm that his female partner has 
used a medically acceptable form of birth control for at least 30 days before study drug 
administration and will continue to do so during the study.  Medically acceptable forms of birth 
control for a male subject’s female partner of childbearing potential include prescription oral, 
vaginal or transdermal contraceptives, contraceptive implants or injections, intrauterine device, 
diaphragm or cervical cap, with spermicide. 
10.6.
Prior and Concomitant Medications and Therapies
Medications that are taken from 30 days prior to surgery until study end (as defined in Section 
10.3.3) will be recorded in the source documents and CRF.  Medications taken between study
end and the follow-up interview (except for those taken for an adverse event) will be recorded 
in the source documents, but not in the CRF. Medications taken between study end and the 
follow-up interview for an adverse event will be recorded in the source documents and CRF.
10.6.1.
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.
10.6.2.
Prohibited Therapies
Long-acting anesthetics are prohibited during the dental surgery. Other medications prohibited 
before entry into the study are listed under Exclusion Criteria.


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The use of any oral OTC or prescription (except contraceptive medications and those required 
for use during oral surgical procedure such as short-acting local anesthetics), vitamin, or herbal 
supplements are prohibited within 5 days or 5 half-lives (whichever is longer) before the oral 
surgical procedure and during the study.
10.7.
Rescue Medicine
Subjects will be encouraged, but not required, to wait at least 1 hour after investigational 
product dosing before using the rescue medicine, hydrocodone bitartrate 7.5 mg / ibuprofen 
200 mg tablets, if the severity of the subject’s pain increases to an intolerable level.
Hydrocodone bitartrate 7.5 mg / ibuprofen 200 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; however, subjects 
will continue to record pain intensity and pain relief.


, 
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11.
ASSESSMENTS
11.1.
Efficacy Assessments
The investigator or designated study staff will ensure the subjects complete the pain intensity 
and pain relief assessments at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, and 4 hours (± 5 minutes) after 
dosing.  Subjects will record their pain intensity and pain relief directly onto the respective 
source worksheet.  Evaluations will include the following parameters:

Pain intensity
o
Four-point categorical scale collected at baseline: (0) no pain; (1) mild pain; (2) 
moderate pain; (3) severe pain
o
0-10 PI-NRS collected at baseline and at each time point (including at time of 
rescue and at time of meaningful relief)

Pain relief– 0-10 PR-NRS collected at each time point (including at time of rescue and 
at time of meaningful relief)

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.

Time to meaningful pain relief – recorded using stopwatch meaningful

Time to rescue – time when rescue therapy was administered

Subject global evaluation – subject’s overall impression of the investigational product 
at hour 4, at time of rescue, or at the time of early termination if a subject is 
discontinued or withdrawn earlier than four hours after dosing:
(0) poor
(1) fair (2) good
(3) very good (4) excellent
11.2.
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 Adverse Event Reporting section of the protocol.


 
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Normal consequences of dental surgery (e.g., dry-socket, pain, swelling, bruising) are not 
considered AEs unless the investigator believes the condition worsened or was aggravated 
following study drug therapy.
11.3.
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.


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12.
ADVERSE EVENT REPORTING
12.1.
Introduction
All observed or volunteered AEs regardless of treatment group, device group or suspected 
causal relationship to the investigational product(s) will be reported as described in the 
following sections.  For all AEs, the Investigator or medically qualified individual 
(MD/DO/Dentist) must pursue and obtain information adequate both to determine the outcome 
of the AE and to assess whether it meets the criteria for classification as a Serious Adverse 
Event (SAE) requiring immediate notification (within 24 hours) to the Sponsor or its 
designated representative.  For all AEs, sufficient information should be obtained by the 
Investigator or medically qualified individual (MD/DO/Dentist) to try to determine causality.
The Investigator / site is required to assess causality.  For AEs with a suspected causal 
relationship to the investigational product, follow-up by the Investigator or medically qualified 
individual (MD/DO/Dentist) is required until the event or its sequelae resolve or stabilize at a 
level acceptable to the Investigator, and the Sponsor concurs with that assessment.
12.2.
Reporting Period
All AEs, whether serious or non-serious will be recorded on the CRF in the AE section 
beginning from the time the informed consent is signed and dated. Informed consent is 
considered the point at which the subject is participating in the clinical study and all events are 
captured even if it is prior to undergoing any study-related procedure and/or receiving 
investigational product or investigational device. Non-serious -AEs will be reported through 
the subject’s last study visit (or termination if the subject terminates early from the study for 
any reason).  Serious AEs will be reported through and including 30 calendar days after 
administration of the subject’s last dose or exposure to investigational product.  Serious AEs 
require immediate notification to the Sponsor or its designated representative.  Any SAE 
occurring any time after the reporting period must be promptly reported if a causal relationship 
to study product is suspected.
12.3.
Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation whether or not a subject 
is administered the investigational product or medical device.  The event does not need to have 
a suspected causal relationship with the investigational product or device.  An AE can therefore 
be any unfavorable and unintended sign, symptom, disease, or injury temporally associated 
with the use of an investigational product or device, whether or not related to the 
investigational product or device.  Examples of - AEs include but are not limited to:

Abnormal test findings,


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
Clinically important symptoms and signs,

Changes in physical examination findings,

Hypersensitivity, and

Progression/worsening of underlying disease.
Additionally, they may include the signs or symptoms resulting from:

Investigational product overdose,

Investigational product withdrawal,

Investigational product abuse,

Investigational product misuse,

Investigational product interactions,

Medication errors,

Investigational product dependency

Exposure in utero, and

Study related procedure
12.4           Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AEs are as follows:

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
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 Investigator or the Sponsor


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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.
12.5.
Serious Adverse Events (SAE)
An AE or suspected adverse reaction is considered “serious” for a drug study if, in the view of 
either the Investigator (physician/dentist) or the Sponsor, it results in any of the following 
outcomes:

Results in death,

Is life-threatening (immediate risk of death),

Requires inpatient hospitalization or prolongation of existing hospitalization,

Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions,

Results in congenital anomaly/birth defect,

Is considered medically significant (medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other situations, 
such as important medical events that may not result in death, be life-threatening or
require hospitalization but may be considered a serious adverse drug experience when, 
based upon appropriate medical judgment, they may jeopardize the subject and may
require medical or surgical intervention to prevent one of the other outcomes listed 
above).  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an Emergency Room or at home, blood dyscrasia, or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse, 
or malignancy), or,

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’.
12.6           Hospitalization
Adverse events 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,


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
Hospice facilities,

Respite care (e.g., caregiver relief),

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 a 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.
12.7.
Resolution
The Investigator will be required to assess the outcome of the AE for investigational product
(drug or device) as one of the following:

Resolved,


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
Not Resolved,

Fatal,

Resolved with sequelae,

Resolving, or

Unknown
Any causally-related AEs unresolved upon completion of the last study visit will be followed 
up by the study staff until the event or its sequelae resolve or stabilize at a level acceptable to 
the Investigator 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 Investigator and 
has concurrence by the Sponsor.
12.8.
Severity Assessment
The severity of AEs will be assessed by the Investigator or medically qualified individual 
(MD/DO/Dentist) using the following general categorical descriptors:
MILD: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with subject's usual function or normal everyday activities
MODERATE: Sufficient discomfort is present to cause interference to some extent with 
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 subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
12.9.
Causality Assessment
The Investigator’s or medically qualified individual (MD/DO/Dentist) assessment of causality
for investigational product (i.e., relationship to investigational product) must be provided for 
all AEs (serious and nonserious).  An Investigator’s causality assessment is the determination 
of whether there exists a reasonable possibility that the investigational product caused or 
contributed to an AE.


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
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 investigational product 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 investigational product 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.
If the Investigator determines a SAE is associated with study procedures, the Investigator must 
record this suspected causal relationship in the source documents and CRF, as appropriate, and 
report such an assessment in accordance with the SAE reporting requirements, if applicable.
12.10.
Exposure In Utero
For investigational products within clinical studies and for marketed products, an exposure in 
utero (EIU) occurs if:
1.   a woman is exposed to the investigational product 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 drug via semen from the male partner who 
is taking the investigational product at the time of conception, thereby possibly exposing the 
fetus to the product.
If any study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s participation, the Investigator must report the pregnancy to the Sponsor on a 
Pregnancy Notification Form (to be provided by the Sponsor when applicable). In addition, the
Investigator must submit information regarding environmental exposure to a Sponsor product 
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) using the Pregnancy Notification Form.  This must 
be done irrespective of whether an AE has occurred and notification must occur within 24 
hours of awareness of the pregnancy. Initial notification via telephone to the Sponsor’s study
team contact must occur immediately upon the Investigator site’s awareness of the pregnancy. 
The Pregnancy Notification Form must then be sent to the Sponsor within 24 hours of the site’s 


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awareness. The information submitted should include the anticipated date of delivery (see 
below for information related to induced termination of pregnancy).
Follow-up is conducted to obtain pregnancy outcome information on all EIU reports.  The 
Investigator will follow the pregnancy until completion or until pregnancy termination (i.e., 
induced abortion) and then notify the Sponsor of the outcome.  The Investigator will provide 
this information as a follow-up to the initial Drug Exposure during Pregnancy Collection Form 
A and/or End of Pregnancy Collection Form B (provided by the Sponsor when applicable).  
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, a
SAE case is created with the event of ectopic pregnancy.
The Investigator should follow the procedures for reporting SAEs if the outcome of the 
pregnancy meets the criteria for immediate classification as a 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 B 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 in 
utero exposure to the investigational product.
12.10.1.
Withdrawal Due to Adverse Events
When a subject withdraws due to a SAE, the SAEs must be reported in accordance with the 
reporting requirements defined below.
12.10.2.
Eliciting Adverse Event Information
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject. In addition, each study subject will be questioned about AEs.
12.10.3.
Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for a SAE. If a SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.


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All AEs will be reported on the AE page(s) of the CRF.  A Clinical Serious Adverse Event 
(SAE) Report Form must also be completed if the event is considered to be serious. It should 
be noted that this Clinical SAE Report Form for collection of SAE information is not the same 
as the AE CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same AE term should be used on both forms.  Adverse 
events should be reported using concise medical terminology on the CRFs as well as on the 
form for collection of SAE information.
12.10.3.1.  Serious Adverse Event Reporting Requirements
If a SAE occurs, the Sponsor is to be initially notified by telephone immediately upon 
awareness of the event by the Investigator’s site. Within 24 hours of the Investigator site’s
awareness of the event, the study site must send the Sponsor the Clinical SAE Report Form. 
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports as well as to the initial and follow-up reporting of EIU cases. In the rare event 
that the Investigator’s site does not become aware of the occurrence of a SAE immediately
(e.g., 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 time of the 
study site’s first awareness of the adverse event.
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 adverse event 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.  Upon 
notification of an SAE at the study site, the Investigator or designated study site staff should 
call and speak to their Sponsor’s study manager contact immediately to initially notify them of 
the SAE.
Within 24 hours of awareness of the event, the Investigator or designated study site staff:

complete the Clinical SAE Report Form ([provided by the Sponsor] with as much 
information as possible, however at a minimum, the subject identification number, 
name of product, SAE, and name of reporter are required);

ensures the Investigator signs the Clinical SAE Report Form prior to sending to the
Sponsor;


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
scans and emails (via secure email) the Clinical SAE Report Form to the Sponsor 
contacts.
The Sponsor contact information is maintained in the table below:
Table 4:
Sponsor Contact Information
 
 
All nonserious adverse events are to be reported on the adverse event CRFs and will be 
submitted to the Sponsor.


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13.
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.
13.1.
Sample Size Determination
A simulation [3] was conducted based on the two previous dental pain studies 
 to evaluate the sample size and power 
within different effect size ranges.  Based on the simulation results, the time to confirmed 
perceptible pain relief (TCPR) is identified as the primary efficacy endpoint, and the primary 
interest is to compare the median survival times in TCPR between 
 and ACM. Based 
on the assumption that the median survival time of 
 will be faster than that of ACM 
within the range of 5.0 – 5.5 minutes, a sample size of n=240 for the
 and ACM 
groups will provide 90% power. If the median survival time in TCPR of 
 is assumed 
to be faster than that of IBU within the range of 6.0 – 6.5 minutes, the sample size of n=240 for 
the 
 group and n=120 for the IBU group will provide greater than 90%  power.
Based on the above, it is recommended that the eligible subjects will be randomly assigned in a 
ratio of 4:4:2:1, with 240, 240, 120, and 60 subjects being assigned to 
, ACM, IBU 
and placebo for a total of 660 subjects.
13.2.
Analysis Sets
13.2.1.
Efficacy Analysis Sets
The primary analysis set for the efficacy analyses will include all subjects who are randomized.  
The per protocol set will exclude subjects who took rescue medication within 60 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.
13.2.2.
Safety Analysis Population
The Safety Set will include all subjects who are randomized and take investigational product.
13.2.3.
Subject Disposition and Protocol Violations
Subject disposition will be summarized by treatment group.  The number of subjects with 
protocol violations will be summarized in a table by treatment and violation as well as in a 
listing by subject.


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13.3.
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.
13.4.
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. In addition, those medications taken between study end 
and the follow-up interview for an adverse event will be considered concomitant medications.  
Medications taken after End of Study (see Section 10.3.3) and up to the follow-up call that 
were not taken for an adverse event 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.
13.5.
Efficacy Analysis
Primary efficacy endpoint

Time to confirmed perceptible pain relief
Secondary efficacy endpoints

Time to meaningful pain relief;

Percentage of subjects with confirmed perceptible relief from 30 minutes to 
successively earlier minutes in one-minute increments (
 versus placebo)
Tertiary efficacy endpoints

Percentage of subjects with meaningful pain relief at 35, 40, and 45 minutes (
 
 versus ACM);

Percentage of subjects with confirmed perceptible relief at 15, 20, and 25 minutes;

Time weighted sum of pain intensity difference from 0 to 4 hours (SPID 0-4);

Time weighted sum of pain relief from 0 to 4 hours (TOTPAR 0-4);

Pain relief (PAR) and pain intensity difference (PID) scores at individual time points;

Time to rescue analgesic (duration of relief after dosing);


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
Subject Global Evaluation.
13.6.
Statistical Hypotheses and Treatment Comparisons
The primary hypothesis is 
2
1
0 :
M
M
H

    vs   
2
1
:
M
M
H A

where 
1
M and 
2
M
are the median survival times of 
 and ACM in TCPR, 
respectively.
Besides the primary hypothesis, the median survival times in TCPR between 
 and 
IBU will be compared. The median survival times in TMPR will be compared between 
 
vs ACM and between 
 vs IBU.
The survival functions of the active treatments will be compared with the survival function of 
placebo.
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. The comparison of 
 to IBU in 
TMPR is not included in the fixed testing sequence. Testing will commence with an assigned 
alpha = 0.049 and an alpha value of 0.001 will be reserved for the comparison of 
 
and placebo on the percentage of subjects with confirmed perceptible relief from 30 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 
 vs PLACEBO
0.049
---
---
TMPR 
 vs PLACEBO
None
0.049
None
TCPR 
 vs ACM
None
0.049
None
TCPR 
 vs IBU
None
0.049
None
TMPR 
 vs ACM
None
0.049
None


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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
Percentage of subjects with 
confirmed perceptible relief from 
30 minutes to successively earlier 
minutes in one-minute increments 
 vs PLACEBO)
0.001
0.05
0.001
13.7.
Data Computations and Data Imputations
13.7.1.
Time to Confirmed Perceptible and Meaningful Pain Relief
The time to meaningful pain relief is defined as the time (in minutes) elapsed from dosing until 
the subject stopped the second stopwatch.  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.
For these relief variables, subjects who do not have relief by 4 hours, who take rescue 
medication before having relief, or who discontinue before having relief will have their time of 
relief set to 4 hours and be censored at 4 hours.
13.7.2.
Endpoints Relating to Pain Intensity and Pain Relief
The pain intensity difference (PID) at each time point will be derived by subtracting the pain 
intensity from the baseline pain intensity.  A higher value is indicative of a greater 
improvement.
Time-weighted sum of the pain intensity difference scores (SPID) will be derived by first 
multiplying each PID score by the time from the previous time point, and adding them together 
for each scheduled time point from 0-4 hours. Time-weighted total pain relief (TOTPAR) for 
each specified interval will be similarly derived.
Pain intensity and pain relief ratings provided at times differing from the intended times by 
more than ± 5 minutes for the scores up to 90 minutes post-dose, and by more than ± 15 
minutes for the remaining measurements will be estimated by linear interpolation.  For subjects 
who use rescue medication, the last reported pain score or baseline pain score, whichever is 
worse, will be carried forward to the remaining time points; pain relief scores after rescue 
medication will be set to zero. For subjects who discontinue the study early, the same 
imputation approach will be used.


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13.8.
Analysis Methods
13.8.1.
Time to Confirmed Perceptible and Meaningful Relief
Time to confirmed perceptible pain relief (TCPR) and time to meaningful pain relief (TMPR) 
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 median survival times for the active 
treatments will be compared using the bootstrap re-sampling method, and the survival 
functions of the active treatments will be compared with the survival function of placebo using 
the Wilcoxon test. The median survival time is chosen as an endpoint for evaluating the effect 
of time to onset, and the bootstrap method is an appropriate method for comparing the median 
survival time when the survival functions are non-proportional.
13.8.2.
Earliest Statistically Significant Separation of 
 and Placebo on
Percentage of Subjects with Confirmed Perceptible Relief
The earliest time of separation between 
 and placebo will be established by 
comparing the percentage of subjects with confirmed perceptible pain relief starting from 30 
minutes to successive earlier minutes in one minute increments, until statistical significance is 
no longer achieved. The dichotomized response will be analyzed using logistic regression 
analysis.
13.8.3.
Percentage of Subjects with Meaningful Pain Relief at 35, 40, and 45 minutes
The percentage of subjects with meaningful pain relief at 35, 40 and 45 minutes will be 
analyzed using logistic regression analysis and compared between 
 and ACM at each 
time point.
13.8.4.
Percentage of Subjects with Confirmed Perceptible Pain Relief at 15, 20, and 
25 minutes
The percentage of subjects with confirmed perceptible pain relief at 15, 20 and 25 minutes will 
be analyzed using logistic regression analysis at each time point.
13.8.5.
SPID0-4 and TOTPAR0-4
SPID0-4 and TOTPAR0-4 will each be analyzed with an analysis of variance with baseline 
pain (moderate or severe) score and treatment group in the model using imputation methods 
defined in Data Imputations Section 13.7.2. 
13.8.6.
PID and PAR at each Time
PID and PAR will be analyzed at each time point with an analysis of variance with baseline 
pain score (moderate or severe) and treatment group in the model.


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13.8.7.
Time to Rescue
Time to first use of rescue medication will be measured as the elapsed time from when the 
investigational product was given until the time rescue medication was first given. Subjects 
who discontinue from the study before 4 hours, but do not use rescue medication, will be 
censored at the time of discontinuation. Subjects who do not use rescue medication during the 
4-hour study period will have their time to rescue set to 4 hours and be censored at.4 hours.
Kaplan-Meier estimates of cumulative percentage of subjects rescuing will be presented by 
treatment group in tabular and graphical formats. The survival functions will be compared 
between the treatment groups using the Wilcoxon test.
13.8.8.
Subject Global Evaluation
Subject Global Evaluation will be analyzed using an analysis of variance with treatment and 
categorical baseline pain as factors. Missing data will not be imputed for this variable. Pairwise 
comparisons specified in Section 13.6 will be analyzed.
13.8.9.
Subgroup Analyses
Time to confirmed perceptible relief and time to meaningful 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. 
13.9.
Safety Analysis
The safety analysis will be based on the safety analysis set.
13.9.1.
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.


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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.
14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The sponsor should ensure that it is specified in the protocol or written agreement that 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.
14.1.
Study Monitoring
Before an investigational site can enter a subject into the study, a representative of Johnson & 
Johnson will visit the investigational study site to:

Determine the adequacy of the facilities

Discuss with the investigator(s) and other site personnel their responsibilities with 
regard to protocol adherence as well as the study and monitoring responsibilities of 
Johnson & Johnson or its representatives.  These responsibilities will be documented in 
a Clinical Study Agreement between Johnson & Johnson and the investigator. During
the study, a monitor from Johnson & Johnson 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 CRF, and that investigational product accountability checks 
are being performed

Perform source data verification. This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, 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 Johnson & Johnson.

Confirm AEs and SAEs have been properly documented on CRFs and confirm any
SAEs have been forwarded to Johnson & Johnson and those SAEs that met criteria for 
reporting have been forwarded to the IRB/IEC.
The monitor will be available between visits if the investigator(s) or other staff needs 
information or study-related direction.


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14.2.
Audits and Inspections
Authorized representatives of Johnson & Johnson, a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification. The purpose of a Johnson & Johnson 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, ICH/GCP and any applicable 
regulatory requirements. The investigator should contact their study contacts immediately if 
contacted by a regulatory agency about an inspection.
14.3.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC
approval of the protocol and all materials approved by the IRB/IEC for this study, including 
the subject consent form and recruitment materials, must be maintained in the Site Master File 
by the Investigator and made available for inspection.
15.
QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits to 
oversee the progress of a clinical trial, and to ensure that it is conducted, recorded, and reported 
in accordance with the protocol, Standard Operating Procedures, ICH/GCP, and the applicable 
regulatory requirement(s).
The monitors may review source documents to confirm that the data recorded on CRFs is 
accurate. The investigator and institution will allow the Sponsor monitors or its agents and 
appropriate regulatory authorities direct access to source documents to perform this 
verification.
The study site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by the Sponsor, and/or to inspection by appropriate regulatory authorities.
In the event that the study site is notified of a regulatory inspection, the Sponsor must be 
notified immediately.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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16.
DATA HANDLING AND RECORDKEEPING
16.1.
Case Report Forms/ Electronic Data Record
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. For this study, the 
Sponsor will provide specific worksheets (NRS scales/Subject Global Evaluation) to serve as 
source document tools to collect pain intensity, pain relief, and global evaluation.
16.2.
Record Retention
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 report forms, source documents, and detailed records of treatment 
disposition. The records should be retained by the investigator according to ICH guidelines, 
local regulations, or as specified in the Clinical Study Agreement, whichever is longer.
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, such as another investigator, another institution, or to the Sponsor. The investigator 
must obtain Sponsor's written permission before disposing of any records, even if retention 
requirements have been met.
17.
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 


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sponsor. In addition, the sponsor retains the right to discontinue development of the 
 
500 mg at any time.
If a study is prematurely terminated or discontinued, the sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects within 
two weeks. All study materials must be collected and all CRFs completed to the greatest extent 
possible.
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.
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 “Simulation based sample size and power for dental 3 study”, 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
APPENDIX 1: PAIN RATING SCALES/ CATEGORICAL PAIN INTENSITY 
SCALE
Finish the statement “My pain at this time is” by checking the appropriate box.
No Pain (0)
Mild Pain (1) Moderate Pain (2) Severe Pain (3)
0-10 PAIN INTENSITY - NUMERICAL RATING SCALE (PI-NRS)
Circle the number that best represents your pain.
No pain   0  1  2  3  4  5  6  7  8  9  10   Very severe pain
0-10 PAIN RELIEF – NUMERICAL RATING SCALE (PR-NRS)
Circle the number that shows your amount of pain relief.
No relief   0  1  2  3  4  5  6  7  8  9  10   Complete relief
APPENDIX 2: SUBJECT GLOBAL EVALUATION
How would you rate the study medication you received as a pain-reliever?
Poor (0) 
Fair (1) 
Good (2)
Very Good (3) 
Excellent (4)

SAP_001.pdf: 
Protocol CO-170317095828-PACT
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND 
ACTIVE- CONTROLLED, SINGLE-DOSE, EFFICACY 
AND SAFETY STUDY OF 
 IN POSTOPERATIVE DENTAL PAIN
Statistical Analysis Plan
(SAP)
Version: Final
Version Date: April 25, 2018


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CONTENTS
1
Introduction......................................................................................................3
1.1
Study Objectives ................................................................................................3
1.2
Study Design......................................................................................................3
2
Interim Analyses ..............................................................................................4
3
Analysis Sets .....................................................................................................4
3.1
Primary Analysis Set..........................................................................................4
3.2
Per-Protocol Set .................................................................................................4
3.3
Safety Analysis Set ............................................................................................5
4
Efficacy assessments and Endpoints ..............................................................5
4.1
Efficacy Assessments.........................................................................................5
4.2
Efficacy Endpoints.............................................................................................5
4.3
Safety Assessments and Endpoints....................................................................6
4.4
Covariates ..........................................................................................................6
5
Statistical Methodology and Statistical Analyses..........................................6
5.1
Statistical Hypotheses ........................................................................................6
5.2
Statistical Decision Rules ..................................................................................7
5.3
Statistical Methods.............................................................................................8
5.3.1
Time to Confirmed Perceptible Pain Relief and Meaningful Pain Relief .........8
5.3.2
Earliest Separation of 
 and PBO on Percentage of Subjects with Confirmed 
Perceptible Relief.............................................................................................10
5.3.3
Percentage of Subjects with Meaningful Pain Relief at 35, 40 and 45 minutes 
 
versus ACM)..........................................................................................10
5.3.4
Percentage of Subjects with Confirmed Perceptible Pain Relief at 15, 20, and 25 
minutes.............................................................................................................10
5.3.5
Pain Intensity and Pain Relief..........................................................................10
5.3.6
Time to Rescue Medication .............................................................................11
5.3.7
Subject Global Evaluation ...............................................................................11
5.3.8
Subgroup Analyses ..........................................................................................12
5.4
Demographic and Baseline Characristics ........................................................12
5.5
Safety Analysis ................................................................................................12
5.5.1
Adverse Events ................................................................................................12
5.5.2
Vital Signs........................................................................................................13
6. references......................................................................................................................13
APPENDICES..................................................................................................................14
APPENDIX 1: SUMMARY TABLES AND FIGURES...............................................14
APPENDIX 2: DATA LISTINGS ..................................................................................17


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1
INTRODUCTION
Acetaminophen is a para-aminophenol derivative with analgesic and antipyretic 
properties, and is thought to produce analgesia by inhibiting prostaglandin synthesis
centrally and elevating the pain threshold.  Acetaminophen is available as an over-the-
counter (OTC) analgesic and antipyretic in many global markets. In the US, 
TYLENOL® is commercially available in extra strength (500 mg) and regular strength 
(325 mg) dosage forms marketed under the Internal Analgesic, Antipyretic and 
Antirheumatic Drug Products for OTC Human Use Tentative Final Monograph.  
TYLENOL® Regular Strength 325 mg is dosed 2 dosage units every 4 to 6 hours and 
TYLENOL® Extra Strength 500 mg is dosed 2 dosage units every 6 hours. It is labeled 
for the temporary relief of minor aches and pains due to the common cold, headache, 
backache, toothache, premenstrual and menstrual cramps, minor pain of arthritis, 
muscular aches and for the temporary relief of fever.
The overall purpose of this study is to evaluate the analgesic onset, efficacy, and safety of
a single dose of 
 
compared with a single dose of 1000 mg acetaminophen administered as two commercial 
acetaminophen 500 mg caplets (ACM), a single dose of 400 mg ibuprofen administered 
as two commercial ibuprofen 200 mg liquid-filled capsules (IBU), and placebo (PBO)
over 4 hours. 
 
  The dental pain model, a 
validated model of acute pain widely used to study analgesic efficacy of compounds, will 
be used in this study [1, 2]. Reference Safety Information (RSI) for the 
 and 
ACM commercial product is the Drug Facts labeling for the ACM commercial product in 
the US, and the RSI for the IBU commercial product is the associated Drug Facts Label 
in the US.
1.1
Study Objectives
To evaluate analgesic onset, efficacy, and safety of 
 
) compared with 1000 mg 
acetaminophen administered as two commercial acetaminophen 500 mg caplets (ACM) 
and 400 mg ibuprofen administered as two commercial ibuprofen 200 mg liquid-filled 
capsules (IBU) 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 
 
compared with two commercial products over a four-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 


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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
Subjects who meet the randomization criteria (post-surgical pain of moderate to severe on 
the four-point categorical pain scale, and at least a score of 5 on the 11-point [0-10] pain
intensity numerical rating scale [PI-NRS] at baseline within 4.5 hours of last stitch from
dental extractions) will be assigned to one of four treatment groups.  Approximately 660
subjects will receive a single dose of either 
, ACM 1000 mg, IBU 
400 mg, or PBO in a 4:4:2:1 allocation ratio, and will be stratified according to gender
and baseline pain rating (moderate or severe).  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).  Pain intensity and pain relief 
will be collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, and 4 hours (± 5 minutes) after the 
dose.  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 hour before using rescue therapy.
2
INTERIM ANALYSES
No interim analysis is planned for this trial.
3
ANALYSIS SETS
3.1
Primary Analysis Set
The primary analysis set for the efficacy analyses will be the intent-to-treat population 
which includes all randomized subjects.  
Subjects who received different treatment from their assigned treatment will be analyzed 
based on the actual received treatment. 
3.2
Per-Protocol Set 
The per protocol set will exclude subjects who took rescue medication within 60 minutes 
after dosing, vomited within 60 minutes after dosing, and those with major protocol 
deviations. The major protocol deviation and the per-protocol set will be determined 
before the database lock.


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3.3
Safety Analysis Set
The Safety Analysis Set will include all subjects who are randomized and take
investigational product.
4
EFFICACY ASSESSMENTS AND ENDPOINTS 
4.1
Efficacy Assessments

Time to perceptible pain relief – recorded using perceptible pain stopwatch

Time to meaningful pain relief (TMPR) – recorded using meaningful pain 
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 stopwatch

Pain intensity  
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, 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h and 4h ( 5min) after dosing

Pain relief 
Numerical 0 – 10 scale (PAR): 0 – no relief to 10 – complete relief, collected at 
0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h and 4h ( 5min) after dosing
(including at time of rescue and at time of meaningful relief)

Time to rescue – time when rescue medication was administered

Subject global evaluation – subject overall impression of the investigational 
product, collected at Hour 4, at time of rescue, or at the time of early termination, 
using the 5-point scale: 0 – poor, 1 – fair, 2 – good, 3 – very good and 4 –
excellent.
4.2
Efficacy Endpoints
Primary efficacy endpoint

Time to confirmed perceptible pain relief (TCPR)
Secondary efficacy endpoints

Time to meaningful pain relief (TMPR)


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
Percentage of subjects with confirmed perceptible relief from 30 minutes to 
successively earlier minutes in one-minute increments (
 versus PBO)
Tertiary efficacy endpoints

Percentage of subjects with meaningful pain relief at 35, 40, and 45 minutes (
 
 versus ACM)

Percentage of subjects with confirmed perceptible relief at 15, 20, and 25 minutes

Time weighted sum of pain intensity difference from 0 to 4 hours (SPID0-4)

Time weighted sum of pain relief from 0 to 4 hours (TOTPAR0-4)

Pain relief (PAR) and pain intensity difference (PID) scores at individual time 
points;

Time to rescue medication

Subject Global Evaluation
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 trial 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 comparison between the active treatments will be based on the median survival 
times. The following hypothesis will be tested using the bootstrap re-sampling method
vs   
2
1
0 :
M
M
H

2
1
:
M
M
H A



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where 
and 
are the median survival times of the two active treatments to be 
compared, respectively.
The comparison between the active treatments and PBO will be based on the survival 
functions. The following hypothesis will be tested using the Wilcoxon test
)
(
)
(
:
0
t
S
t
S
H
PBO
Active

(all t)    versus   
)
(
)
(
:
t
S
t
S
H
PBO
Active
A

(at least some t)
where
)
(t
S Active
and
)
(t
S PBO
are the survival functions of the active treatments and the 
PBO, respectively.
5.2
Statistical Decision Rules
In order to control the family-wise Type I error rate at 0.05 level for primary and 
secondary endpoints, the 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. The 
comparison of 
 to IBU in TMPR is not included in the fixed testing sequence. 
Testing will commence with an assigned α = 0.049 and an α value of 0.001 will be 
reserved for the comparison of 
 and PBO on the percentage of subjects with 
confirmed perceptible relief from 30 minutes to successively earlier minutes in one-
minute increments.
Table 1: Fixed Test Sequence and Assigned α-value
Pre-Assigned 
α-value
α-value available if 
previous test positive
α-value 
available if 
previous 
test(s) 
negative
TCPR 
 vs PBO 
0.049
---
---
TMPR 
 vs PBO
0.000
0.049
0.000
TCPR 
 vs ACM
0.000
0.049
0.000
TCPR 
 vs IBU
0.000
0.049
0.000
TMPR 
 vs ACM
0.000
0.049
0.000
1
M
2
M


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Pre-Assigned 
α-value
α-value available if 
previous test positive
α-value 
available if 
previous 
test(s) 
negative
Percentage of subjects with 
confirmed perceptible relief from 30 
minutes to successively earlier 
minutes in one-minute increments 
 vs PBO
0.001
0.05
0.001
The six tests in the above family will be conducted as follow: The survival functions in 
TCPR between 
 and PBO will be compared. If it is non-significant at the 0.049 
level, then the first test and the following 4 tests will be failed, and the last test (the 
percentage of subjects in TCPR) will be tested at the 0.001 level.  If the first test is 
significant at the 0.049 level, then the second test, the survival functions in TMPR 
between 
 and PBO, will be compared at the 0.049 level and the following tests 
will follow the same pattern as for the first test. If all previous 5 tests are significant at the
0.049 level, the last test, the percentage of subjects in TCPR, will be tested at the 0.05 
level.
5.3
Statistical Methods
5.3.1
Time to Confirmed Perceptible Pain Relief and Meaningful Pain Relief
The time to meaningful pain relief is defined as the time (in minutes) elapsed from 
dosing until the subject stopped the second stopwatch. 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.  
For subjects who do not have both perceptible and meaningful pain relief by 4 hours, 
their values of the TCPR and the TMPR will be censored at 4 hours. For subjects who 
have perceptible pain relief but do not have meaningful pain relief by 4 hours, their 
values of TCPR and TMPR will be censored at 4 hours. For subjects who discontinue 
before having relief, their values of TCPR and TMPR will be censored at 4 hours. For 
subjects who take rescue medication before having relief, their values of the TCPR and 
TMPR will be censored at 4 hours.
TCPR and TMPR will be analyzed using the 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 (KM) method for each treatment. 
The survival functions of the active treatments will be compared with the survival 


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function of PBO using the Wilcoxon test. The median survival time of
 will be 
compared with the median survival times of ACM and IBU using the bootstrap re-
sampling method.
The estimation of the survival functions and the comparison of the survival functions 
between the active treatments and PBO 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;
The median survival time is used as an endpoint to evaluate the onset of pain relief. The 
median survival times of the active treatments can be estimated by the KM method. The 
median survival time of 
 will be compared with the median survival times of 
ACM and IBU by the bootstrap re-sampling method using the following procedure:
1) Independently take B=2000 bootstrap samples from each active arm. Each 
bootstrap sample is obtained by sampling with replacement from the original 
observed time-to-event (TTE) data (ie,
}
,
,1
  ,
2,1
:
,
,
{
1
B
b
i
t
t
b
in
b
i
i




).
2) Within each bootstrap sample, estimate the median survival time using the KM 
method (ie,
}
,
,1
  ,2,1
:
ˆ
{
B
b
i
mb
i



). 
3) Calculate the difference in median survival times 
B
b
m
m
b
b
b
,
,1
  ,
ˆ
ˆ
ˆ
2
1





.
4) The dataset 
}
,
,1
  :
ˆ
{
B
b
b



constitutes a bootstrap sampling distribution of 
the difference in median survival times. The cumulative probability function of 
this distribution is given by 
B
t
t
F
b
B
/
}
ˆ
{
#
)
(



.
5) From the cumulative probability function of the bootstrap sampling distribution, 
B
t
t
F
b
B
/
}
ˆ
{
#
)
(



, the 2-sided bootstrap percentile p-value for testing the 
hypothesis of 
0
:
2
1
0

M
M
H
vs 
0
:
2
1

M
M
H A
is given by 
 = 2 ∗	(0)
and the 95% bootstrap percentile confidence interval for the difference in median 
survival times is given by
(	
(0.025), 	
(0.975))


Protocol CO-170317095828-PACT
Statistical Analysis Plan
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Page 10 of 17
5.3.2
Earliest Separation of 
 and PBO on Percentage of Subjects with 
Confirmed Perceptible Relief
The earliest time of separation between 
 and PBO will be established by 
comparing the percentage of subjects with confirmed perceptible pain relief starting from 
30 minutes to successive earlier minutes in one minute increment, until statistical 
significance is no longer achieved. The time to confirmed perceptible pain relief will be 
dichotomized to binary response at each time point and analyzed using the logistic 
regression analysis.
The following is the sample SAS code for the logistic regression analyses: 
proc GENMOD data=DATASET ;
  class trt;
  model responder = trt / dist=BIN link=LOGIT;
  lsmeans trt / diff cl exp;
run;
5.3.3
Percentage of Subjects with Meaningful Pain Relief at 35, 40 and 45 minutes 
(
 versus ACM)
The percentage of subjects with meaningful pain relief at 35, 40 and 45 minutes in the
 and ACM groups will be analyzed using the logistic regression analysis.
5.3.4
Percentage of Subjects with Confirmed Perceptible Pain Relief at 15, 20, and 
25 minutes
The percentage of subjects with confirmed perceptible pain relief at 15, 20 and 25 
minutes will be analyzed using the logistic regression analysis. Each active treatment will 
be compared to PBO, and 
 will be compared to ACM and IBU.
5.3.5
Pain Intensity and Pain Relief  
For subjects who use rescue medication, the last reported pain intensity score or 
baseline pain intensity score, whichever is worse, will be carried forward to the 
remaining time points; the pain relief scores after rescue medication will be set to zero.  
For subjects who discontinue the study early, the same imputation approach will be 
used.
Pain intensity and pain relief scores collected outside the window 5 minutes of 
scheduled time prior to 90 minutes post-dose and outside the window 15 minutes of 
scheduled time 90 minutes post-dose will be replaced by the linear interpolation.
The pain intensity difference (PID) at each post-baseline time point will be derived by


Protocol CO-170317095828-PACT
Statistical Analysis Plan
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Page 11 of 17
the baseline PI score minus the post-baseline PI score. A positive value indicates a reduction 
in pain intensity.
PID and PAR will be analyzed at each post-baseline time point separately using 
analysis of variance with baseline pain level (moderate or severe) and treatment as 
the factors in the model. Summary statistics (number of subjects, least square mean, 
standard error and 95% confidence interval) will be tabulated by treatment group.
Time-weighted sum of the pain intensity difference scores (SPID0-4) will be derived
by first multiplying each PID score by the time difference (in hours) from the 
previous time point (in nominal time), and adding them together for each scheduled 
time point from 0.25 to 4 hours. 
Time-weighted total pain relief (TOTPAR0-4) will be derived by first multiplying 
each PAR by the time difference in hours from the previous time point (in nominal
time), and adding them together from 0.25 to 4 hours.
SPID0-4 and TOTPAR0-4 will each be analyzed using analysis of variance with 
baseline pain level (moderate or severe) and treatment as the factors in the model.
Summary statistics (number of subjects, least square mean, standard error and 95% 
confidence interval) will be tabulated by treatment group.
5.3.6
Time to Rescue Medication
Time to rescue medication will be measured as the elapsed time from the time of 
dosing to the time of the rescue medication. Subjects who discontinue from the study
before 4 hours, but do not use rescue medication, will be censored at the time of 
discontinuation.  Subjects who do not use rescue medication during the 4-hour study
period will be censored at 4 hours.  
The cumulative percentage of subjects who used rescue medication will be estimated by 
the Kaplan-Meier method, the survival functions of active treatment groups will be 
compared with the survival function of PBO and the survival function of 
 will 
be compared with the survival functions of ACM and IBU using the Wilcoxon test.
5.3.7
Subject Global Evaluation 
Subject global evaluation score will be analyzed using analysis of variance with the 
baseline pain level (moderate or severe) and treatment as the factors. The adjusted means 
will be compared for the pairwise comparisons, each active treatment will be compared to 
PBO, and 
 will be compared to ACM and IBU.


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Statistical Analysis Plan
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Page 12 of 17
5.3.8
Subgroup Analyses 
TCPR will be analyzed within the following subgroups: age (<18 years, ≥18 years), 
gender (male, female), race (white, non-white) and baseline pain level (moderate, severe). 
The survival functions and the median survival time of each treatment will be estimated 
by the Kaplan-Meier method within each subgroup. 
The protocol stated that the TCPR and the TMPR will be analyzed within the above 
subgroups. It was determined after the protocol finalization that subgroup analyses are 
only needed for the primary efficacy endpoint of TCPR.
5.4
DEMOGRAPHIC AND BASELINE CHARACRISTICS 
Summary statistics (number of subjects, mean, standard deviation, median, minimum and 
maximum) will be provided by treatment group for numerical variables.
Frequency summary statistics (number and percentage of subjects) will be provided by 
treatment group for categorical variables.
Number and percentage of subjects receiving previous medication, concomitant 
medication and non-drug therapy/procedure will be provided by treatment group. 
Medications that were stopped before the date and time the study medication was taken 
will be considered previous medications. All other medications will be considered 
concomitant medications.
Concomitant medications taken by greater than or equal to 5% of subjects in one or more 
treatment groups will be provided by treatment group.
5.5
SAFETY ANALYSIS 
5.5.1
Adverse Events 
Number and percentage of subjects with treatment-emergent AE will be summarised by 
treatment group, MedDRA system organ class and preferred term. The most commonly
reported treatment-emergent AE (≥5% in one or more treatment groups) will also be 
provided. Treatment-emergent adverse events are those with a start date and time on or 
after the date and time of study dose administration, or those AEs that start before the 
dose administration but worsen after dosing.
Number and percentage of subjects who discontinued the trial due to an AE will be 
summarised by treatment group, MedDRA system organ class and preferred term. This 
display will include subjects who discontinued due to an AE whether or not it was a 
treatment-emergent AE.


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Number and percentage of subjects with serious AEs will be summarised by treatment 
group, MedDRA system organ class and preferred term. This display will include 
subjects who discontinued due to an AE whether or not it was a treatment-emergent AE.
Number and percentage of subjects with treatment-related AEs will be summarised by 
treatment group, MedDRA system organ class and preferred term. Treatment-related AEs 
are events evaluated by the investigator as possible, probable or very likely related to 
study medication. 
The number of subjects with treatment-emergent adverse events will be summarized by 
gender (male, female), age group (<18 years, ≥18 years), and race (white, non-white).
Number and percentage of subjects with treatment-emergent AEs will be summarised by 
severity (mild, moderate and severe) for all AEs and also for treatment-related AEs.
Subjects will be counted only once for each system organ class and preferred term by 
selecting the most severe event.
5.5.2
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. 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. Vo l 18. New York, NY: Raven Press, Ltd., 1991:117-24.


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Page 14 of 17
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 Deviation
All Randomized Subjects
Table 14.1.3
Demographic and Baseline Characteristics
All Randomized Subjects
Table 14.1.3.1
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
Non-Drug/Therapy
All Randomized Subjects
Table 14.1.7
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 
Intent-to-Treat 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
Intent-to-Treat Subjects
Table 14.2.1.3
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Severe Baseline Pain
Intent-to-Treat Subjects
Table 14.2.1.4
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Male
Intent-to-Treat Subjects
Table 14.2.1.5
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Female
Intent-to-Treat Subjects
Table 14.2.1.6
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Age < 18 Years Old
Intent-to-Treat Subjects
Table 14.2.1.7
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Age >= 18 Years Old
Intent-to-Treat Subjects
Table 14.2.1.8
Kaplan-Meier Estimates of The Cumulative Intent-to-Treat Subjects


Protocol CO-170317095828-PACT
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Page 15 of 17
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – White Subjects
Table 14.2.1.9
Kaplan-Meier Estimates of The Cumulative 
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief – Non-White Subjects
Intent-to-Treat Subjects
Table 14.2.2
Kaplan-Meier Estimates of The Cumulative 
Percentage of Subjects with Meaningful Pain 
Relief
Intent-to-Treat Subjects
Table 14.2.2.1
Kaplan-Meier Estimates of The Cumulative 
Percentage of Subjects with Meaningful Pain 
Relief
Per-Protocol Subjects
Table 14.2.3
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief at Specified Times –
 
 vs Placebo
Intent-to-Treat Subjects
Table 14.2.4
Percentage of Subjects with Meaningful Pain 
Relief at 35, 40 and 45 Minutes –
 vs 
ACM
Intent-to-Treat Subjects
Table 14.2.5
Percentage 
of 
Subjects 
with 
Confirmed 
Perceptible Pain Relief at 15, 20 and 25 Minutes 
Intent-to-Treat Subjects
Table 14.2.6
Time Weighted Sum of Pain Intensity Difference 
0 – 4 Hours (SPID0-4)
Intent-to-Treat Subjects
Table 14.2.7
Time Weighted Total Pain Relief Scores 0 – 4 
Hours (TOTPAR0-4)
Intent-to-Treat Subjects
Table 14.2.8
Pain Intensity Difference (PID) from Baseline At 
Each Time Point
Intent-to-Treat Subjects
Table 14.2.9
Pain Relief Score (PAR) At Each Time Point
Intent-to-Treat Subjects
Table 14.2.10
Kaplan-Meier Estimates of The Cumulative 
Percentage of Subjects Using Rescue Medication
Intent-to-Treat Subjects
Table 14.2.11
Subject Global Evaluation of Study Medication
Intent-to-Treat Subjects
14.3 Safety
Section /
Table No
Title
Population / Analysis Sets
Table 14.3.1
Summary of Adverse Events 
Safety Analysis Subjects
Table 14.3.2
Summary of Treatment-Emergent Adverse 
Events by System Organ Class and MedDRA 
Preferred Term
Safety Analysis Subjects
Table 14.3.3
Summary of Treatment-Emergent Adverse 
Events by Demographic Characteristics
Safety Analysis Subjects
Table 14.3.4
Summary of Treatment-Emergent Adverse 
Events by Severity
Safety Analysis Subjects
Table 14.3.5
Most Commonly Reported (>=5% of Subjects in 
One or More Treatment Groups) Treatment-
Emergent Adverse Events
Safety Analysis Subjects
Table 14.3.6
Summary of Treatment-Related Adverse Events
Safety Analysis Subjects
Table 14.3.7
Most Commonly Reported (>=5% of Subjects in 
One or More Treatment Groups) Treatment-
Related Adverse Events
Safety Analysis Subjects
Table 14.3.8
Summary of Treatment-Related Adverse Events 
By System Organ Class and MedDRA Preferred 
Safety Analysis Subjects


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Page 16 of 17
Term 
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 Safety Analysis Subjects
FIGURES:
Figure 14.1
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief
Intent-to-treat subjects
Figure 14.1.1
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Moderate Baseline Pain
Intent-to-treat subjects
Figure 14.1.2
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Severe Baseline Pain
Intent-to-treat subjects
Figure 14.1.3
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Male
Intent-to-treat subjects
Figure 14.1.4
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Female
Intent-to-treat subjects
Figure 14.1.5
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Age < 18 Years Old
Intent-to-treat subjects
Figure 14.1.6
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Age >= 18 Years Old
Intent-to-treat subjects
Figure 14.1.7
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – White Subjects
Intent-to-treat subjects
Figure 14.1.8
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Confirmed Perceptible 
Pain Relief – Non-White Subjects
Intent-to-treat subjects
Figure 14.2
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects with Meaningful Pain 
Relief
Intent-to-treat subjects
Figure 14.3
SPID by Treatment
Intent-to-treat subjects
Figure 14.4
TOTPAR by Treatment
Intent-to-treat subjects
Figure 14.5
Pain Intensity Difference (PID) from Baseline at 
Each Time Point
Intent-to-treat subjects
Figure 14.6
Pain Relief Score (PAR) at Each Time Point
Intent-to-treat subjects
Figure 14.7
Kaplan-Meier Estimates of the Cumulative 
Percentage of Subjects Using Rescue Medication
Intent-to-Treat Subjects


Protocol CO-170317095828-PACT
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Page 17 of 17
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
Perceptible Pain Relief, Meaningful Pain Relief and Subject 
Global Evaluation
All Randomized
16.2.5.2
Pain Intensity and Pain Relief Assessments
All Randomized
16.2.5.3
Pain Intensity and Pain Relief Assessments Out of 
Assessment Window and Imputed Values 
All Randomized
16.2.5.4
Time to Rescue Medication and Pain Intensity and Pain Relief 
Prior to Rescue
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