Conditions: Pain
Keywords: third molar extraction ibuprofen ibuprofen/caffeine post-surgical dental pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 374
Healthy volunteers: no

Brief summary:
An efficacy study assessing analgesic effect of ibuprofen/caffeine in post-surgical dental pain.

Detailed description:
The purpose of this study is to assess the analgesic efficacy of a fixed dose combination of ibuprofen/caffeine compared to ibuprofen alone and also to placebo.

Arms:
arm 1: Ibuprofen 400 mg/ Caffeine 100 mg fixed-dose combination arm 2: Ibuprofen 400 mg arm 3: Placebo comparator

Interventions: intervention 1: Ibuprofen/Caffeine intervention 2: Ibuprofen intervention 3: Placebo
Intervention descriptions: intervention 1: Ibuprofen/Caffeine fixed-dose combination intervention 2: Ibuprofen capsule intervention 3: Placebo treatment

Protocol document:
Prot_000.pdf: 


 
 
Pfizer Inc 
Pfizer Consumer Healthcare 
One Giralda Farms 
Madison, NJ 07940 
 
 
October 23, 2017 
 
RE: Protocol Administrative Changes and Clarifications for Study B3741002 – A PHASE 3, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY COMPARING THE 
ANALGESIC EFFICACY AND SAFETY OF A SINGLE ORAL DOSE OF A NOVEL FIXED-DOSE 
COMBINATION OF IBUPROFEN 400 MG WITH CAFFEINE 100 MG TO IBUPROFEN 400 MG 
AND TO PLACEBO IN THE TREATMENT OF POST-SURGICAL DENTAL PAIN IN OTHERWISE 
HEALTHY SUBJECTS 
 
Dear Investigator, 
 
This Protocol Administrative Change Letter (PACL) is to notify you of the following administrative 
changes and clarifications to the B3741002 protocol; version 13 Jul 2016: The edits described below are 
to clarify inconsistencies in the text of the protocol and provide administrative changes that do not impact 
the safety of subjects, the scope of the trial, or the scientific quality of the study, and therefore do not 
qualify as an amendment. 
This PACL makes the following changes: 
 
 
Page 8, under the Schedule of Activities, under section “e” – revise “staring” to “starting” 
 
Section 1.2, paragraph 3 – the statement beginning with “The results demonstrated the 
combination was 2.4 to 4.8 times more effective…” should actually state “The results 
demonstrated the combination was 2.4 to 2.8 times more effective…” 
 
Section 4.2, exclusion criteria #9 states: “Use of any type of systemic corticosteroid within the 
past 30 days or a history of current or previous use of anabolic steroids.” To clarify, systemic 
corticosteroids refer to oral corticosteroids and are disallowed. However, topical and inhaled 
corticosteroids are not considered systemic and are allowed. 
 
In the event that this protocol requires substantial changes in the future, the administrative changes 
described in this letter will be incorporated into the amended protocol. 
 
Please inform your institutional review board/independent ethics committee of these changes, as required. 
 
If you have any questions please feel free to contact me via email at 
 
 
Sincerely, 
 
 
 Ph.D. 
 Global Clinical Research 
Pfizer Consumer Healthcare 
One Giralda Farms, Madison, NJ 07940 
 
cc: Trial Master File 
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Caffeine with Ibuprofen 
B3741002
Final Protocol, 13 Jul 2016
Page 1
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
COMPARING THE ANALGESIC EFFICACY AND SAFETY OF A SINGLE ORAL 
DOSE OF A NOVEL FIXED-DOSE COMBINATION OF IBUPROFEN 400 MG
WITH CAFFEINE 100 MG TO IBUPROFEN 400 MG AND TO PLACEBO IN THE 
TREATMENT OF POST-SURGICAL DENTAL PAIN IN OTHERWISE HEALTHY
SUBJECTS
Investigational Product Number:
PF-06359262
Investigational Product Name:
Caffeine with Ibuprofen
United States (US) Investigational New 
Drug (IND) Number:
125,736
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
B3741002
Phase:
3
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Final Protocol, 13 Jul 2016
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Document History
Document
Version Date
Summary of Changes and 
Rationale
Original protocol
13 Jul 2016
Not applicable (N/A)
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Final Protocol, 13 Jul 2016
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................6
1. INTRODUCTION .................................................................................................................9
1.1. Mechanism of Action/Indication...............................................................................9
1.2. Background and Rationale ........................................................................................9
1.2.1. Design Rationale.........................................................................................10
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................10
2.1. Objectives................................................................................................................10
2.2. Endpoints.................................................................................................................10
2.2.1. Primary Endpoint........................................................................................10
2.2.2. Secondary Endpoints ..................................................................................11
3. STUDY DESIGN.................................................................................................................12
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................13
4.1. Inclusion Criteria.....................................................................................................13
4.2. Exclusion Criteria....................................................................................................14
4.3. Randomization Criteria ...........................................................................................17
4.4. Lifestyle Requirements ...........................................................................................17
4.4.1. Contraception..............................................................................................17
4.4.2. Dietary Restrictions ....................................................................................18
4.5. Sponsor’s Qualified Medical Personnel..................................................................18
5. STUDY TREATMENTS.....................................................................................................19
5.1. Allocation to Treatment ..........................................................................................19
5.2. Breaking the Blind ..................................................................................................20
5.3. Subject Compliance.................................................................................................20
5.4. Investigational Product Supplies.............................................................................21
5.4.1. Dosage Form(s) and Packaging..................................................................21
5.4.2. Preparation and Dispensing........................................................................21
5.5. Administration.........................................................................................................22
5.6. Investigational Product Storage ..............................................................................22
5.7. Investigational Product Accountability...................................................................23
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5.7.1. Destruction of Investigational Product Supplies ........................................23
5.8. Concomitant Treatment(s).......................................................................................24
5.9. Rescue Medication ..................................................................................................24
6. STUDY PROCEDURES .....................................................................................................25
6.1. Screening.................................................................................................................25
6.2. Day of Surgery ........................................................................................................26
6.3. Study Period ............................................................................................................26
6.3.1. Post-baseline Assessment...........................................................................27
6.4. End of Study Assessments ......................................................................................28
6.4.1. Follow-up Contact ......................................................................................28
6.5. Rescue Medication Assessments.............................................................................29
6.6. Subject Withdrawal/ Early Termination .................................................................29
7. ASSESSMENTS..................................................................................................................31
7.1. Baseline Efficacy Assessments ...............................................................................31
7.1.1. 11-Point Numerical Pain Severity Rating (NPSR).....................................31
7.1.2. VAS Pain Severity Rating Scale (VAS PSR).............................................32
7.2. Post-Baseline Efficacy Assessments.......................................................................32
7.2.1. Numerical Pain Severity Rating (NPSR)....................................................32
7.2.2. Categorical Pain Relief Rating (PRR) Scale ..............................................32
7.2.3. Time to First Perceptible Relief..................................................................33
7.2.4. Time to Meaningful Relief .........................................................................33
7.2.5. Global Evaluation.......................................................................................33
7.3. Laboratory Tests......................................................................................................34
7.3.1. Temperature................................................................................................34
7.3.2. Blood Pressure and Heart Rate...................................................................35
7.3.3. Respiratory Rate .........................................................................................35
7.4. Pregnancy Testing...................................................................................................35
7.5. Contraception Check...............................................................................................35
8. ADVERSE EVENT REPORTING......................................................................................36
8.1. Requirements...........................................................................................................36
8.1.1. Additional Details On Recording Adverse Events on the CRF..................37
8.1.2. Eliciting Adverse Event Information..........................................................37
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8.1.3. Withdrawal From the Study Due to Adverse Events (see Also the 
Subject Withdrawal Section) ...........................................................................37
8.1.4. Time Period for Collecting AE/SAE Information......................................37
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................38
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................38
8.1.5. Causality Assessment .................................................................................38
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................38
8.2. Definitions...............................................................................................................39
8.2.1. Adverse Events...........................................................................................39
8.2.2. Abnormal Test Findings .............................................................................39
8.2.3. Serious Adverse Events ..............................................................................40
8.2.4. Hospitalization............................................................................................41
8.3. Severity Assessment................................................................................................42
8.4. Special Situations ....................................................................................................42
8.4.1. Protocol-Specified Serious Adverse Events ...............................................42
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................43
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................44
8.4.3.1. Exposure During Pregnancy......................................................44
8.4.3.2. Exposure During Breastfeeding ................................................46
8.4.3.3. Occupational Exposure .............................................................46
8.4.4. Medication Errors .......................................................................................46
8.4.4.1. Medication Errors......................................................................46
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................47
9.1. Sample Size Determination.....................................................................................47
9.2. Efficacy Analysis ....................................................................................................47
9.2.1. Analysis Populations ..................................................................................47
9.2.1.1. Primary Analysis Set.................................................................47
9.2.1.2. ‘Per Protocol’ Analysis Set .......................................................48
9.2.2. Analysis of the Primary Endpoint...............................................................48
9.2.3. Analysis of Secondary Endpoints...............................................................48
9.2.4. Adjustment for Multiple Comparisons.......................................................48
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9.2.5. Derivation of Endpoints..............................................................................48
9.2.6. Data Conventions/ Handling of Missing Data............................................49
9.4. Safety Analysis........................................................................................................50
9.5. Interim Analysis ......................................................................................................50
9.6. Data Monitoring Committee ...................................................................................50
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................50
11. DATA HANDLING AND RECORD KEEPING .............................................................51
11.1. Case Report Forms/Electronic Data Record .........................................................51
11.2. Record Retention...................................................................................................52
12. ETHICS..............................................................................................................................52
12.1. Institutional Review Board/Ethics Committee......................................................52
12.2. Ethical Conduct of the Study ................................................................................52
12.3. Subject Information and Consent..........................................................................53
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................54
13. DEFINITION OF END OF TRIAL...................................................................................54
14. SPONSOR DISCONTINUATION CRITERIA ................................................................54
15. PUBLICATION OF STUDY RESULTS..........................................................................54
15.1. Communication of Results by Pfizer ....................................................................54
15.2. Publications by Investigators ................................................................................55
16. REFERENCES ..................................................................................................................57
LIST OF TABLES
Table 1.
Investigational Product Description .....................................................................19
Table 2.
Study Number Assignment Sequence ..................................................................20
Table 3.
Laboratory Tests ...................................................................................................34
APPENDICES
Appendix 1. Abbreviations......................................................................................................59
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1. INTRODUCTION
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
Caffeine, a methylxanthine, behaves as a competitive adenosine receptor antagonist at the A1 
and A2 receptors, when plasma concentrations are between 10-100 µM, which has directly 
been implicated in action of caffeine in humans including the blockage of hyperalgesic 
effects of adenosine.2
1.2. Background and Rationale
Ibuprofen (IBU) is one of the most widely used nonprescription analgesic/antipyretic agents 
available. Serum concentrations of IBU have demonstrated a linear relationship to the level 
of analgesia.4 The 400 mg strength of IBU is considered to be the most efficacious over-the-
counter (OTC) dose of IBU in terms of efficacy and safety when compared to other available 
OTC NSAIDs.7,8
Caffeine, a methylxanthine, exerts a variety of pharmacological actions both peripherally and 
centrally in the body.9 Generally, when caffeine is consumed in foods and drinks, the intake 
of caffeine can be classified into three broad categories: low (<100 mg per day), moderate 
(100-400 mg per day), and high intake (>400 mg per day), with a majority of individuals 
falling into the moderate consumption category.5,6 Caffeine is also available as an oral 
pharmacologic agent at doses of 100-200 mg every 3-4 hours as needed for somnolence.2
Clinical studies have demonstrated that the combination of NSAIDs with caffeine is more 
effective than the NSAID alone in postpartum, headache, and postsurgical (dental) pain 
states.3 Forbes et al, intended to quantify the relative incremental efficacy of the addition of 
caffeine 100 mg with IBU 100 mg and 200 mg using the postsurgical dental pain model. The 
results demonstrated the combination was 2.4 to 4.8 times more effective than IBU alone, 
and that the combination provides more rapid onset and longer duration of analgesic effect
than IBU alone.4 Subsequent studies of the combination of IBU with caffeine have shown 
that it may provide similar enhancement of analgesic effect versus the IBU alone and placebo 
in dental pain, post-episiotomy pain, tension headache, migraine headache, and 
dysmenorrhea pain.10,11,12,13
Pfizer Consumer Healthcare (PCH) has developed a novel fixed-dose liquid-filled gelatin
capsule (subsequently referred to as liquid capsule) formulation consisting of 400 mg IBU 
with 100 mg of caffeine. The aim of this clinical study is to evaluate the relative analgesic 
efficacy of this novel formulation of IBU 400 mg with 100 mg of caffeine in a liquid capsule 
compared to IBU liquid capsule alone, providing consumers with a novel more effective 
formulation of IBU 400 mg for extra-strength pain relief.
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PCH has not conducted any previous efficacy or safety studies using the IBU with caffeine 
combination. However, recently Boehringer Ingelheim has completed a study that has shown
positive results with the combination of IBU and caffeine. However, a full publication is not 
yet available.  Their preliminary data in abstract form suggest that the combination of IBU 
400 mg and caffeine 100 mg provides 30-50% greater reduction in pain over 0-8 hours and 
0-2 hours versus IBU alone.14
IBU and caffeine individually have safety and efficacy information that is available in the 
literature. Additional information for this compound may be found in the single reference 
safety document (SRSD), which for this study is the Investigator’s Brochure (IB) for the 
combination of IBU with caffeine. The SRSD for the comparator is the IB for Ibuprofen as a 
single agent.
1.2.1. Design Rationale
The dental pain model was chosen for this trial because the surgical procedure is elective, 
relatively consistent, and has a proven record of assay sensitivity, ie, separating active drugs 
from one another as well as from placebo.  This acute pain model is accepted by the 
Agencies of interest for the proposed application and is the most widely used model to 
evaluate the efficacy of NSAID-type analgesics.  The results from dental pain studies have 
been widely extrapolated to other general pain conditions including the most common non-
prescription pain indications. The design of this study was presented and agreed to by the 
Agencies of interest, Health Canada and ANVISA (Agência Nacional de Vigilância 
Sanitária; Brazilian Health Surveillance Agency), with the intent of obtaining market 
approval for the same indication and dosing schedule as the currently marketed IBU liquid 
capsule formulation.
The patient-reported outcomes (PROs) and design elements of this study have been described 
in further detail and are recommended in the Food & Drug Administration (FDA) Draft 
Guidance for Industry Analgesic Indications: Developing Drug and Biological Products.15
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
The primary objective of this study is to assess analgesic efficacy of a single oral dose of 
IBU 400 mg plus caffeine 100 mg, versus IBU 400 mg alone, and placebo, in subjects 
undergoing dental surgery for third molar extraction.
The secondary objective of the study is to assess the safety and tolerability of IBU 400 mg
with caffeine 100 mg, IBU 400 mg, and placebo.
2.2. Endpoints
2.2.1. Primary Endpoint

Time-weighted sum of pain relief rating (PRR) and pain intensity difference (PID) 
from 0 to 8 hours (SPRID0-8) for IBU 400 mg with caffeine 100 mg versus IBU 
400 mg.
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4. SUBJECT ELIGIBILITY CRITERIA
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.  
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Males and females 16 years to 40 years of age (inclusive).
2. Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; and have a serum follicle-stimulating hormone (FSH) level confirming the 
postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are considered 
to be of childbearing potential. 
3. In good general health, and have no contraindications to any of the investigational 
products, rescue medications, or anesthetic drugs.
4. 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. Subjects requiring a parent or legal 
guardian to sign the informed consent form will also be required to sign an assent
document.
5. Subjects who have undergone outpatient surgical extraction of 3 or more third molars, of 
which at least 2 must be a partial or complete bony mandibular impaction within 30 days 
of Screening and have met baseline pain criteria as described in this protocol. (Note: 
dosing of study medication must occur within approximately 5 hours (ie, less than or 
equal to 5 hours, 15 minutes) after surgery is complete).
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6. Subjects who are medically eligible to use 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.
7. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests and other study procedures.
8. Reliable, cooperative, and of adequate intelligence to record the requested information on 
the analgesic questionnaire form.
9. Subjects who are willing and able to comply with the Lifestyle Guidelines listed in
Section 4.4.
10. Examined by the attending dentist or physician and medically cleared to participate in the 
study.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, metabolic or allergic 
disease (including drug allergies, but excluding untreated, asymptomatic, seasonal 
allergies at the time of dosing) 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:

Bleeding disorder;

Gastrointestinal ulcer or gastrointestinal bleeding;

Paralytic ileus or other gastrointestinal obstructive disorders.
2. Other severe acute or chronic medical or psychiatric condition including recent (within 
the past year) or active suicidal ideation or behavior 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 inappropriate for entry into this 
study.
3. Subjects at risk for excessive bleeding, eg, those on anticoagulant therapy, etc.
4. Acute localized dental alveolar infection at the time of surgery that could confound the 
post-surgical evaluation.
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5. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female 
subjects of childbearing potential who are unwilling or unable to use a highly effective 
method of contraception as outlined in this protocol for the duration of the study and for 
14 days after the last dose of investigational product.
6. Hypersensitivity to ibuprofen, naproxen, aspirin, or any other NSAID, caffeine, or other 
component of the product.
7. History of asthma, urticaria, or other allergic-type reaction following aspirin or other 
NSAID or caffeine administration.
8. Use of a prescription or over the counter (OTC) drug with which administration of IBU,
caffeine, or any other NSAID; codeine, tramadol or any other opioid is contraindicated
and in the opinion of the Investigator will harm the subject to be included in the study
(including: opioids, antipsychotics, antianxiety agents, or other central nervous system 
depressants [including alcohol]).
9. Use of any type of systemic corticosteroid within the past 30 days or a history of current 
or previous use of anabolic steroids.
10. Use of prescription or OTC antihistamines within 24 hours prior to taking study
medication.  (Note exceptions: loratadine [Claritin®], desloratadine [Clarinex®], cetirizine 
[Zyrtec®], levocetirizine [Allegra®], and azelastine [intranasal, Astelin®]).
11. Habituation to analgesic medications or caffeine (ie routine use of oral analgesics 5 or
more times per week or ingestion of 4 or more caffeine-containing drinks daily); 
consumption of caffeine-containing “high energy” drinks (eg, Red Bull, Monster, etc.) 
more than once per week.
12. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at least 
5 minutes of supine rest.  If BP is 140 mm Hg (systolic) or 90 mm Hg (diastolic), the 
BP should be repeated two more times and the average of the three BP values, which are 
taken approximately 5 minutes apart, should be used to determine the subject’s eligibility.
13. Subjects who have ingested any caffeine-containing beverages, chocolate or alcohol, 
within 48 hours prior to taking study medication.
14. Inability or unwillingness to comply with the requirements of the protocol as judged by
the Investigator.
15. Use of a bisphosphonate (eg, pamidronate [Aredia®], risedronate [Actonel®], alendronate 
[Fosamax®], or ibandronate [Boniva®]) within the past 5 years.
16. Prior use of any type of analgesic or NSAID within five half-lives of that drug or less 
before taking the first dose of study medication, except for pre-anesthetic medication and 
anesthesia required for the surgical procedure.
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17. 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).

Patients 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).
18. 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. Patients 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.
19. Clinically significant abnormalities on the screening laboratory tests determined by the 
Investigator or designee that would place the subject at increased risk, or subjects with 
ANY of the following abnormalities in clinical laboratory tests at screening, as assessed 
by the study-specific laboratory and confirmed by a single repeat, if deemed necessary:  

Aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT)  
or alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) 
3 × upper limit of normal (ULN);

Total bilirubin (Tbili) 1.5 × ULN; subjects with a history of Gilbert's syndrome may 
have a direct bilirubin measured and would be eligible for this study provided the 
direct bilirubin is less than or equal to ULN;

Hemotologic abnormality that is judged by the Investigator to be clinically 
significant, as evidenced by screening hematology assessment. 
20. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
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21. 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, including their family members,
directly involved in the conduct of the study.
4.3. Randomization Criteria 
Subjects must have at least a pain severity score of ≥5 on the 0-10 NPSR, confirmed by 
≥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 to be eligible for randomization.
4.4. Lifestyle Requirements
4.4.1. Contraception
All fertile male subjects and female subjects who are of childbearing potential as applicable 
to the study who are, in the opinion of the investigator, sexually active and at risk for 
pregnancy with their partner(s) must agree to use a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for 14 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 from the permitted list of contraception 
methods (see below) and will confirm that the subject has been instructed in its consistent 
and correct use.  At time points indicated in the Schedule of Activities, the investigator or 
designee will inform the subject of the need to use highly effective contraception consistently 
and correctly and document the conversation and the subject’s affirmation in the subject’s 
chart (subjects needs to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or 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 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 associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’s female partner 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.
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4. Male sterilization with absence of sperm in the postvasectomy 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).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the 
investigational products) may obviate the need for contraception ONLY if this is the 
preferred and usual lifestyle of the subject.
4.4.2. Dietary Restrictions
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, clear liquids or gelatin may be provided to the subject prior to surgery.  
Subjects may not ingest any caffeine containing beverages, chocolate, or alcohol within 
48 hours prior to taking study medication or during the entire 8 hour evaluation period.
No food will be allowed following surgery through 2 hours after the ingestion of study 
medication.  Low fat (≤20% of calorie intake from total fat)10 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 
pain assessment time point.  The times of food consumption will be recorded in the source 
document.
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 located in the supporting study documentation.
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 product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator 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 number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator 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 investigator site.
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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator 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).  
For this study, the investigational product(s) are: 
Table 1.
Investigational Product Description
Strength and Product 
Identification
Dosage Form and 
Package Size
Route of 
administration
Test
Ibuprofen 400 mg + caffeine 
100 mg 
Advil Migraine Liqui-Gels 
(International, Unprinted)
(WH-1769-0002-001)
Liquid filled gelatin 
capsule unprinted
(72-count bottle)
Oral
Active 
Comparator
Ibuprofen 400 mg 
Advil Extra Strength LiquiGels 
(Canada)
(WH-1121-0004-001)
Liquid filled gelatin 
capsule printed
(80-count bottle)
Oral
Placebo
Placebo capsule
Placebo for Advil Migraine 
Liqui-Gels II (Unprinted)
(WH-0689-0017-001))
Liquid filled gelatin 
capsule unprinted 
(identical to Test 
product; 72-count 
bottle)
Oral
5.1. Allocation to Treatment
Treatment assignments will be determined by a computer generated randomization schedule
and will be maintained by Pfizer Global Randomization Operations team. 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 study medication will have access to the 
randomization schedule and dispensing records during the study period.
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Subjects will be stratified by gender and baseline pain severity (moderate or severe, where a 
score of 5 to 7 on the 11-point NPSR will be classified as “moderate”  and a score of 8 to
10 will be classified as “severe”), and be randomized to receive one of the following study 
medications in a 3:3:1 ratio:

Test: IBU 400 mg with caffeine 100 mg liquid capsule;

Active Comparator: Advil Extra Strength LiquiGels® 400 mg liquid capsule;

Placebo (administered as a liquid capsule).
Randomization numbers will be assigned in consecutive ascending order within each stratum 
as shown in Table 2. The site will be provided with sufficient study medication to allow for 
the enrollment of approximately 385 subjects.
Table 2.
Study Number Assignment Sequence
Gender
Baseline Pain
Randomization Number Series (allocation system)
Male
Moderate
Ascending 10000 series (eg, 10001, 10002, 10003, …)
Male
Severe
Ascending 20000 series (eg, 20001, 20002, 20003, …)
Female
Moderate
Ascending 30000 series (eg, 30001, 30002, 30003, …)
Female
Severe
Ascending 40000 series (eg, 40001, 40002, 40003, …)
Note: Subjects will also be assigned an 8-digit enrollment ID number at Screening.
5.2. Breaking the Blind
The study will be investigator- and subject-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 should consult 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 in the case report form (CRF).
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 investigational product 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 Sponsor’s Clinician 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 be recorded in the CRF and in the source 
document. Any AE or serious adverse events (SAE) associated with breaking the blind must 
be recorded and reported as specified in this protocol.
5.3. Subject Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigator site.
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5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
The Sponsor will provide the investigational products described above in bulk and will send 
prepared labels for the corresponding medication to the site.  
Rescue medications, tramadol and codeine, will be supplied by the site.
5.4.2. Preparation and Dispensing
The Sponsor, PCH Clinical Supplies will provide instructions on how to prepare the 
investigational product for administration.  Investigational product (ie, study medication and 
placebo) and rescue medication should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, practitioner, or pharmacist) as allowed by local and state laws, and institutional 
guidance. 
On the day of surgery, each subject entered into the study will be given one dose (1 liquid 
filled capsule) of the randomly assigned investigational product with approximately 
6-8 ounces of room temperature water when they are experiencing post-surgical pain of at 
least moderate severity.  From the time that study medication is taken, the duration of 
evaluation will be 8 hours.
The Sponsor will supply the investigational products in bulk and in an unblinded fashion.  
PCH Consumer Study Supplies will provide randomization codes generated by the Pfizer 
Global Randomization Operations directly to the individual identified by the study site.  A 
documentation packet consisting of the investigational product dispensing record that will 
contain the randomization codes and 2-part double-blind labels will be provided to the 
assigned third party person(nel) only.  Opaque plastic bottles and caps will be supplied 
separately from the labels to the third party person(nel) as well.
The third party dispenser will prepare study medication for each subject in a designated 
dispensing room.  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 by the appropriately qualified site staff member, 
just prior to the completion of the baseline NPSR for pain severity and VAS PSR.  The study 
coordinator will communicate the subject’s pain severity to the dispenser.  If qualified for 
randomization, the dispenser will assign the next available randomization number.  The 
dispenser will dispense the randomized investigational product (2 liquid-filled gelatin 
capsules per dose) 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 identification tab will be affixed to 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.
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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 qualifying baseline pain assessments by the third party dispenser. To 
maintain blinding to study treatments, no other study personnel should be present at the time 
of dosing.
After the subject has been blindfolded, while the subject is sitting up, the dispenser will give 
the capsule to the subject with approximately 6-8 ounces of room temperature water 
(Time=0). Subjects will swallow the study medication 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 comparator and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  
Any storage conditions stated in the IB will be superseded by the storage conditions stated on 
the product label.
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 evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
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temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  
Upon receipt at the study site, the carton containing the investigational product will be stored 
unopened in the study treatment storage room.  The Principal Investigator or an appropriate 
designee, and a representative of PCH will conduct an inventory and complete the study
treatment inventory record, preferably at study initiation, but prior to first subject first visit 
(FSFV).  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 Principal Investigator or an appropriate designee, upon dispensing the investigational 
product, must record the information in an investigational product dispensing/return log.  For 
accounting purposes and assessing subject compliance, a representative of PCH will review 
the investigational product dispensing/return log, inventory the investigational product, and 
inspect the storage facility at appropriate time intervals throughout the clinical investigation, 
depending on the length of the study. The Principal Investigator must account for any 
significant discrepancy and/or deficiency.
5.7.1. Destruction of Investigational Product Supplies 
All investigational products shipped for this clinical trial will be returned to the Sponsor upon 
conclusion or 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 product.  PCH will retain the original shipment documentation 
and inventory record, and the Investigator will retain a copy for his/her files.  All used 
investigational product (empty containers), as well as all unused investigational product will 
then be returned to:
Pfizer Consumer Healthcare
Consumer Study Supplies
1211 Sherwood Avenue
Richmond, VA 23220
Attention: Returned Study Supplies
Protocol No.  B3741002
(804) 257-2905
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5.8. Concomitant Treatment(s)
Rescue medication as defined in Rescue Medication, will be allowed during the course of the 
study. Ice packs may only be applied once the subject has completed the 2-hour pain 
assessment, and they may not be applied within 30 minutes prior to any other pain 
assessment.  
Except for the above treatments, no other treatments expected to confound the evaluation of 
the investigational product. All concomitant medications used during the study will be 
recorded in the case report form. Antibiotics are permitted at the discretion of the 
Investigator.
5.9. Rescue Medication
Rescue medications should be dispensed and administered by an appropriately qualified 
member of the site in accordance with state and local laws, and institutional guidance.
Subjects not experiencing adequate relief after the one-hour time point evaluation may be 
given tramadol hydrochloride (immediate release tablets) 50 to 100 mg orally, based on the 
discretion of the Investigator, as rescue medication.  If needed, subjects may receive up to 
2 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 
8 hours after dosing with study medication).  The total maximum dose of tramadol, which 
may be taken at the study center, is 300 mg (total daily dose should not exceed 400 mg).
Alternatively, any subject not experiencing adequate relief after the one-hour time point 
evaluation may be given 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 up to 2 additional doses of rescue medication (ie, codeine sulfate 15 to 60 mg orally 
every 4 hours as needed (prn) [based on the discretion of the Investigator]) at the study center 
(ie, within 8 hours after dosing with study medication). The total maximum dose of codeine
sulfate, which may be taken at the study center, is 180 mg (total daily dose should not exceed 
360 mg).
Subjects may not take any study rescue medication home with them.
Subjects who take rescue medication during the course of the evaluation period will remain 
in the study for the full 8-hour duration and continue to perform their efficacy assessments.  
Subjects taking rescue medication within one hour after dosing will be considered 
discontinued and must be replaced.  They will remain in the study for the full 8-hour duration 
and continue to perform their efficacy assessments.
The use of rescue medication will be recorded in the appropriate section of the CRF.  The 
date, time, name of rescue medication taken, and reasons for use will be recorded.
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6. STUDY PROCEDURES 
6.1. Screening
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 in 
order to determine the subject’s eligibility.  Screening procedures include:

Informed consent/assent;

Review Inclusion and Exclusion criteria;

Demographic information;

Medical history including history of drug and alcohol use;

Prior medications;

Vital signs, including sitting blood pressure (BP), heart rate (HR), respiratory rate
(RR), temperature (T);

Contraception check;

Assess for spontaneous reporting of adverse events and/or serious adverse events
(AEs/SAEs) by asking the subjects to respond to a non-leading question such as 
“How do you feel?

Laboratory testing (See Laboratory Tests for further details); Following at least a 
4-hour fast, collect blood and urine specimens for the following:  

Hematology; 

Blood chemistry (complete metabolic panel);

Urinalysis; 

Coagulation tests;

Serum pregnancy test (females of CBP only);

Serum FSH (post-menopausal women only).
Screening procedures must be completed within 30 days of the surgery. Subjects will be 
screened only once and are assigned a screening number.  Subjects may undergo screening 
procedures again only if the surgery cannot be scheduled within 30 days. 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 and Enrollment Record (provided by PCH) will be maintained to 
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document all subjects screened for entry into the study.  All subjects/parent(s)/legal 
guardian/legally acceptable representative will provide written informed consent before 
participating in the study.  Subjects are required to read, comprehend, and sign the informed 
consent/assent.
6.2. Day of Surgery
Surgery will be scheduled within 30 days of the screening visit.
Subjects will not be allowed to wear a watch during the study, and they may not have access 
to a clock, including mobile electronic devices that display time.  Furthermore, stopwatches 
used in the study will have the time display covered when in use by the subject.
Day of Surgery procedures that should be completed prior to surgery include: 

Review Inclusion and Exclusion criteria;

Check for concomitant medications (assessed through hour 8);

Assess for any AEs or SAEs (assessed through hour 8): An assessment of symptoms 
should be completed for spontaneous reporting of adverse events by asking the 
subjects to respond to a non-leading question such as “How do you feel?”

Females of child-bearing potential (CBP) must be given a urine pregnancy test on the 
morning of, but before the surgery.
Upon surgery, the following will be noted and recorded on the CRF:

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); 

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 scale;

The time of the last meal prior to surgery will be noted in the source document only.
6.3. Study Period
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.  
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Subjects will be asked to rest quietly at the study center until they experience post-surgical 
pain at a level that meets the entry criteria for randomization (See Randomization Criteria).  
At that time, subjects will be asked to complete the baseline 11-point Numerical Rating Scale 
and the 100 mm VAS PSR scale.

11-point Numerical Pain Severity Rating (NPSR);

A minimum score of 5 out of 10 must be indicated before the subject can enter the 
trial. The NPSR will be assigned a whole number value where 0= none and 10= 
worst possible pain.

VAS Pain Severity Rating Scale (VAS PSR);

A minimum score of 50 mm on the VAS PSR is required to confirm that the 
subject has at least moderate pain at baseline in order to be randomized.  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 6 or greater on NPSR
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 randomized to 
receive investigational product.
Baseline vital signs (HR, BP, RR, and T) will also be measured and recorded and should be 
complete within approximately 15 minutes prior to dosing. 
Upon completion of the baseline scales, eligible subjects will be randomized to receive a 
single oral dose of investigational product (consisting of 2 liquid-filled capsules) under 
double blind conditions. Investigational product must be administered within approximately 
7 minutes of baseline measurements.  The time of dosing “time 0” is recorded in the source 
and CRF.
When the subject is administered study medication at time 0, the Study Coordinator will start 
two stopwatches (see Time to First Perceptible Relief and Time to Meaningful Relief for 
further details). 
Throughout the study period, an assessment of symptoms should be completed for reporting
of adverse events by asking the subjects to respond to a non-leading question such as “How 
do you feel?”
6.3.1. Post-baseline Assessment
The following assessments will be conducted at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours 
post-dose:

11-point NPSR;
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
5-point Categorical PRR Scale. 
Subjects will also evaluate the time to “First Perceptible” Relief by depressing a stopwatch at 
the moment they first begin to experience “perceptible” relief as well as the time to 
“Meaningful” Relief by depressing a second stopwatch at the moment they first begin to 
experience “meaningful” relief (see Time to First Perceptible Relief and Time to Meaningful 
Relief for further details).  These elapsed times will be recorded up to 8 hours after dosing, or 
until the time of (first) rescue medication use, whichever is sooner.
6.4. End of Study Assessments
At the 8-hour assessment for the study, ie, after the last efficacy assessment is collected and 
assuming there are no outstanding AEs of concern, the subject will undergo the following
study assessments.  
At this time, the following procedures will be completed:

6-point Categorical Global Evaluation of the study medication;

Assess vital signs (ie, HR, BP, RR, and T) within 15 minutes of last collection of 
efficacy assessments;

Review of any reported AE/SAEs;

Assess for concomitant treatments;

Laboratory test;

Contraception check; 

Discharge from clinical research unit (CRU).
For any subject with outstanding AEs, the end of study procedures are performed after the 
Principal Investigator is satisfied that all AEs are resolved. In the event that the subject is 
unwilling to complete end of study assessments, every effort should be made to contact the 
subject and document outcome appropriately.
6.4.1. Follow-up Contact
Follow-up contact will be completed at least 14 calendar days, and up to 17 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the subject 
will be done via a phone call.
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6.5. Rescue Medication Assessments
The following assessments will be conducted immediately before (within 5 minutes) the first 
use of rescue medication or at the time of withdrawal (if applicable):

11-point NPSR; 

5-point categorical PRR Scale; 

6-point categorical Global Evaluation of the study medication;

Assess for AE/SAEs;

Vital signs (ie, HR, BP, T, and RR) will be measured and recorded within 15 minutes 
of administration of the rescue medication.  
6.6. Subject Withdrawal/ Early Termination
Subjects will be withdrawn from the study at any time under the following circumstances:

Any subject who violates any condition of the entrance criteria after having been 
entered into the study;

Any subject who reports inadequate relief and requires rescue medication prior to one 
hour after taking the study medication;

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 investigational product;

Any subject who becomes uncooperative, does not adhere to the requirements of the 
study protocol, or refuses to complete the study;

Any subject who requires any concomitant medication (other than rescue medication) 
during the course of the study that could confound the study results;

Any subject who vomits within 1 hour following dosing.
The following assessments will be conducted at the time of withdrawal/Early Termination, if 
possible:

11-point NPSR;

5-point categorical PRR Scale; 

6-point categorical Global Evaluation of the study medication;

Assess vital signs (ie, HR, BP, T, and RR);
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
Contraception Check;

Review of any reported AE/SAEs;

Assess for concomitant treatments;

Discharge from clinical research unit (CRU).
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved. The early termination visit 
only applies to subjects who are randomized and then are prematurely withdrawn from the 
study.
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or post-treatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
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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 (see also the 
Withdrawal From the Study Due to Adverse Events section) 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 that the subject return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved adverse events (AEs) or serious 
adverse events (SAEs).
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.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.  
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 manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Baseline Efficacy Assessments
7.1.1. 11-Point Numerical Pain Severity Rating (NPSR)
The 11-point NPSR for pain severity will be completed at all of 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
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Subjects will be instructed to circle the number that best matches their pain severity. A score 
of 5 or above must be indicated to confirm subject entry into the trial. Subjects with a score 
of 5 to 7 are considered to be moderate pain and a score of 8 to 10 will be considered to be 
severe pain.
7.1.2. VAS Pain Severity Rating Scale (VAS PSR)
The 100 mm VAS PSR is administered after the NPSRand will also be used to rate the 
severity of baseline pain.  Subjects will be instructed to:
"Draw a single vertical line on the scale that shows how much pain you have at this time."
None
Severe
(Figure not to scale)
Scores on the 100 mm linear scale will be measured to the nearest millimeter from the left 
(none=0 to severe=100).  A minimum score of 50 mm is required to confirm that the subject 
has reached an appropriate level of pain measured by the 11-point NPSR 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. Post-Baseline Efficacy Assessments
7.2.1. Numerical Pain Severity Rating (NPSR)
The 11-point NPSR for pain severity will be completed at all of 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.
7.2.2. Categorical Pain Relief Rating (PRR) Scale
The 5-point Categorical Pain Relief Rating (PRR) Scale will be completed at the times 
specified in the Schedule of Activities, and immediately before rescue medication is taken 
(for the first time, as necessary) or at the time of withdrawal, to evaluate pain relief in 
response to the question:
"How much relief do you have from your starting pain?"
None               A Little               Some               A Lot               Complete
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Each category on this scale will be assigned a whole number value of 0 (none), 1 (a little), 
2 (some), 3 (a lot), or 4 (complete) and the corresponding number will be recorded in the 
CRF.
7.2.3. Time to First Perceptible Relief
When the subject is administered study medication at time 0 hours, the Study Coordinator 
will start two stopwatches.  Each stopwatch will have its face covered; one will be labeled 
“first perceptible relief” and the other “meaningful relief.”  In an effort to determine the exact 
moment that the subject begins to obtain noticeable pain relief, the subjects will be given the 
stopwatch labeled “first perceptible relief” and will be instructed as follows:
“Stop the stopwatch when you first begin to feel any pain relieving effect whatsoever of 
the drug.  That is, when you first feel a little relief.  This does not necessarily mean that 
you feel completely better, although you might, but when you first feel any difference in 
the pain that you have now.”
The elapsed time of this stopwatch will be recorded in the CRF.  The stopwatch will remain 
active for 8 hours, until stopped by the subject, or until rescue medication is administered.
7.2.4. Time to Meaningful Relief
In an effort to determine the exact moment that the subject begins to obtain meaningful pain 
relief, the subjects will be given the stopwatch labeled “meaningful relief” and 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 of this stopwatch will be recorded in the CRF.  The stopwatch will remain 
active for 8 hours, until stopped by the subject, or until rescue medication is administered.
7.2.5. Global Evaluation
At the time points specified in the Schedule of Activities (at the 8-hour time-point), or 
immediately before taking rescue medication (for the first time, as necessary), a Global 
Evaluation of the study medication will be performed.  The Global Evaluation, on a 6-point 
categorical scale, will be performed in response to the following question:
"How would you rate this medication as a pain reliever?"
Very Poor        Poor         Fair         Good         Very Good         Excellent
Responses on this categorical scale will be assigned values of 0 (Very Poor), 1 (poor), 
2 (fair), 3 (good), 4 (very good) or 5 (Excellent) and the corresponding number will be 
recorded in the CRF.
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7.3. Laboratory Tests
The following safety laboratory tests will be performed at screening.  Additional laboratory 
results may be reported on these samples as a result of the method of analysis or the type of 
analyzer used by the clinical laboratory; or as derived from calculated values.  These 
additional tests would not require additional collection of blood.  Unscheduled clinical labs 
may be obtained at any time during the study to assess any perceived safety concerns. All 
laboratory data will be collected in the source documentation.
Table 3.
Laboratory Tests
Hematology
Blood Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
RBC
WBC
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Hyaline Casts
Granular Casts
Epithelium
Bacteria
Crystals
Mucous Threads
Microscopya
FSHb
β-hCGc
Coagulation
PT
PTT
INR
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
At Screening only, in female subjects who are amenorrheic for at least 12 consecutive months.
c.
Serum β-hCG at screening, and urine β-hCG pregnancy test at all other listed time points for females of childbearing 
potential.
RBC = red blood cell; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; WBC = white blood cell; Abs = absolute; BUN = blood urea nitrogen; AST = 
aspartate transaminase; ALT = alanine transaminase; pH= potential of Hydrogen; PT = prothrombin time; PTT= partial 
thromboplastin time; INR = international normalized ratio; qual = qualitative; FSH = follicle-stimulating hormone; β-hCG 
= beta human chorionic gonadotropin
7.3.1. Temperature 
Oral temperature will be measured at times specified in the STUDY PROCEDURES section 
and recorded in the source document and CRF to the nearest 0.1° Fahrenheit. No eating, 
drinking or smoking is allowed for 15 minutes prior to the measurement (with the exception 
of baseline measurement following dosing). Additional collection times, or changes to 
collection times will be permitted, as necessary, to ensure appropriate collection of safety 
data.
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7.3.2. Blood Pressure and Heart Rate
BP and HR will be measured at times specified in STUDY PROCEDURES section of this 
protocol.  Additional collection times, or changes to collection times of blood pressure and 
pulse rate will be permitted, as necessary, to ensure appropriate collection of safety data.
Sitting BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after at least approximately 5 minutes of rest. Repeated 
measures should be taken after 5 minutes of rest as well. When possible the same arm 
(preferably the dominant arm) will be used throughout the study. Subjects should be 
instructed not to speak during measurements.
The same properly sized and calibrated blood pressure cuff will be used to measure BP each 
time.  The use of an automated device for measuring BP and pulse rate is acceptable, 
although, when done manually, pulse rate will be measured in the brachial/radial artery for at 
least 30 seconds.  When the timing of these measurements coincides with a blood collection, 
BP and HR should be obtained prior to the nominal time of the blood collection and recorded 
to the nearest mm Hg in the source and CRF.
7.3.3. Respiratory Rate
Respiratory rate (RR) will be measured after approximately 5 minutes rest in sitting position 
by observing and counting the respirations of the subject for 30 seconds and multiplied by 2.  
When BP is to be taken at the same time, respiration measurement will be done during the 
5 minutes of rest and before BP measurement. Measurements will be recorded to the nearest 
breaths per minute in the source and CRF.
7.4. 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 and a urine pregnancy test of the same 
sensitivity will be performed at admission before investigational product administration at 
the baseline visit to confirm the subject has not become pregnant during the study.  
A negative pregnancy test result is required before the subject may receive the investigational 
product.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy 
tests may also be repeated if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.
7.5. Contraception Check
Subjects need to affirm that they meet adequate methods of contraception as outlined in the 
protocol. The investigator or his/her designee will discuss with the subject the need to use 
highly effective contraception consistently and correctly according to the schedule of 
activities (SOA) and document such conversation in the source document. In addition, the 
investigator or his/her designee will instruct the subject to call immediately if a selected 
contraception method is discontinued or if pregnancy is known or suspected.
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) non-
serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
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subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious 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.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian/legally acceptable representative.  In 
addition, each study subject/parent(s)/legal guardian/legally acceptable representative will be 
questioned about the occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see Also the Subject 
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject /parent(s)/legal guardian/legally 
acceptable representative provides informed consent, which is obtained before the subject’s 
participation in the study (ie, before undergoing any study-related procedure and/or receiving 
investigational product), through and including a minimum of 14(+3) calendar days after the 
last administration of the investigational product.  At Day 14 (or up to Day 17) following the 
last administration of study medication (final telephone contact), the subject /parent(s)/legal 
guardian/legally acceptable representative will be contacted by telephone to inquire about 
SAEs, including hospitalizations and newly diagnosed chronic medical conditions since the 
day of the surgery when the last study medication was administered.
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For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety 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 must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship on the CRF, 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.  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 CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. 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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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or
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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) 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 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event 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;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
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.
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8.2.4. 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 is 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 a persistent pretreatment 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 SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, 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.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
Unless the investigator believes that there is a causal relationship between the 
investigational product and an event specified below, these events should not be 
reported to Pfizer Safety by the investigator as SAEs.  These events are anticipated to 
occur commonly in a population requiring surgical extraction. However, these events should 
still be recorded as AEs on the CRF.
Protocol-specified SAEs that will not normally be reported to Pfizer Safety in an expedited 
manner: 

Paresthesia;

Fracture of the mandible;

Fracture of the maxilla;

Oroantral communication.
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected, 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 
analyses of safety data will be performed on a regular basis per internal standard operating 
procedures.  
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8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
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The subject should return to the investigator 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 and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

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;
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
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).

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 subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT 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) to Pfizer Safety 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 Safety 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 pre-
procedure 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 to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

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.
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Additional information regarding the EDP may be requested by the sponsor.  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 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.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. 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 Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;
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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the Sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
One hundred forty-eight (148) subjects in each of the IBU with caffeine and IBU treatment 
groups will assure at least 85% power to detect a difference of 10.5 units in SPRID 0-8 using 
a two-sided t-test at the 0.05 significance level.  This calculation was based on a root mean 
square error of 30, which was observed in an earlier study.14 Additionally, a sample size of 
50 subjects in the placebo group will provide at least 85% power to detect a difference of 
14.83 units in SPRID 0-8 between each active treatment and placebo at the 5% significance 
level (two-sided). 
Thus, a total of 346 (148 for each active treatment and 50 for the placebo) subjects are 
required to complete the study per protocol. To allow for 10% drop-outs, a total of 
approximately 385 (165 for each active treatment group and 55 for the placebo) subjects will 
be enrolled.
9.2. Efficacy Analysis
9.2.1. Analysis Populations
9.2.1.1. Primary Analysis Set
The full analysis set (FAS) will be the primary analysis population and it is defined as all 
randomized subjects who dosed with the study medication and provided a baseline 
assessment.
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9.2.1.2. ‘Per Protocol’ Analysis Set
The ‘per-protocol’ analysis set will include all subjects who completed the study per protocol 
(evaluable subjects). Thus, this analysis set will exclude any subjects who were discontinued 
from the study, or had a significant protocol violation.  The subjects who will be excluded 
from the ‘per-protocol’ analysis set will be documented prior to breaking of the study blind. 
If the per protocol population consists of 90% or more of the FAS subject population, a per 
protocol analysis will not be performed.
9.2.2. Analysis of the Primary Endpoint 

The primary endpoint SPRID 0-8 will be analyzed using an analysis of covariance
(ANCOVA) model with treatment, gender, and baseline pain severity terms in the 
model. Ninety five percent (95%) confidence limits for the treatment difference will 
be reported.
9.2.3. Analysis of Secondary Endpoints

The summary scores of SPID, TOTPAR and SPRID from 0-2, 0-4, 0-6 and 0-8 hours, 
as well as PRR, PID and PRID scores at each post-dosing time point will be analyzed 
using ANCOVA with treatment, gender, and baseline numerical pain severity terms 
in the model. Ninety five percent (95%) confidence limits for the treatment 
difference will be reported.

Time to onset of meaningful relief will be analyzed using the Gehan-Wilcoxon test to
compare treatments, stratifying by gender and baseline pain severity (moderate or 
severe) factors. It will also be summarized using the Kaplan-Meier method and 
displayed graphically where appropriate. Confidence intervals for the median will be 
reported by treatment.

Time to onset of first perceptible relief, confirmed by meaningful pain relief, and
duration of relief as measured by the time to rescue medication, will be analyzed 
using the Gehan-Wilcoxon test to compare treatments, stratifying by gender and 
baseline pain severity (moderate or severe) factors. They will also be summarized 
using the Kaplan-Meier method and displayed graphically where appropriate. 
Confidence intervals for the median will be reported by treatment.
9.2.4. Adjustment for Multiple Comparisons
No multiple comparisons are planned for primary endpoint.
9.2.5. Derivation of Endpoints

PID: based on the 11-point NPSR scale ranging from 0 (”no pain”) to 10 (”worst 
possible pain”), will be derived by subtracting the score at each post-dosing time 
point from the baseline score, so that a higher positive value is indicative of greater
improvement.

PRID: will be calculated by summing the PID and PRR at each post-dosing time
point.
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
SPIDt: time-weighted sum (weighted by the time since the prior scheduled
assessment) of PID scores from time 0 to t (where t=2, 4, 6 and 8).

TOTPARt: time-weighted sum of pain relief rating from time 0 to t (where t=2, 4,
6 and 8).

SPRIDt, time-weighted sum of PRID scores from time 0 to t (where t=2, 4, 6 and 8).
9.2.6. Data Conventions/ Handling of Missing Data
Efficacy assessments are scheduled to be completed at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 
8 hours post-dose and the analyses will be done corresponding to these time points. Because 
some subjects may complete their assessments at times differing from the scheduled time 
points, each such score will be adjusted so as to reflect more accurately the score that would 
have been observed had it been recorded at the scheduled time point. For each analysis time 
point, time windows will be created, using a width of ±5 minutes for time points which are 
less than one hour apart, and a width of ±10 minutes for time points which are one hour or 
more apart. All pain relief and pain severity scores for each subject will be assigned to 
analyzed time points according to these windows. The assignment rules will be as follows:

All assessments completed more than a minute after a subject takes the first dose of 
rescue medication will be ignored. Remaining efficacy scores subsequent to the time 
of rescue medication will be extrapolated (see below for method of extrapolation).

If an assessment is performed within a time point window, the corresponding value 
will be assigned to that time point (eg, an assessment performed anywhere between 
115 and 125 minutes, regardless of when it was scheduled, will be assigned to the 
2-hour time point). If more than one value falls within a window (this may include 
assessments completed at the time of rescue medication), a simple average of the 
values will be used.

If a particular time point has no value within its window, then a value will be 
assigned by either interpolation or extrapolation. If an assessment is available before 
and after the time point window, then a value will be interpolated by calculating the 
weighted average of the values immediately preceding and subsequent to the time 
point window, with weights inversely proportional to the duration between the 
analyzed time point and the actual time.

If a window is empty and no subsequent scores are available, a value will be assigned 
to the empty window via extrapolation. The extrapolated value will depend on 
whether rescue medication was taken or whether the subject dropped out due to lack 
of efficacy during or before the particular time point’s window. If so, the worse of 
the preceding score (this may be the assessment completed at the time of rescue 
medication) and the baseline score will be assigned as the pain severity scores, and a
score of 0 (no relief) as the pain relief score. If the missing data are not due to subject 
taking rescue medication, or discontinuation due to lack of efficacy, then the last 
observation will be carried forward for the pain severity scores and the pain relief 
scores.
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During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/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 investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  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 CRF 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.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs 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 CRFs 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 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs 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 or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
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11.2. Record Retention
To enable evaluations and/or inspections/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, CRFs and hospital records), all original signed 
informed consent/assent documents, copies of all CRFs, 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.
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/assent 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 the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
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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 numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking 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/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.
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.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.  
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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 and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC. The 
investigator will retain the original of each subject's signed consent/assent document.
At the conclusion of the study treatment period, subjects must return all products to the site. 
No products should be given to the subjects or legal guardian or parents to take home.
12.4. 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 
regulatory 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
The end of trial is defined as the last subject last visit (LSLV).
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 
fixed- dose combination of ibuprofen with caffeine at any time.
If a study is prematurely terminated, 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 CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
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.
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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 (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD 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 PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
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 (PI) of the results of the study based on information collected or 
generated by the PI, 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 it is 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.
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If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI 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.
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16. REFERENCES
1.
Ibuprofen. In: DRUGDEX System (Micromedex Pharmaceutical Knowledge).
Greenwood Village, CO: Truven Health Analytics; c1974-2016. 
http://www.micromedexsolutions.com.proxy1.athensams.net. Accessed 31 May 2016.
2.
Caffeine. In: DRUGDEX System (Micromedex Pharmaceutical Knowledge).
Greenwood Village, CO: Truven Health Analytics; c1974-2016. 
http://www.micromedexsolutions.com.proxy1.athensams.net. Accessed 31 May 2016.
3.
Laska EM, Sunshine A, Marrero I, et al. The correlation between blood levels of 
ibuprofen and clinical analgesic response. Clin Pharmacol Ther. 1986; 40:1–7.
4.
Forbes JA, Beaver WT, Jones KF, et al. Effect of caffeine on ibuprofen analgesia in 
postoperative oral surgery pain. Clin Pharmacol Ther 1991;49:674-84.
5.
Derry CJ, Derry S, Moore RA. Caffeine as an analgesic adjuvant for acute pain in 
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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
Analysis of covariance
ANVISA
Agência Nacional de Vigilância Sanitária (Brazilian Health 
Surveillance Agency)
AST
aspartate aminotransferase
BP
blood pressure
CBP
child-bearing potential
CMH
Cochrane Mantel-Hanzel 
CK
creatine kinase
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
DILI
drug-induced liver injury
EC
ethics committee
EDP
exposure during pregnancy
EMA
European Medicines Agency
FDA
Food & Drug Administration
FSFV
first subject first visit
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
IB
Investigator’s Brochure
IBU
ibuprofen
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
LFT
liver function test
LSLV
last subject last visit 
MAOI
monoamine oxidase inhibitor
MedDRA
Medical Dictionary for Regulatory Activities
N/A
not applicable
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Abbreviation
Term
NPSR
Numerical Pain Severity Rating Scale
NSAID
non-steroidal anti-inflammatory drug
OTC
Over the counter
PCH
Pfizer Consumer Healthcare
PCD
Primary completion date
PI
principal investigator
PRID
Sum of pain relief rating and pain intensity difference score
PRR
Pain relief rating
PSR
Pain severity rating
PT
prothrombin time
SAE
serious adverse event
SAP
statistical analysis plan
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SNRI
selective norepinephrine reuptake inhibitor
SOA
schedule of activities
SOC
System Organ Class
SOP
standard operating procedure
SPID
Time-weighted sum of pain intensity difference
SPRID
Time-weighted sum of pain relief and pain intensity difference
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
t
time
TBili
total bilirubin
TCA
tricyclic antidepressant
ULN
upper limit of normal
US
United States
VAS
Visual analog scale
VAS-PSR
Visual analog scale- pain severity rating
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