Clinical trial NCT02837952
Conditions: Pain
Keywords: Ibuprofen, acetaminophen, pain, molar extraction
Sponsor: Pfizer
Start date: 2016-08-31; Completion date: 2017-02-01
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to determine the overall analgesic efficacy and safety of a fixed-dose ibuprofen 250 mg / acetaminophen 500 mg formulation compared to placebo in subjects who are experiencing post operative pain following surgical extraction of 3 or more third molar teeth. A review of any reported adverse events will also be completed.

Detailed description:

Arms: arm 1: FDC IBU/APAP 250 mg/500 mg arm 2: Placebo
Interventions: intervention 1: FDC IBU/APAP 250 mg/500 mg intervention 2: Placebo
Intervention descriptions: intervention 1: FDC IBU/APAP 250 mg/500 mg intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 1
A PHASE 3, DOUBLE-BLIND, RANDOMIZED SAFETY AND EFFICACY STUDY 
COMPARING MULTIPLE ADMINISTRATIONS OF IBU 250 MG/APAP 500 MG 
(ADMINISTERED AS TWO TABLETS OF IBU/APAP 125 MG/250 MG) TO 
PLACEBO IN THE TREATMENT OF POST SURGICAL DENTAL PAIN IN 
ADULT SUBJECTS
Compound:
PF-06438867
Compound Name:
Not Applicable
United States (US) Investigational New 
Drug (IND) Number:
112538
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
B5061004
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information 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 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Original Protocol
13 May 2016
Not Applicable (N/A)
Original final protocol
15-Dec-2015
Not Applicable (N/A)
Revised final protocol
12-Jan-2016
Addition of 28-day post final dose call visit 
added to schedule of activities and Section 6.3 
modified to describe this call.
Modification of the rescue medication from 
codeine phosphate to codeine sulfate.
Revised final protocol
2-Feb-2016
Modification of Section 1.2.2, so that first 
sentence of the 4th paragraph now reads: 
IBU/APAP combinations at OTC levels have 
been studied in humans, including single and 
multiple dose pharmacokinetics, single and 
multiple dose oral surgery studies, and a 
multiple dose knee pain study.  
Modification of Section 4.1 so that inclusion 
criterion 8 now reads: Male subjects able to 
father children and female subjects of 
childbearing potential and at risk for pregnancy 
must agree to use a highly effective method of 
contraception as outlined in this protocol for the 
duration of the study and for at least 28 days 
after the last dose of assigned treatment.  
Modification of Section 4.4, so that the first 
sentence of the first paragraph now reads: All 
male subjects who are able to father children 
and female subjects who are of childbearing 
potential and are sexually active and at risk for 
pregnancy must agree to use a highly effective 
method of contraception consistently and 
correctly for the duration of the active treatment 
period and for at least 28 days after the last dose 
of investigational product. 
Modification of Section 5.2, 2nd paragraph, first 
sentence which now reads: In the event of a 
medical emergency that necessitates breaking 
the code, the third party person(nel) will be 


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permitted to inform the Investigator what study 
drug the subject was given. 
Section 5.4.1, second sentence inserted: Rescue 
medication, tramadol and codeine sulfate, and 
supplies will be provided by the study site.
Modification of Section 5.5, first sentence, 
which now reads: Investigational product will 
be administered to the subject within 7 minutes 
of the completion of the baseline pain 
assessments and, thereafter, every 8 hours by the 
third party dispenser.  
Modification of Section 5.7, first paragraph, 
second sentence which now reads: Study 
product will be sent to the third party dosing 
person(nel). Confirmation of receipt of study 
product by the third party dosing person(nel) 
must be documented.   
Modification of Section 6.2, so that the last 
sentence now reads: Each subject’s vital signs 
(heart rate, blood pressure, temperature, and 
respiratory rate) will be measured and recorded 
at baseline, prior to other assessments being 
performed.
Revised final protocol
13-May-2016
Section 4.1 Inclusion Criteria. Inclusion 
Criterion add was modified and now reads:
1. Male subjects able to father children and 
female subjects of childbearing potential 
who are, in the opinion of the investigator, 
sexually active at risk for pregnancy with 
their partner(s) must agree to use a highly 
effective method of contraception as 
outlined in this protocol for the duration of 
the study and for at least 28 days after the 
last dose of assigned treatment.  
Section 4.4 Lifestyle Guidelines was modified 
to allow the investigator to allow sexual 
abstinence, defined as completely and 
persistently refraining from all heterosexual 
intercourse (including during the entire period of 
risk associated with study treatments) to obviate 


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the need for contraception ONLY if this is the 
preferred and usual lifestyle of the subject.
Section 5.1.  Allocation to Treatment was 
modified and now reads: Treatment assignments 
will be determined by a computer generated 
randomization schedule generated and 
maintained by Pfizer Randomization 
Administration.  
Section 5.4.2 Preparation and Dispensing. 
Investigational Product preparation was 
modified to allow for preparation up to 48 
(forty-eight) hours in advance of actual 
dispensing.  
5.6. Investigational Product Storage was 
modified to clarify storage conditions for IP 
prepared up to 48 hours in advance of actual 
dispensing.
5.9 Rescue Medication. The text was modified 
to indicate that rescue medication should be 
administered within 5 minutes of rescue 
assessments being performed.  
6.1 Screening & Day of Surgery. Section was 
modified to include information and instructions 
relating to the day of surgery.
Add Section 9.2.1. which now reads:
9.2.1.1 Primary Analysis Set: The full 
analysis set (primary population) is the 
intent to treat (ITT) subject population, 
defined as all randomized subjects who 
dosed with the study medication and 
provided a baseline assessment.
 
 
 
 
 
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9.2.1.3. Safety Analysis Set
The safety analysis set will include all 
subjects who received at least once dose of 
the study product.
Section 9.2.2. Modified ANCOVA model and 
now reads:
Analysis of Primary Endpoint.  Primary 
efficacy endpoint SPID[11] 0 24 will be 
analyzed by an analysis of covariance 
model (ANCOVA) with treatment, 
categorical baseline PSR, baseline 
numerical PSR, and gender terms.
 
 
 
 
Section 9.2.3 Modified using 
log-rank(Gehan-Wilcoxon) test for time to event 
endpoints to using Gehan-Wilcoxon test for 
time to event endpoints.
Amendment 1
09 Feb 2017
 
 
 
 
Throughout the protocol gender was changed to 
sex. 
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This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
APPENDICES .........................................................................................................................10
PROTOCOL SUMMARY.......................................................................................................11
1. INTRODUCTION ...............................................................................................................17
1.1. Mechanism of Action/Indication.............................................................................17
1.2. Background and Rationale ......................................................................................17
1.2.1. Study Rationale...........................................................................................18
1.2.2. Safety Data..................................................................................................18
1.2.3. Dose Rationale............................................................................................19
1.2.4. Single Reference Safety Document............................................................20
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................20
2.1. Objectives................................................................................................................20
2.2. Endpoints.................................................................................................................20
2.2.1. Primary Efficacy Endpoint .........................................................................20
2.2.2. Secondary Endpoints ..................................................................................20
2.2.3. Other Endpoints..........................................................................................20
3. STUDY DESIGN.................................................................................................................21
4. SUBJECT SELECTION......................................................................................................22
4.1. Inclusion Criteria.....................................................................................................22
4.2. Exclusion Criteria....................................................................................................23
4.3. Randomization Criteria ...........................................................................................25
4.4. Lifestyle Guidelines ................................................................................................25
4.5. Sponsor’s Qualified Medical Personnel..................................................................27
5. STUDY TREATMENTS.....................................................................................................27
5.1. Allocation to Treatment ..........................................................................................27
5.2. Breaking the Blind ..................................................................................................28
5.3. Subject Compliance.................................................................................................28
5.4. Investigational Product Supplies.............................................................................29
5.4.1. Dosage Form(s) and Packaging..................................................................29
5.4.2. Preparation and Dispensing........................................................................29
5.5. Administration.........................................................................................................30


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5.6. Investigational Product Storage ..............................................................................30
5.7. Investigational Product Accountability...................................................................31
5.7.1. Destruction of Investigational Product Supplies ........................................32
5.8. Concomitant Treatment(s).......................................................................................32
5.9. Rescue Medication ..................................................................................................32
6. STUDY PROCEDURES .....................................................................................................33
6.1. Screening & Day of Surgery...................................................................................33
6.2. Study Period ............................................................................................................34
6.2.1. Post-Baseline Assessments.........................................................................35
6.2.2. End of Study ...............................................................................................36
6.3. Follow-up Visit .......................................................................................................37
6.4. Subject Withdrawal.................................................................................................37
7. ASSESSMENTS..................................................................................................................38
7.1. Pregnancy Testing...................................................................................................38
7.2. Baseline Efficacy Assessments ...............................................................................38
7.2.1. Categorical Pain Severity Rating Scale ......................................................38
7.2.2. VAS Pain Severity Rating Scale (VAS PSR).............................................39
7.2.3. Numerical Pain Severity Rating Scale........................................................39
7.3. Post-Baseline Efficacy Assessments.......................................................................39
7.3.1. Categorical Pain Severity Rating Scale ......................................................39
7.3.2. 
..........................................................40
7.3.3. Numerical Pain Severity Rating Scale........................................................40
7.3.4. Time to Relief.............................................................................................40
7.3.4.1.
...................40
7.3.4.2. Time to Meaningful Relief for the First Dose...........................41
7.3.5. 
.......................................................................................41
7.4. Safety Assessments .................................................................................................41
7.5. Laboratory Assessments..........................................................................................42
7.5.1. Hematology.................................................................................................42
7.5.2. Coagulation.................................................................................................42
7.5.3. Urinalysis....................................................................................................42
7.6. Assessment of Suicide.............................................................................................43
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8. ADVERSE EVENT REPORTING......................................................................................43
8.1. Adverse Events........................................................................................................43
8.2. Reporting Period .....................................................................................................43
8.3. Definition of an Adverse Event...............................................................................44
8.4. Medication Errors....................................................................................................45
8.5. Abnormal Test Findings..........................................................................................45
8.6. Serious Adverse Events (SAE) ...............................................................................45
8.6.1. Protocol-Specified Serious Adverse Events...............................................46
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................46
8.7. Hospitalization ........................................................................................................48
8.8. Severity Assessment................................................................................................49
8.9. Causality Assessment..............................................................................................49
8.10. Exposure During Pregnancy..................................................................................50
8.11. Occupational Exposure .........................................................................................51
8.12. Withdrawal Due to Adverse Events (See Also Section 6.4 on Subject 
Withdrawal)...............................................................................................................51
8.13. Eliciting Adverse Event Information ....................................................................51
8.14. Reporting Requirements........................................................................................51
8.14.1. Serious Adverse Event Reporting Requirements .....................................52
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................52
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................52
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................53
9.1. Sample Size Determination.....................................................................................53
9.2. Efficacy Analysis ....................................................................................................53
9.2.1. Analysis Populations ..................................................................................53
9.2.1.1. Primary Analysis Set.................................................................53
9.2.1.2. ‘Per Protocol’ Analysis Set .......................................................53
9.2.1.3. Safety Analysis Set....................................................................54
9.2.2. Analysis of Primary Endpoint ....................................................................54
9.2.3. Analysis of Secondary Endpoints...............................................................54
9.2.4. Analysis of Other Endpoints.......................................................................54
9.3. Data Adjustment/Handling of Missing Data...........................................................55


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9.4. Safety Analysis........................................................................................................56
9.5. Data Monitoring Committee ...................................................................................56
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................56
11. DATA HANDLING AND RECORD KEEPING .............................................................56
11.1. Case Report Forms/Electronic Data Record .........................................................56
11.2. Record Retention...................................................................................................57
12. ETHICS..............................................................................................................................58
12.1. Institutional Review Board /Ethics Committee.....................................................58
12.2. Ethical Conduct of the Study ................................................................................58
12.3. Subject Information and Consent..........................................................................58
12.4. Subject Recruitment ..............................................................................................59
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................59
13. DEFINITION OF END OF TRIAL...................................................................................59
13.1. End of Trial in All Participating Countries ...........................................................59
14. SPONSOR DISCONTINUATION CRITERIA ................................................................60
15. PUBLICATION OF STUDY RESULTS..........................................................................60
15.1. Communication of Results by Pfizer ....................................................................60
15.2. Publications by Investigators ................................................................................61
16. REFERENCES ..................................................................................................................62
LIST OF TABLES
Table 1.
B5061004 – Study Number Assignment Sequence..............................................28
Table 2.
B50610014 — Study Product...............................................................................29
Table 3.
Detailed Description of Each Treatment Group ...................................................29
APPENDICES
Appendix 1. Abbreviations......................................................................................................64


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Final Protocol Amendment 1, 09 February 2017 
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PROTOCOL SUMMARY
Background and Rationale
Ibuprofen (IBU) and acetaminophen (APAP) are the two most widely used non-prescription 
analgesic/ antipyretic drugs both in the United States and globally. Ibuprofen, a “traditional” 
non-steroidal anti-inflammatory drug (NSAID), decreases the synthesis of pain- and 
inflammation-promoting prostaglandins via non-selective inhibition of cyclo-oxygenase-1 
(COX-1) and cyclo-oxygenase-2 (COX-2).1 Both drugs have been extensively studied, and 
their efficacy and safety profiles in humans are well-established. IBU and APAP do not 
share metabolic pathways, which diminishes the likelihood of drug-drug interactions.4
Pharmacokinetic studies5,6 have demonstrated that there are no alterations in drug levels 
when the two analgesics are administered together, which is consistent with a lack of 
drug-drug interactions.
Pfizer Consumer Healthcare (PCH) conducted a proof-of-concept (POC) dental pain study 
(B5061001) to determine the minimum dose of IBU and APAP fixed-dose combination that 
was superior to IBU 400 mg. Three IBU/APAP fixed dose combinations (FDCs) were 
evaluated for overall analgesic efficacy: 200 mg/500 mg, 250 mg/500 mg, and 
300 mg/500 mg, provided as two tablets, compared to IBU 400 mg and placebo in the third 
molar extraction model of dental pain. The results indicated that all active treatments were 
significantly better than placebo for all endpoints. Furthermore, the 200 mg/500 mg FDC 
formulation was numerically better compared to IBU 400 mg for the primary and most of the 
secondary endpoints. As anticipated, the overall incidence of adverse events (AEs) was 
comparable across all treatment groups with no meaningful differences observed in any 
system organ class (SOC). There were no safety concerns observed and all treatments were 
well tolerated.
Previous-published studies7,8 have also shown that FDC IBU 200 mg/APAP 500 mg was 
statistically superior to APAP 1000 mg and nearly significantly superior to IBU 400 mg, 
suggesting a synergistic analgesic effect.  This potential synergistic analgesic effect would 
suggest lower doses of each medication can be used in combination to provide superior 
analgesia compared to maximum amounts of either medication alone.
Based on these results, PCH proposes to continue the development of a non-prescription 
IBU/APAP 250 mg/500 mg FDC (administered as two tablets of 125 mg/250 mg 
IBU/APAP) to support the over the counter (OTC) approval of an FDC of IBU and APAP 
tablet that would provide superior analgesia and antipyresis compared to the maximum single 
OTC dose of either monocomponent alone.
Objectives and Endpoints
The objective of the study is to compare the analgesic efficacy and safety of FDC IBU/APAP 
250 mg/500 mg dosed every 8 hours compared to placebo in a 48-hour period following 
extraction of 3 third molar teeth. 


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Primary Efficacy Endpoint
•
SPID [11] (sum of pain intensity difference scores) from 0-24 hours (time-weighted 
sum of PID[11] scores based on the 11-point numerical Pain Severity Rating [PSR]
scale).
Secondary Endpoints
•
SPID [11] (time-weighted sum of Pain Intensity Difference scores PID[11] based on 
the 11-point Numerical PSR scale) from 0-8, 6-8, 8-16, 0-16, and 0-48 hours;
•
Duration of relief after first dose, as measured by the time from first dose to rescue 
medication or second dose whichever occurs first;
•
Time to onset of “meaningful” relief for the first dose.
Other Endpoints
•
 
•
 
;
•
 
;
•
 
 
•
 
•
 
;
•
 
;
•
 
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•
 
•
 
•
 
;
•
•
 
Study Design
This will be a Phase 3, 48-hour, single-center, in-patient, multiple-dose, fixed dosing interval, 
randomized, placebo-controlled, sex and baseline pain severity-stratified, double-blind, 
parallel group trial. Subjects will be adult males and females (18 to 40 years of age, 
inclusive) who are experiencing post-operative pain following surgical extraction of 3 or 
more third molar teeth.  Following extraction of 3 or more third molar teeth, subjects will rest 
quietly at the study center until they experience post-surgical pain of at least moderate 
severity. At that time, subjects will be asked to assess their pain intensity and severity using 
categorical, numerical, and/or visual scales.  Subjects with a qualifying baseline pain 
threshold within approximately 5 hours of completion of surgery will be entered into the 
study. Upon completion of the baseline scales, eligible subjects will receive an oral dose of 
investigational product at 0 hours (baseline) and at 8, 16, 24, 32, and 40 hours post-baseline 
under randomized, double-blind conditions. At 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 16, 24, 32, 40, and 48 hours post-baseline, subjects will provide self-ratings of pain 
severity using the categorical and numerical PSRs. Subjects will also provide a self-rating of 
pain relief at each time point (except at baseline) using a categorical 
 scale. 
At 24 and 48 hours, or at the first rescue medication administration on the respective day, 
subjects will also complete a 
 of the investigational product. Additionally, 
subjects will also evaluate the time to
 and time to meaningful relief 
using a double stopwatch method up to 8 hours post-baseline (ie, up to the second dose 
administration), or until the time of first rescue medication use, whichever is sooner. A 
review of any reported adverse events will also be completed.
Study Treatments
Study treatments will be: A) FDC IBU/APAP 250 mg/500 mg and B) Placebo.
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Statistical Methods
A detailed methodology for the summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP).  The SAP may modify the 
plans outlined in the protocol; however, any major modifications to the primary endpoint 
definition and/or its analysis will also be reflected in a protocol amendment.
All statistical tests will be performed at a two-sided 0.05 level of significance.  The primary 
end point, SPID[11]0-24 hours (based on numerical pain scale), will be analyzed by an 
analysis of covariance (ANCOVA) model with treatment, sex, baseline categorical PSR, and 
baseline numerical PSR terms in the model.
Safety (adverse events [AE]/serious adverse events [SAE]) data will be summarized.
Sample Size: Using root mean square of error (RMSE) data for SPID[11] over 2, 8 and 
12 hours from Study B5061001, a single dose dental pain study, it was estimated that the 
RMSE for SPID[11] over 0-24 will be approximately 52 units.  Based on this assumption, a 
sample size of 68 subjects for IBU/APAP 250 mg/500 mg group and 34 for placebo group (a 
ratio of 2:1) will provide 85% power (at 5% level of significance, two sided) to detect a 
treatment difference of at least 33 units for SPID[11] 0-24.  
Thus, a total of 102 subjects are required to complete the study (evaluable subjects).  
Assuming a 10% drop-outs rate, a total of approximately 112 subjects will be enrolled.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the STUDY PROCEDURES and ASSESSMENTS sections of the protocol for 
detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
well-being of the subject.
Schedule of Activities
Visit Identifier
Time (hours)
Screena
Surgery
0
0.25
0.5
1.0
1.5
2.0, 3.0, 4.0, 
5.0, 6.0, 7.0
8.0
9.0, 10.0, 
11.0, 12.0
16.0
24.0
32.0
40.0
48.0
28 Calendar 
Days after 
Last Dose
Informed Consent
x
Inclusion & Exclusion 
Criteria
x
x
Demographic Information
x
Medical History
x
Physical Examination
x
Screening Laboratory Testsb
x
Hematology
x
Blood Chemistry
x
Urinalysis
x
Coagulation
x
Serum Pregnancy Test
x
Urine Pregnancy Testc
x
Surgical Procedure
x
Surgical Trauma Scale
x
Vital Signs (HR, BP, T, RR)d
x
x
x
x
Randomizatione
x
Dosing
x
x
x
x
x
x
Pain Evaluations
VAS Pain Severity Ratingf
x
Categorical Pain Severity 
Ratingg
x
x
x
x
x
x
x
x
x
x
x
x
x
Numerical Pain Severity 
Ratingh
x
x
x
x
x
x
x
x
x
x
x
x
x
 
x
x
x
x
x
x
x
x
x
x
x
x
 
j
Time to ‘Meaningful’ Reliefk
 
x
x
Subjects taking a rescue 
medication during this time 
will be considered:
Discontinued
Treatment Failure
Prior/Concomitant 
Medications
Adverse Events
Recorded at any time during the study as they occur.
xm
Follow-Up Callm
x
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a.
Screening must be within 30 days of surgery; it may occur on the morning of surgery.  
b.
Screening laboratory tests include complete blood count (CBC) with differential count, prothrombin time (PT), partial 
thromboplastin time (PTT), international normalized ratio (INR), chemistry panel including liver function tests, and 
urinalysis. In addition, females of child bearing potential will be given a serum pregnancy test at screening.
c.
Females of child bearing potential must be given a urine pregnancy test on the morning of surgery.
d.
Vital signs also done at time of rescue if applicable.
e.
Those subjects meeting all inclusion/exclusion criteria, including at least moderate baseline pain on the Categorical 
PSR Scale confirmed by a score of at least 50 mm on a 100 mm Visual Analog PSR Scale.
f.
100 mm Visual Analog PSR Scale: none=0 to severe=100.
g.
: none=0, mild=1, moderate=2, and severe=3.  Completed at each post-baseline time 
point and immediately before rescue medication use.
h.
11 point Numerical PSR Scale: none=0 to 10 = Worst Possible Pain.  Completed at each time point and immediately 
before rescue medication use.
i.
: none=0, a little=1, some=2, a lot=3, and complete=4.  Completed at each 
time point and immediately before rescue medication use.
j.
Subject is instructed to stop the first stopwatch “when you first begin to feel any pain relieving effect whatsoever of the 
drug.” Stopwatches should only be maintained for the first 8 hours.
k.
Subject is instructed to stop the second stopwatch “when you have meaningful relief, that is, when the relief from the 
pain is meaningful to you”.
l.
: very poor=0, poor=1, fair=2, good=3, very good=4, excellent=5.  
Completed at the designated time points or immediately before taking rescue medication on each day.
m.
Study site personnel will conduct a safety follow-up 28 calendar days after last dose via a telephone call to the subject 
to ascertain if any SAEs have occurred.
End of Study procedures will include the assessment/reporting of vital signs and a review of AEs.
Abbreviations: →= ongoing/continuous event; BP = blood pressure; HR = heart rate; multiple-admin. 
= multiple administrations; RR = respiration rate; T = temperature.
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1. INTRODUCTION
Ibuprofen (IBU) and acetaminophen (APAP) are the two most widely used non-prescription 
analgesic/ antipyretic drugs both in the United States and globally. Ibuprofen, a “traditional” 
non-steroidal anti-inflammatory drug (NSAID), decreases the synthesis of pain- and 
inflammation-promoting prostaglandins via non-selective inhibition of cyclo-oxygenase-1 
(COX-1) and cyclo-oxygenase-2 (COX-2).1  The mechanism of action of APAP, which has
no significant anti-inflammatory activity, is not clear.  However, it may involve COX 
inhibition in the central nervous system (CNS) and activation of central serotonergic 
pathways.2,3 Both drugs have been extensively studied, and their efficacy and safety profiles 
in humans are well-established. IBU and APAP do not share metabolic pathways, which 
diminishes the likelihood of drug-drug interactions.4  Pharmacokinetic studies5,6 have 
demonstrated that there are no alterations in drug levels when the two analgesics are 
administered together, which is consistent with a lack of drug-drug interactions.
The main safety concern with IBU use, primarily at higher prescription doses over extended 
periods of time, is gastrointestinal toxicity.  In contrast, APAP over dosage may cause 
potentially fatal hepatic failure.  Based on safety concerns related to APAP, in June 2009 an 
FDA Analgesics Advisory Committee recommended reducing the maximum single adult 
dose of APAP in OTC products (from 1000 mg to 650 mg), and lowering the current 
maximum total daily dose APAP (from 4000 mg to 3250 mg) 
(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
DrugSafetyandRiskManagementAdvisoryCommittee/UCM174697.pdf).
This study will compare the efficacy and safety of a fixed-dose combination (FDC) of 
IBU/APAP 250 mg/500 mg (administered as two tablets of IBU/APAP 125 mg/250 mg)
administered every 8 hours compared to placebo over a 48-hour period in subjects with at 
least moderate dental pain after extraction of 3 third molar teeth.
1.1. Mechanism of Action/Indication
Ibuprofen, a “traditional” non-steroidal anti-inflammatory drug (NSAID), decreases the 
synthesis of pain- and inflammation-promoting prostaglandins via non-selective inhibition of 
cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2).1 The mechanism of action of 
APAP, which has no significant anti-inflammatory activity, is not clear. However, it may 
involve COX inhibition in the CNS and activation of central serotonergic pathways.2,3  
IBU/APAP is an analgesic/antipyretic that is being developed for OTC use.  The fixed dose 
combination is intended to have the same indications as each individual medication: the relief 
of minor aches and pains due to headache, toothache, backache, menstrual cramps, the 
common cold, muscular aches, minor pain of arthritis and the temporary reduction of fever.
1.2. Background and Rationale
IBU and APAP are among the most widely used non-prescription medications, both in the 
United States and globally, and have well established efficacy and safety profiles.  For many 
of those who use currently marketed OTC pain relievers, no single analgesic agent can 
completely relieve moderate to severe acute pain.  A ceiling effect is obtained with 


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non-opioid analgesics such as IBU and APAP, in which increasing doses produce little or no 
analgesic benefit but increase the risk of adverse effects.  Therefore, there is an unmet 
consumer need for a superior non-prescription analgesic with a favorable safety profile.  
Combining two different analgesics with different mechanisms of action, such as IBU and 
APAP, may provide superior efficacy to either agent alone without increasing the risk of side 
effects.  In addition, an analgesic with superior efficacy may reduce the need for additional 
doses of other analgesics, thereby reducing the total amount of analgesics consumed and 
leading to improved consumer safety.  
1.2.1. Study Rationale
Two published studies7,8 demonstrated that a combination of IBU 400 mg plus APAP 
1000 mg provided analgesic efficacy superior to either analgesic alone in post-surgical dental 
pain, without increasing the occurrence of side effects.  Furthermore, the same combination, 
at a dose of IBU/APAP 200 mg/500 mg, was statistically superior to APAP 1000 mg and 
nearly significantly superior to IBU 400 mg.  The finding that IBU 200 mg/APAP 500 mg is 
nearly statistically superior to IBU 400 mg suggests that slightly higher doses of IBU in the 
combination may be significantly superior to IBU 400 mg. 
The modern version of the dental pain model, developed in the mid-1970s, has been used in 
hundreds of clinical trials conducted by many different investigators.9 One of the most 
widely utilized of all acute pain models, the surgical procedure is extremely standardized, 
and the surgery requires either minimal or no use of CNS depressant anesthetics.  While the 
methodology is similar to that utilized in other acute pain models, the assay sensitivity is very 
good due to the homogeneity of the study population, the predictable level and appropriate 
intensity of the postsurgical pain, and the minimization of variability by using only a small 
number of study centers.  The dental impaction pain model has been used to evaluate 
NSAIDs, opioids, and combination analgesics, as well as some investigational drugs with 
unique mechanisms of action.  The model is particularly useful for proof of concept studies 
that require dose ranging and profiling the time effect curve for efficacy including onset, 
peak effect, and duration of analgesic activity.
1.2.2. Safety Data
Ibuprofen and APAP each have an extensive literature evaluation in nonclinical studies.  
Most studies have been performed in rodents which are more sensitive to IBU and APAP, 
particularly to gastrointestinal (GI) toxicity associated with IBU.  IBU has been linked to 
vomiting, gastric irritation and ulceration in dogs, with additional duodenal and jejunal 
ulceration in rats, mice, and monkeys.  There are significant interspecies differences in the 
severity and location of GI toxicity and the differences are thought to be associated with 
levels of COX 1 and COX 2 and the ratio of COX 1 to COX 2 in the GI tract. Both COX 1 
expression and relative COX 1/COX 2 expression are highest in the rat and dog compared to 
humans.  Of the species tested, rats are the most sensitive to GI toxicity, showing effects at 
doses that are therapeutic in humans (Radi and Khan, 2006).10  Therefore, quantitative dose 
comparisons between animals and humans regarding gastrointestinal toxicity are not useful.


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Two year rodent assays have shown that neither IBU (up to 180 mg/kg, lowered at week 55 
to 60 mg/kg due to gastric lesions) nor APAP (up to 320 mg/kg) present a risk for human 
carcinogenicity, despite some mixed findings in genotoxicity assays.  Neither compound is 
teratogenic, with APAP, however, having some potential effect on fertility.  
Two studies11,12 have been conducted in rats to investigate the toxicity of an IBU and APAP 
combination.  The doses of APAP and IBU used were very high, up to 100 mg/kg and 
200 mg/kg, respectively.  Both studies reported an increase in the number and severity of 
lesions in the stomach of rats when the drugs were administered in combination.  Neither 
study, however, tested a range of doses nor identified a no observed adverse effect level 
(NOAEL), so it is not possible to calculate a safety factor based on data from these studies. 
IBU/APAP combinations at OTC levels have been studied in humans, including single and 
multiple dose pharmacokinetics, single and multiple dose oral surgery studies, and a multiple 
dose knee pain study.  These studies show that the adverse event (AE) profile of an 
IBU/APAP combination product at the doses proposed in this document is not materially 
different than the AE profile of the individual components at their maximum dose level.6,7,8,13
In a more recent Pfizer Consumer Health (PCH)-sponsored proof of concept study, the safety 
of three IBU/APAP FDCs (200 mg/500 mg, 250 mg/500 mg, and 300 mg/500 mg 
administered as two tablets) was compared to IBU 400 mg and placebo in the third molar 
extraction model of dental pain.  The overall incidence of adverse events (AEs) was 
comparable among all treatment groups with no meaningful differences observed in any 
SOC. There were no safety concerns observed and all treatments were well tolerated. (Data 
on file).
In summary, IBU and APAP have good safety profiles at OTC doses.  In combination, at 
very high doses, increased frequency and severity of stomach lesions were observed in rats.  
However, these data are of limited relevance to human use for three reasons.  First, rats are 
more sensitive than humans to GI toxicity and a NOEL was not identified.  Second, the doses 
of APAP and IBU used, up to 100 mg/kg and 200 mg/kg, respectively, are many fold higher 
than the proposed maximum single human doses.  Third, increased gastrointestinal toxicity 
has not been observed with IBU and APAP combination products in human studies at the 
dose levels proposed for this program.
1.2.3. Dose Rationale
The dose to be evaluated in this study is a multiple oral dose of FDC IBU/APAP
250 mg/500 mg (administered as two tablets of IBU/APAP 125 mg/250 mg).  Based on once 
per day dosing, the proposed maximum daily dose of the IBU/APAP combination will be 
250 mg/500 mg, which is well below the current daily OTC maxima of 1200 mg and 
4000 mg, respectively and is in line with the FDA’s Analgesics Advisory Committee 
recommendation of lowering the current maximum total daily dose APAP (from 4000 mg to 
3250 mg).  
(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
DrugSafetyandRiskManagementAdvisoryCommittee/UCM174697.pdf).


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In the PCH-sponsored proof of concept study (B5061001), the efficacy of three IBU/APAP 
FDCs (200 mg/500 mg, 250 mg/500 mg, and 300 mg/500 mg administered as two tablets) 
was compared to IBU 400 mg and placebo in the third molar extraction model of dental pain.  
The results indicated that all active treatments were significantly better than placebo for all 
endpoints.  (Data on file).
1.2.4. Single Reference Safety Document
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator Brochure. 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
The objective of the study is to compare the analgesic efficacy and safety of FDC IBU/APAP 
250 mg/500 mg (administered as two tablets of IBU/APAP 125 mg/250 mg) every 8 hours 
compared to placebo in a 48-hour period following extraction of ≥3 third molar teeth. 
2.2. Endpoints
This protocol will not use an independent endpoint adjudication committee to determine 
whether certain investigator-reported events meet the definition of disease-related efficacy 
endpoints, using pre-defined endpoint criteria.
2.2.1. Primary Efficacy Endpoint
•
SPID[11] (sum of pain intensity difference scores) from 0-24 hours (time-weighted 
sum of PID[11] scores based on the 11-point Numerical PSR scale).
2.2.2. Secondary Endpoints
•
SPID[11] (time-weighted sum of Pain Intensity Difference scores PID[11] based on 
the 11-point Numerical PSR scale) from 0-8, 6-8, 0-16, 8-16, and 0-48 hours;
•
Duration of relief after first dose, as measured by the time from first dose to rescue 
medication or second dose whichever occurs first;
•
Time to onset of “meaningful” relief for the first dose.
2.2.3. Other Endpoints
•
 
•
 
 
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;
•
 
 
•
 
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•
 
 
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•
 
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•
 
 
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•
 
;
•
 
;
•
 
;
•
;
•
 
3. STUDY DESIGN
This will be a Phase 3, 48-hour, single-center, in-patient, multiple-dose, fixed dosing interval, 
randomized, placebo-controlled, sex- and baseline pain severity-stratified, double-blind, 
parallel group trial in approximately 102 subjects (68 subjects for IBU/APAP 
250 mg/500 mg group and 34 for placebo group [a ratio of 2:1]).  Subjects will be adult 
males and females (18 to 40 years of age, inclusive) who are experiencing post-operative 
pain following surgical extraction of 3 or more third molar teeth.  
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Following extraction of 3 or more third molar teeth, subjects will rest quietly at the study 
center until they experience post-surgical pain of at least moderate severity.  At that time, 
subjects will be asked to assess their pain intensity and severity using categorical, numerical, 
and/or visual scales.  Subjects with a qualifying baseline pain threshold within approximately 
5 hours of completion of surgery will be entered into the study.  
Upon completion of the baseline scales, eligible subjects will receive an oral dose of 
investigational product at 0 hours (baseline) and at 8, 16, 24, 32, and 40 hours post-baseline 
under randomized, double-blind conditions.  At 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 16, 24, 32, 40, and 48 hours post-baseline, subjects will provide self-ratings of pain 
severity using the categorical and numerical PSRs.  Subjects will also provide a self-rating of 
pain relief at each time point (except at baseline) using a categorical 
 scale.  
At 24 and 48 hours, or at the time of first rescue medication on each respective day, subjects 
will also complete a 
 of the investigational product.  Additionally, subjects 
will also evaluate the time to 
 and time to meaningful relief using a 
double stopwatch method up to 8 hours post-baseline (ie, up to the second dose 
administration)  or until the time of first rescue medication use, whichever is sooner.  A 
review of any reported adverse events will also be completed.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Males and females 18 years to 40 years of age (inclusive).
2. Outpatients who have undergone surgical extraction of 3 or more third molars, of 
which at least 2 must be a partial or complete bony mandibular impaction.
3. Subject must have at least moderate pain on the 4-point categorical scale, confirmed 
by at least 50 mm on the 100 mm VAS PSR scale within approximately 5 hours (ie, 
less than or equal to 5 hours, 15 minutes) after surgery is completed.
4. Use of only the following pre-operative medication(s)/anesthetic(s): topical 
benzocaine, a short acting parenteral (local) anesthetic (mepivacaine or lidocaine) 
with or without vasoconstrictor and/or nitrous oxide.
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5. Examined by the attending dentist or physician and medically cleared to participate in 
the study.
6. In general good health and have no contraindications to the study or rescue 
medication.  
7. Female subjects are not pregnant, as verified by a urine based pregnancy test, or 
breast feeding female subjects.
8. Male subjects able to father children and female subjects of childbearing potential
who are, in the opinion of the investigator, sexually active at risk for pregnancy with 
their partner(s) must agree to use a highly effective method of contraception as 
outlined in this protocol for the duration of the study and for at least 28 days after the 
last dose of assigned treatment.  
9. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative/parent(s)/legal guardian has been 
informed of all pertinent aspects of the study.  
10. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.  
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Presence or history of any significant hepatic, renal, endocrine, cardiovascular, 
neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic 
disorder determined by the Investigator to place the subject at increased risk, 
including the presence or history within 2 years of screening of the following medical 
conditions/disorders:

Gastrointestinal ulcer or gastrointestinal bleeding;

Paralytic ileus or other gastrointestinal obstructive disorders;

Bleeding disorder.
2. Clinically significant abnormalities on the screening laboratory tests determined by 
the Investigator or designee that would place the subject at increased risk.
3. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
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4. Subjects at risk for excessive bleeding, eg, those on anticoagulant therapy, etc.
5. Acute localized dental alveolar infection at the time of surgery that could confound 
the post-surgical evaluation.
6. Hypersensitivity to ibuprofen, naproxen, aspirin, or any other NSAID; or to APAP, 
tramadol, other opioids, or to their combinations.
7. Use of a prescription or OTC drug with which administration of ibuprofen or any 
other non-steroidal anti-inflammatory drug; acetaminophen; codeine, tramadol or any 
other opioid is contraindicated (including: opioids, antipsychotics, antianxiety agents, 
or other CNS depressants [including alcohol]).
8. Use of prescription or OTC antihistamines within 24 hours prior to taking 
investigational product.  (Note exceptions: loratadine [Claritin®], desloratadine 
[Clarinex®], cetirizine [Zyrtec®], levocetirizine [Xyzal®], fexofendadine 
[Allegra®], and azelastine [intranasal, Astelin®]).
9. Use of a bisphosphonate (eg, pamidronate [Aredia®], risedronate [Actonel®], 
alendronate [Fosamax®], or ibandronate [Boniva®]) within the past 5 years.
10. Prior use of any type of analgesic or NSAID within five half-lives of that drug or less 
before taking the first dose of investigational product, except for pre-anesthetic 
medication and anesthesia for the procedure.
11. Currently taking a monoamine oxidase inhibitor (MAOI), antipsychotic, or any other 
neuroleptic or has taken:

A MAOI within 2 months of screening (Note: subjects may not discontinue taking 
an MAOI solely for the purpose of qualifying for the study);

An antipsychotic or other neuroleptic within 14 days of surgery (Note: subjects 
may not discontinue taking these medications solely for the purpose of qualifying 
for the study).

Subjects who are currently taking any selective serotonin reuptake inhibitor 
(SSRI), serotonin norepinephrine reuptake inhibitor or selective norepinephrine 
reuptake inhibitor (SNRI), or tricyclic antidepressant (TCA), and are not on a 
stable dose of this medication for at least 30 days prior to screening or will not 
maintain this dose throughout the study and their condition is judged by the 
Investigator to not be well controlled (Note: subjects may not discontinue taking 
these medications solely for the purpose of qualifying for the study).


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12. History of regular alcohol consumption exceeding 7 drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces 
(360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of screening, 
or currently abusing other mood altering drugs (eg, cocaine, tetrahydrocannabinol 
(THC), opiates/opioids, benzodiazepines and amphetamines, etc) within 6 months of 
screening.  Subjects who are taking St. John’s Wort, or any other nutritional 
supplement known to have psychotropic effects may be enrolled if they have been on 
stable doses of medication for at least 2 months prior to screening will maintain this 
dose throughout the study, and their condition is judged by the Investigator to be 
well-controlled.
13. Habituation to analgesic medications (ie, routine use of oral analgesics 5 or more 
times per week).
14. Subjects who have ingested any caffeine-containing beverages, chocolate, or alcohol, 
within 4 hours prior to taking investigational product.
15. Inability or unwillingness to comply with the requirements of the protocol as judged 
by the Investigator.
16. Subject has previously participated in this study.
17. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
18. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.
4.3. Randomization Criteria
Subject must have at least moderate pain on the 4-point categorical scale, confirmed by at 
least 50 mm on the 100 mm visual analog scale (VAS) PSR scale within approximately 
5 hours after surgery to be eligible for randomization.
4.4. Lifestyle Guidelines
All male subjects who are able to father children and female subjects who are of childbearing 
potential and in the opinion of the investigator, are sexually active and at risk for pregnancy 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and his or her partner from the permitted list of contraception methods 
(see below) and instruct the subject in its consistent and correct use.  Subjects need to affirm 
that they meet the criteria for correct use of at least 1 of the selected methods of 
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use highly effective contraception consistently and correctly according to the Schedule of 
Activities and document such conversation in the subject’s chart.  In addition, the 
investigator or his or her designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
the subject’s partner.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception is associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject 
plans to remain on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female partner who meets the criteria for non-childbearing potential, as described 
below:
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed by having a serum follicle stimulating hormone 
(FSH) level confirming the post-menopausal state.
All other female subjects (including females with tubal ligations) will be considered to be of 
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NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list in the site master file.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact center number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should only be used in the event that the established communication pathways between the 
investigational site and the study team are not available. It is therefore intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study. 
The contact number is not intended for use by the subject directly, and if a subject calls that 
number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Treatment assignments will be determined by a computer generated randomization schedule 
generated and maintained by Pfizer Randomization Administration. In order to maintain the 
double-blind integrity of the study at the investigator and subject levels, only a third party 
person(nel) at the investigational site (ie, not involved in any other aspect of the trial) 
assigned to prepare and administer the investigational product (Section 5.4.2) will have 
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Subjects will be stratified by sex and baseline pain (moderate or severe pain as determined by 
their baseline categorical pain severity scores), and will randomly receive one of the 
following investigational products under randomized, double-blind conditions in a 2:1 ratio:
•
IBU/APAP 250 mg/500 mg (administered as 2 tablets of IBU/APAP 
125 mg/250 mg);
•
Placebo (administered as 2 tablets).
 
.
5.2. Breaking the Blind
The study will be subject and investigator blinded.  At the initiation of the study, the study 
site will be instructed on the method for breaking the blind.  Blinding codes should only be 
broken in emergency situations for reasons of subject safety.  Whenever possible, the 
investigator or sub investigator consults with a member of the study team prior to breaking 
the blind.  When the blinding code is broken, the reason must be fully documented and 
entered on the electronic case report form (eCRF).  
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. This disclosure will only be broken by the Investigator in the event of an emergency 
for which knowledge of the subject’s double blind investigational product will have a direct 
impact on treatment decisions.  Every effort will be made to discuss the decision to break the 
blind with the PCH monitor in advance.
When the blind is broken, the Investigator will notify the Sponsor’s Clinician 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 on the eCRF and in the 
source document.  Any AE or SAE associated with breaking the blind must be recorded and 
reported as specified in this protocol.
5.3. Subject Compliance
Study treatment will be administered under the supervision of qualified investigative site 
personnel.
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5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
The Sponsor will supply investigational product and matched placebo in bulk (See Table 2) 
suitable for administration by a disinterested third party (ie, not involved in any other aspect 
of the trial). Rescue medication, tramadol and codeine sulfate, and supplies will be provided 
by the study site.
Table 2.
B50610014 — Study Product
Investigational Product Description/ 
 
 
IBU/APAP 125/250 mg tablets
 
Placebo
A detailed description of each treatment (ie, the investigational product and placebo that each 
subject will receive) is shown in Table 3.
Table 3.
Detailed Description of Each Treatment Group
Treatment Group
Strength Per Tablet
Strength Per Dose/Route
A: IBU/APAP 250/500 mg 
IBU/APAP 125/ 250 mg per 
tablet
2 tablets (equivalent to IBU/APAP 
250 mg/500 mg) Orally
B: Placebo
Not Applicable
2 tablets Orally
5.4.2. Preparation and Dispensing
On the day of surgery, each subject entered into the study will be given one dose (2 tablets) 
of the randomly assigned investigational product with approximately 6 to 8 ounces of room 
temperature water when they are experiencing post-surgical pain of at least moderate 
severity.  Thereafter, subjects will receive investigational product in the same manner every 
8 hours. From the time that investigational product is taken, the duration of evaluation will 
be 48 hours.
The Sponsor will supply investigational product in an unblinded fashion.  To maintain the 
double blind status of the study, the following dispensing and dosing procedures will be 
followed.  The site will identify a qualified third party and alternate(s) who will be 
responsible for dispensing and administering the investigational product.  
 
 
 
 
 
  The opaque plastic bottles and caps will be supplied 
separately from the labels to the third party person(nel) as well.
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The third party dispenser will prepare investigational product for each subject in a designated 
dispensing room.  Investigational product may be prepared up to 48 (forty-eight) hours in 
advance of actual dispensing to enrolled subjects.  Baseline pain assessments and drug 
administration will be completed in the subject’s room.  Investigational product will be 
dispensed at the time the subject’s pain level is determined by verbal assessment, just prior to 
the completion of the baseline categorical pain severity scale and VAS PSR.  The study 
coordinator will communicate the subject’s pain severity to the dispenser.  The dispenser will 
assign the next available randomization number.  The dispenser will dispense the appropriate 
2 tablets from the appropriate bulk supply containers into an individual opaque plastic bottle.  
The double-blind label with the same randomization number will be affixed to the bottle and 
the tear off portion of the label will be attached to the investigational product dispensing 
record. The third party dispenser will affix the identification tab to the investigational 
product dispensing record and complete the investigational product dispensing record.  The 
investigational product dispensing record will remain in a secure locked area with access 
limited to the dispenser and the alternate(s).  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 investigational product
dispensing.  No other individuals will be able to see the investigational product in the bottle 
once the bottle cap is closed.
The third party dispenser will inform the study coordinator once the investigational product
is dispensed and is ready to be administered to the subject.  The dispenser will deliver the 
investigational product from the designated dispensing room to the subject’s room.  
5.5. Administration
Investigational product will be administered to the subject within 7 minutes of the 
completion of the baseline pain assessments and, thereafter, every 8 hours by the third party 
dispenser.  No other study personnel will be present at the time of dosing.
After the subject has been blindfolded, while the subject is sitting up, the dispenser will give 
the 2 tablets to the blindfolded subject with 6 to 8 ounces of room temperature water 
(time=0).  Subjects will swallow the investigational product whole, and will not manipulate 
or chew the medication prior to swallowing.
5.6. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.  A PCH representative will inspect the 
study product storage area and discuss the study product accountability system with the 
Principal Investigator before any agreements are concluded between the Principal 
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Investigational product should be stored in its original container and in accordance with the 
label.  Investigational product prepared in advance of actual dispensing to enrolled subjects 
must be stored under the same conditions, and along with, bulk containers from which the 
subject-specific product container was prepared.  Storage conditions stated in the single 
reference safety document (SRSD) (eg, IB) will be superseded by the storage conditions 
stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order.  
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.  Specific details regarding 
information the site should report for each excursion will be provided to the site. 
5.7. Investigational Product Accountability
Upon receipt at the study site, the carton containing the study product will be stored 
unopened in the study treatment storage room. Study product will be sent to the third party 
dosing person(nel). Confirmation of receipt of study product by the third party dosing 
person(nel) must be documented.   At the study initiation, the Principal Investigator or an 
appropriate designee, and a representative of PCH will conduct an inventory and complete 
the study treatment inventory record.  The original will be sent to PCH and the Principal 
Investigator will retain a copy.  Any interim shipments will be inventoried by the Principal 
Investigator or his/her designee, and if possible, a representative of PCH.  For all interim 
shipments, a study treatment inventory record will be completed.  The original will be 
returned to PCH and the Principal Investigator will retain a copy.  
The Principal Investigator or an appropriate designee, upon dispensing the study treatment, 
must record the information on a study treatment dispensing/return log.  For accounting 
purposes and assessing subject compliance, a representative of PCH will review the study 
treatment dispensing/return log, inventory the study treatment, and inspect the storage facility 
at appropriate time intervals throughout the clinical investigation, depending on the length of 


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the study.  The Principal Investigator must account for any significant discrepancy and/or 
deficiency.
5.7.1. Destruction of Investigational Product Supplies
All investigational study treatment shipped for this clinical trial will be returned to the 
Sponsor at the termination of the study.  At the conclusion of the study, the Principal 
Investigator or an appropriate designee, and a representative of PCH will inventory all used 
and unused investigational study treatment.  The study treatment inventory record for 
returned study treatment will then be completed.  PCH will retain the original, and the 
Investigator will retain a copy for his/her files.  All used investigational study treatment 
(empty containers), as well as all unused study treatment will then be returned to the sponsor 
(see Section 5.7).
Upon receipt at PCH Consumer Study Supplies,
, a letter acknowledging the 
receipt of returned materials and a copy of the packing slip will be sent to the Clinician.
5.8. Concomitant Treatment(s)
Except for rescue medication as defined in Section 5.9, no other medications expected to 
confound the evaluation of the study product will be allowed during the course of the study.  
All concomitant medications used during the study will be recorded in the eCRF.  Antibiotics 
are permitted at the discretion of the Investigator (refer to Section 4.1).
5.9. Rescue Medication
Subjects not experiencing adequate relief after the one-hour time point evaluation may take 
tramadol (immediate release tablets) 50 to 100 mg orally, based on the discretion of the 
Investigator, as rescue medication.  If needed, subjects may receive additional doses of 
rescue medication (ie, tramadol 50 to 100 mg orally every 4 to 6 hours as needed [prn] based 
on the discretion of the Investigator) at the study center (ie, within 48 hours after first dose of
investigational product).  The total maximum daily dose of rescue medication, tramadol 
hydrochloride, which may be taken at the study center, should not exceed 400 mg.
Alternatively, any subject not experiencing adequate relief after the one-hour time point 
evaluation may take codeine sulfate (immediate release tablets) 15 to 60 mg orally, based on 
the discretion of the Investigator, as rescue medication.  If needed, subjects may receive 
additional doses of rescue medication (ie, codeine sulfate 15 to 60 mg orally every 4 hours 
prn [based on the discretion of the Investigator]) at the study center (ie, within 8 hours after 
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dosing with investigational product).  The total maximum daily dose of rescue medication, 
codeine sulfate, which may be taken at the study center should not exceed 360 mg.
Subjects may not take any rescue medication home with them.  Subjects who take rescue 
medication during the course of the evaluation period will remain in the study continue to 
perform their efficacy assessments.
Rescue medication should be administered within 5 minutes of rescue assessments being 
performed.  Subjects taking rescue medication within one hour after dosing will be 
considered discontinued and must be replaced.  The use of rescue medication will be
recorded in the appropriate section of the case report form.  The date, time, name of rescue 
medication taken, and reasons for use will be recorded.
6. STUDY PROCEDURES 
6.1. Screening & Day of Surgery
During the screening period (for this protocol, defined as the time period from the screening 
visit until start of surgery), the Investigator or his/her designee will examine each subject and 
complete a checklist of the inclusion and exclusion criteria (see Section 4.1 and Section 4.2) 
in order to determine the subject’s eligibility.  Screening procedures include:

Medical history;

Prior/Concomitant medication review;

Brief physical examination, including blood pressure, heart rate, respiratory rate, 
temperature;

Laboratory testing (See Section 7.5);

Hematology; 

Coagulation tests;

Serum chemistry (complete metabolic panel);

Urinalysis; 

Serum pregnancy test (females only).
Screening procedures may be performed on the morning of surgery, but if a separate 
screening visit is conducted, it must be completed within 30 days of the surgery.  The 
Investigator or his/her designee will enter the pertinent historical information (including any 
medication taken recently) and clinical findings in the appropriate section(s) of the source 
documents.  A Subject Screening Record (provided by PCH) will be maintained to document 
all subjects screened for entry into the study.  Subjects will be screened only once.  All 
subjects will provide written informed consent before participating in the study.  Subjects are 


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required to read, comprehend, and sign the informed consent.  Appropriate screening 
information for eligible subjects who are assigned a subject number and receive 
investigational product will be transcribed onto the corresponding sections of the eCRF.  
AEs and concomitant medications will be collected throughout the study.
NOTE: Surgery will be scheduled within 30 days of the screening visit.
Subjects will report to the study center on the morning of their surgery in a fasted state (ie, 
they should not ingest food or drink after midnight of the preceding evening).  At the 
surgeon's discretion, liquids or Jell-O® may be provided to the subject prior to surgery.  
Subjects may not ingest any caffeine containing beverages, chocolate, or alcohol within 
4 hours prior to taking study medication or during the entire 48 hour evaluation period.
No food will be allowed from 1 hour before to 2 hours after the scheduled ingestion times of 
all doses of study medication.  Low fat (≤20% of calorie intake from total fat) xanthine free 
beverages, soups, or soft foods suitable for consumption by a post-surgical dental patient will 
be available to the subject at all other times provided that no food is consumed within 30 
minutes before a time point assessment.  The times of food consumption will be recorded in 
the source document.
On the morning of surgery, females with reproductive potential will have a urine based 
pregnancy test.  At surgery, the following will be noted and recorded on the eCRF:

Date of surgery and the times surgery was initiated and completed (for this protocol, 
surgery initiation and completion are defined as the time of first incision and as the 
time of last suture completion, respectively); 

Any medications that have been administered, including pre-operative medications 
and anesthetics: name, dose, and time;

Surgical status of each extracted tooth (ie, erupted, soft tissue impacted, partial bony 
impacted, full bony impacted);

The identifying number of each tooth extracted (this may not exceed four third 
molars; a single additional supernumerary tooth may be extracted if necessary), and

The surgical trauma rating;

The time of the last meal prior to surgery will be noted in the source document only.
6.2. Study Period
Subjects will not be allowed to wear a watch during the study, and they may not have access 
to a clock or any electronic device with a time function (including iPods, iPads, Nooks, 
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Post-operatively, no ice packs may be applied to the patient until completion of the 2-hour 
pain assessment, and they may not be applied within 30 minutes prior to any other pain 
assessment. 
Post-operatively, subjects will be asked to rest quietly at the study center until they 
experience post-surgical pain of at least moderate severity.  At that time, subjects will be 
asked to complete pain rating scales in the following order: baseline 4-point categorical PSR
scale, 100 mm VAS PSR scale followed by the 11-point numerical pain rating scale.
•
Categorical PSR Scale:
•
A score of at least moderate must be indicated before the subject can enter the 
trial.  Each category on this scale will be assigned a whole number value from 
0 (none) to 3 (severe);
•
Numerical PSR Scale.
•
VAS PSR Scale (VAS PSR):
•
A minimum score of 50 mm is required to verify that the subject has at least 
moderate pain at baseline.  Subjects with scores < 50 mm by approximately 
5 hours (ie, less than or equal to 5 hours, 15 minutes) after surgery will not be 
randomized.
Subjects who do not reach a qualifying baseline pain threshold (at least moderate pain 
indicated by a score of 2 or greater on the categorical scale, confirmed by a score of at least 
50 mm on the VAS PSR) within approximately 5 hours (ie, less than or equal to 5 hours, 
15 minutes) of completion of surgery will not be entered into the study.
Upon completion of the baseline scales, eligible subjects will receive an oral dose of 
investigational products at 0 hours (baseline) and at 8, 16, 24, 32, and 40 hours post-baseline
under randomized, double blind conditions. Subjects will be stratified by sex and baseline 
pain (moderate or severe pain as determined by their baseline categorical pain severity 
scores).  
Each subject’s vital signs (heart rate, blood pressure, temperature, and respiratory rate) will 
be measured and recorded at baseline, prior to other assessments being performed.
6.2.1. Post-Baseline Assessments
The following assessments will be conducted at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 16, 24, 32, 40, and 48 hours:
•
; 
•
11 point Numerical PSR Scale;
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•
;
•
A review of any reported adverse events and concomitant medications will also be 
completed.
The following additional assessments will be conducted at 8 hours post-Baseline:
•
Vital signs (ie, heart rate, blood pressure, temperature, and respiratory rate) will be 
measured and recorded.  
•
A review of any reported adverse events and concomitant medications will also be 
completed.
The following additional assessment will be conducted at 24 and 48 hours post-Baseline (or 
at the time of first rescue medication dosing on each day):
•
;  
•
Vital signs (ie, heart rate, blood pressure, temperature, and respiratory rate) will be 
measured and recorded (hour 48 only). 
The following assessments will be conducted immediately before the first use of rescue 
medication use or at the time of withdrawal (if applicable):
•
; 
•
11 point Numerical PSR Scale;
•
; 
•
;
•
Vital signs (ie, heart rate, blood pressure, temperature, and respiratory rate) will be 
measured and recorded.  
Subjects will also evaluate the time to 
 Relief by depressing a stopwatch at 
the moment they first begin to experience “perceptible” relief and the time to “Meaningful” 
Relief by depressing a second stopwatch at the moment they first begin to experience 
“meaningful” relief (see Section 7.3.4 for further details).  These times will be recorded up to 
8 hours after dosing (ie up to the time the subjects are administered the second dose) or until 
the time of (first) rescue medication use, whichever is sooner.
6.2.2. End of Study
The following assessments will be conducted at the end of the study:
•
Vital signs (ie, heart rate, blood pressure, temperature, and respiratory rate) will be 
measured and recorded; 
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
A review of any reported adverse events will also be completed.
6.3. Follow-up Visit
The investigator (or an appropriate designee at the investigator site) will contact the subject 
via telephone, 28 calendar days after the last dose of the study medication to ascertain if any 
SAEs have occurred. Reporting of SAEs discovered during this process must be completed 
as outlined in Section 8.1 in the protocol. Every effort (three telephone contact attempts) 
should be made to contact the subject. All attempts to contact the subject and information 
received during contact attempts must be documented.  
6.4. Subject Withdrawal
A subject will be withdrawn from the study at any time under the following circumstances:
1. Any subject who violates any condition of the entrance criteria after having been 
entered into the study.
2. Any subject who reports inadequate relief and requires rescue medication prior to one 
hour after taking the investigational product.
3. Any subject who develops a confounding concomitant illness (discontinuation as 
deemed necessary by the subject, research coordinator or investigator), serious AE, or 
a hypersensitivity to the study product.
4. Any subject who becomes uncooperative, does not adhere to the requirements of the 
study protocol, or refuses to complete the study.
5. Any subject who requires any concomitant medication (other than rescue medication) 
during the course of the study that could confound the study results.
6. Any subject who vomits within 1 hour following dosing.
Subjects may withdraw from the study at any time at their own request, or they may be
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the subject to return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved Adverse Events (AEs).  


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If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Additional coded study product will be provided to the study site for replacement subjects.  
Should a subject discontinue, he/she will be replaced by the next available subject number.  
Subjects who discontinue due to an AE will not be replaced {except subjects who vomit the 
study product within 1 hour of dosing, if applicable}.  The reason(s) why a subject has been 
discontinued from the study should be recorded in the appropriate section of the eCRF.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at screening.  On the day of surgery, before 
investigational product administration at the baseline visit, a urine pregnancy test will be 
administered.  A negative pregnancy result is required before the subject may receive the 
investigational product.  Pregnancy tests may also be repeated as per request of institutional 
review boards (IRBs)/ethics committees (ECs) or if required by local regulations.
In the case of a positive confirmed pregnancy see Section 8.10. 
7.2. Baseline Efficacy Assessments
7.2.1. Categorical Pain Severity Rating Scale
The following 4 point Categorical PSR Scale will be used to rate the severity of baseline pain 
in response to the query:
"My starting pain is:"
None                  Mild                 Moderate                 Severe
A score of at least moderate must be indicated before the subject can enter the trial.  Each 
category on this scale will be assigned a whole number value from 0 (none) to 3 (severe).


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7.2.2. VAS Pain Severity Rating Scale (VAS PSR)
The 100 mm VAS PSR will be used to rate the severity of baseline pain.  Subjects will be 
asked to:
"Draw a single vertical line on the scale that shows how much pain you have at this time."
None
Severe
Scores on the 100 mm linear scale will be measured to the nearest millimeter from the left.  
A minimum score of 50 mm is required to verify that the subject has at least moderate pain at 
baseline.  Subjects with scores <50 mm by approximately 5 hours (ie, less than or equal to 
5 hours, 15 minutes) after surgery will not be randomized.
7.2.3. Numerical Pain Severity Rating Scale
The following 11 point Numerical PSR Scale will be used to rate the severity of baseline pain 
in response to the query:
"My starting pain is:"
None 0   1   2   3   4   5   6   7   8   9   10 Worst Possible Pain
Subjects will be instructed to circle the number that best matches their pain severity.
Upon completion of the baseline scales, eligible subjects will receive a single oral dose of 
investigational product under randomized, double blind conditions.
7.3. Post-Baseline Efficacy Assessments
 
                 
                 
                 
 
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7.3.3. Numerical Pain Severity Rating Scale
The 11 point Numerical PSR Scale will be completed at the times specified in the Schedule 
of Activities, and immediately before rescue medication is taken (if necessary) or at the time 
of withdrawal, to evaluate pain intensity in response to the question:
“How much pain do you have at this time?"
None 0   1   2   3   4   5   6   7   8   9   10 Worst Possible Pain
Subjects will be instructed to circle the number that best matches their pain severity.
7.3.4. Time to Relief
When the subject is administered investigational product at time 0, the Study Coordinator/ 
Designee will start two stopwatches.  Each stopwatch will have its face covered; one will be 
labeled “first perceptible relief” (Section 7.3.4.1) and the other “meaningful relief” (Section 
7.3.4.2).  
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7.3.4.2. Time to Meaningful Relief for the First Dose
In an effort to determine the exact moment that the subject begins to obtain meaningful relief
for the first dose, the subject will be instructed as follows:
“Stop this stopwatch when you have meaningful relief, that is, when the relief from the 
pain is meaningful to you.”
The elapsed time will be recorded in the case report form. The stopwatch will remain active 
for 8 hours or until stopped by the subject, or until second dose or a rescue medication
whichever is administered first.
7.4. Safety Assessments
Adverse events will be recorded as they occur or reported.  During surgery and the pain 
assessment period, subjects will be closely monitored for any AE.  The Principal Investigator 
or designated Investigator will decide if any treatment is necessary.  All AEs, whether serious 
or not, will be recorded on source documents.  All AEs and SAEs for subjects who are not 
screen failures will be recorded in the eCRFs.  The recording period for a non-serious AE 
starts at the time the subject takes the first dose of the study product.  For SAEs, the reporting 
period to Pfizer or its designated representative begins from the time that the subject provides 
informed consent, which is obtained prior to the subject’s participation in the study, ie, prior 
to undergoing any study related procedure and/or receiving investigational product, through 
and including 28 calendar days after the last administration of the investigational product.  
This includes events that emerge during screening.  Any SAE occurring any time after the 
reporting period must be promptly reported if a causal relationship to investigational product 
is suspected.  For non-serious AEs, the reporting period starts at the time of first 
administration of study product.  The reporting period is 28 days after the subject’s last 
administration of study product, regardless of the relationship to the study product or 
protocol.
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Each subject’s vital signs (ie, pulse, heart rate, blood pressure, respiratory rate and 
temperature) will be measured at baseline (prior to dosing), at 8 hours and again at the end of 
study or at the time of rescue medication (if needed).  A review of any reported AEs will be 
completed at the end of the study, and collected at the time of subject withdrawal from the 
study.
Note: Details about any recorded AE will be obtained from the subject at the end of an in 
house study.  The Principal Investigator or study coordinator will review the start and stop 
dates and times, severity, action taken, present at end of study, and whether present 
pre-treatment for each AE.  Only the Principal Investigator will determine the relationship to 
study product for each AE.  The information will be recorded on the appropriate eCRF.
7.5. Laboratory Assessments
Laboratory assessments will be performed at Screening only.
7.5.1. Hematology
Hematology assessments will include:

White blood cells, red blood cells, hemoglobin, hematocrit, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution 
width, platelets, differential count (neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils).

Mean platelet volume will not be assessed as part of the hematology assessment.
7.5.2. Coagulation 
Coagulation assessments will include:

Prothrombin time (PT), partial thromboplastin time (PTT), international normalized 
ratio (INR);

Serum chemistry (complete metabolic panel):  

Sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, 
calcium, total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, 
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, 
glucose.
7.5.3. Urinalysis
Urinalysis assessments will include:

Appearance, color, specific gravity, pH, glucose, ketones, blood, protein, bilirubin, 
urobilinogen, nitrites, leukocyte esterase, red blood cells, white blood cells, hyaline 
casts, granular casts, epithelium, bacteria, crystals, mucous threads.


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7.6. Assessment of Suicide
This blinded, controlled trial is for non-CNS indications.  The FDC IBU/APAP formulations 
have no known effects on mood.  There are no concerns about the mechanism of action, and 
neither the subject population nor disease under study is associated with a substantial risk of 
suicidality.  Therefore, additional information on spontaneously reported suicidality adverse 
events may be collected at the time the event is reported using the suicidality narrative guide.  
No additional screening or detection methods are recommended at this time.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator 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 an
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.  
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
For non-serious AEs, the reporting period starts at the time of first administration of study 
product.  The reporting period is 28 calendar days after the subject’s last administration of 
study product, regardless of the relationship to the study product or protocol.


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AEs (serious and nonserious) should be recorded on the Case Report Form (eCRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last
visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.


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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE eCRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events (SAE)
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;


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•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
•
Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
Unless the investigator believes that there is a causal relationship between investigational 
product and an event specified below, these events should not be reported by the investigator 
as SAEs as described in the Serious Adverse Event Reporting Requirements section on this 
protocol. These events are anticipated to occur commonly in a population with undergoing 
surgical extraction of third molars.  However, these events should still be captured as AEs in 
the eCRF.
Protocol-specified events that will not normally be reported in an expedited manner: 
•
Paresthesia; Fracture of the mandible or maxilla;
•
Oro antral communication.
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected based on the expectation of frequency of the event(s) in question in the 
population for comparison, eg, based on epidemiological data, literature, or other data, then 
this will be submitted and reported in accordance with Pfizer’s safety reporting requirements.  
Aggregate analysis of safety data will be performed on a regular basis per internal standard 
operating procedures (
).  
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a subject, such LFT results should be handled and followed up 
as described below.  
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Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X the upper limit of normal [ULN]) concurrent with a total bilirubin value 
2 X ULN with no evidence of hemolysis and an alkaline phosphatase value 2 X 
ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or
if the value reaches ≥3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 


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results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;


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Diagnostic and therapeutic noninvasive 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.
8.8. Severity Assessment
If required on the AE eCRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the eCRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  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; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and eCRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.


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8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE Report Form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;


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
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE Report 
form is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also Section 6.4 on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE eCRF 
page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. 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.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
As noted in the Protocol-Specified Serious Adverse Events section, should an investigator 
judge one of the identified protocol-specified SAEs to have a causal relationship with the 
investigational product, the investigator must report the event to Pfizer within 24 hours of 
investigator awareness, even if that event is a component of the endpoint.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE eCRF.  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, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the eCRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE eCRF.  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.  AEs should be reported using concise medical 
terminology on the eCRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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9. DATA ANALYSIS/STATISTICAL METHODS
A detailed methodology for the summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be maintained by 
the sponsor.  The SAP may modify the plans outlined in the protocol; however, any major 
modifications to the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
Pfizer Consumer Healthcare will perform statistical analyses of data.  All computations will 
be performed using SAS® version 9.2 or higher (SAS Institute, Cary, NC).  Statistically 
significant treatment differences will be declared if the probability of random occurrence 
among or between treatments, p, is ≤0.05 (two-sided). Treatment differences will be 
considered marginally significant if 0.05<p≤0.10.
9.1. Sample Size Determination
Using RMSE data for SPID[11] over 2, 8 and 12 hours from Study B5061001, a single dose 
dental pain study, it was estimated that the RMSE for SPID[11] over 0-24 will be 
approximately 52 units.  Based on this assumption, a sample size of 68 subjects for 
IBU/APAP 250 mg/500 mg group and 34 for placebo group (a ratio of 2:1) will provide 
85% power (at 5% level of significance, two sided) to detect a treatment difference of at least 
33 units for SPID[11] 0-24.  
Thus, a total of 102 evaluable subjects are required to complete the study.  Assuming a 
10% drop-out rate, a total of approximately 112 subjects will be enrolled.
9.2. Efficacy Analysis
The statistical analysis methods will be detailed in the SAP, and are briefly summarized 
below.
9.2.1. Analysis Populations
9.2.1.1. Primary Analysis Set
The full analysis set (primary population) is the intent to treat (ITT) subject population, 
defined as all randomized subjects who dosed with the study medication and provided a 
baseline assessment.
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9.2.1.3. Safety Analysis Set
The safety analysis set will include all subjects who received at least once dose of the study 
product.
9.2.2. Analysis of Primary Endpoint
Primary efficacy endpoint SPID[11] 0-24 will be analyzed by an analysis of covariance 
model (ANCOVA) with treatment, categorical baseline PSR, baseline numerical PSR, and 
sex terms.  
9.2.3. Analysis of Secondary Endpoints
•
Secondary efficacy endpoints of SPID[11] over 0-8, 6-8, 0-16, 8-16, and 0-48 hours 
will be analyzed by ANCOVA model with treatment, categorical baseline PSR, 
baseline numerical PSR and sex terms.
•
Time to onset of “meaningful” relief, and duration of relief as measured by the time 
to treatment failure will be analyzed using the Gehan-Wilcoxon test to compare 
treatments, adjusting for sex, and baseline categorical PSR terms.  
9.2.4. Analysis of Other Endpoints
•
Other efficacy endpoints of PID (both scales), PRR 
 at each time point, the 
corresponding summary measures SPID,
, will be analyzed by 
ANCOVA 
 
models with 
treatment, 
, baseline numerical PSR (
) 
and sex terms. 
•
 
 
.  
•
•
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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•
 
 
•
 
 
 
 
 
•
 
 
 
 
 
•
 
 
 
 
CCI
CCI
CCI
CCI
CCI


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9.4. Safety Analysis
Adverse event (AE) analyses will include all events which initially occurred, or worsened 
following treatment.  Adverse events will be summarized by the MedDRA SOC and 
preferred term and classified according to their severity (mild, moderate, or severe) and 
relationship (related or not related) to study product.  For the summary by severity, subjects 
who have multiple occurrences of the same AE will be classified according to the worst 
reported severity of the AE.  Similarly, for the summary by relationship to the study product, 
the AE will be classified according to the worst relationship.
9.5. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on eCRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.  During study conduct and/or after study 
completion, the study site may be subject to review by the institutional review board 
(IRB)/ethics committee (EC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term eCRF should be understood to refer to either a paper form 
or an electronic data record or both, depending on the data collection method used in this 
study.


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An eCRF is required and should be completed for each included subject.  The completed 
original eCRFs are the sole property of Pfizer and should not be made available in any form 
to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
eCRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the eCRFs are true. Any corrections to entries made in the eCRFs or
source documents must be dated, initialed, and explained (if necessary) and should not 
obscure the original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the eCRFs must match the data in those charts. 
In some cases, the eCRF, or part of the eCRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the eCRF, and for which the eCRF will stand as 
the source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, eCRFs and hospital records), all original signed informed 
consent documents, copies of all eCRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board /Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study, each subject’s
numerical code to his or her actual identity.  In case of data transfer, Pfizer will maintain high 
standards of confidentiality and protection of subjects’ personal data consistent with 
applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.


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The investigator must ensure that each study subject, or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature 
and objectives of the study and possible risks associated with participation.  
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse) and that the subject’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian, before any study-specific activity is performed. The investigator will retain the 
original of each subject's signed consent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries
The end of the trial is defined as the last visit by the last subject.


PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 60
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of the 
investigational product at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 15 days.  As directed by Pfizer, all study 
materials must be collected and all eCRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
Publication of study results is further discussed in the CSA.
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.


PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 61
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the
principal investigator will reference that primary publication..  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 62
16. REFERENCES
1.
Grosser T, Smyth E, FitzGerald GA. “Chapter 34. Anti-inflammatory, Antipyretic, and 
Analgesic Agents; Pharmacotherapy of Gout.” (Chapter). Bruner LL, Chamber BA, 
Knollman BC: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 
12e: http://www.accessmedicine.com/content.aspx?aID=16670422.
2.
Graham, GG, Scott KF. Mechanism of action of paracetamol. Am. J. Therap. 2005; 12: 
46-55.
3.
Anderson BJ. Paracetamol (acetaminophen): Mechanisms of action. Paediatr. Anaesth. 
2008; 18: 915-921.
4.
Davies NM. Clinical pharmacokinetics of ibuprofen: The first 30 years. Clin. 
Pharmacokin. 1998; 34: 101-154.
5.
Wright CE, Antal EJ, Gillespie WR, Albert KS. Ibuprofen and acetaminophen kinetics 
when taken concurrently. Clin. Pharmacol. Ther. 1983; 34: 707-701.
6.
Tanner T, Aspley S, Munn A, Thomas T. The pharmacokinetic profile of a novel 
fixed-dose combination tablet of ibuprofen and paracetamol. BMC Clin. Pharmacol. 
2010; 10: 10 (http://www.biomedcentral.com/1472-6904/10/10).
7.
Mehlisch DR, Aspley S, Daniels, SE, Bandy DP. Camparison of the analgesic efficacy 
of ibuprofen and paracetamol with ibuprofen or paracetamol alone in the management 
of moderate to severe acute postoperative dental pain in adolescents and adults: A 
randomized, double-blind, placebo-controlled parallel-group, single-dose, two-center 
modified factorial study. Clin Therap. 2010a; 32: 882-895.
8.
Mehlisch DR, Aspley S, Daniels SE, Southerden KA, Christensen KS. A single-tablet 
fixed dose combination of racemic ibuprofen/paracetamol in the management of 
moderate to severe postoperative dental pain in adult and adolescent patients: A 
multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, 
factorial study. Clin. Therap. 2010b; 32: 1033-1049.
9.
Cooper SA, Desjardins PJ,  The value of the dental impaction pain model in drug 
development.  Methods Mol Biol 2010; 617: 175 90.
10.
Radi, ZA and Khan NK. Effects of cyclooxygenase inhibition on the gastrointestinal 
tract. Exp. Toxicol. Pathol. 2006; 58: 163 173.
11.
Kumar G, Hota D, Saikia UM, Pandhi P. Evaluation of analgesic efficacy, 
gastrotoxicity and nephrotoxicity of fixed dose combinations of nonselective, 
preferential and selective cyclooxgenase inhibitors with paracetamol in rats. Exp. 
Toxicol. Pathol. 2010; 62; 653 662.
12.
Bhattacharya SK, Goel, RK, Bhattacharya, SK., Tandon, R. Potentiation of gastric 
toxicity of ibuprofen by paracetamol in the rat. J. Pharm. Pharmacol. 1991; 43: 520 521.


PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 63
13.
Doherty M, Hawkey C, Goulder M, Gibb I, Hill N, Aspley S, Reader S. A randomized 
controlled trial of ibuprofen, paracetamol, or a combination tablet of 
ibuprofen/paracetamol in community derived people with knee pain. Ann Rheum Dis 
2011; 70: 1534 41.


PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 64
Appendix 1. Abbreviations
This is a list of abbreviations used in the protocol.
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APAP
acetaminophen
AST
aminotransferase
CMH
Cochran Mantel Haenszel
COX-2
cyclooxygenase 2
eCRF
electronic case report form
EDP
exposure during pregnancy
CSA
clinical study agreement
DMC
data monitoring committee
EC
ethics committee
FDA
Food and Drug Administration (United 
States)
FDC
fixed dose combination
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
THC
tetrahydrocannabinol
IBU
ibuprofen
ICH
International Conference on Harmonisation
IND
Investigational New Drug
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
LFT
liver function tests
MAOI
monoamine oxidase inhibitor
NOAEL
no observed adverse effect level
NSAID
non-steroidal anti-inflammatory drug
OTC
over the counter
PCH
Pfizer Consumer Health
POC
proof-of-concept
PT
prothrombin time
PTT
partial thromboplastin time
SAE
serious adverse event
SAP
statistical analysis plan
SNRI
norepinephrine reuptake inhibitor
CCI
CCI
CCI
CCI


PF-06438867
Protocol Number: B5061004
Final Protocol Amendment 1, 09 February 2017 
PFIZER CONFIDENTIAL
Page 65
SOA
schedule of activities
SOC
system organ class
SPID
sum of pain intensity difference scores
 
SRSD
single reference safety document
SSRI
serotonin reuptake inhibitor
TCA
tricyclic antidepressant
 
ULN
upper limit of normal
US
United States
USPI
United States package insert
UTN
Universal Trial Number
CCI
CCI
CCI
CCI

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CCI
CCI
090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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CCI
090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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CCI
090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)


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090177e18d9e1ef1\Approved\Approved On: 30-Jan-2018 09:07 (GMT)