Clinical trial NCT03722238
Conditions: Pain
Sponsor: Pfizer
Start date: 2018-12-27; Completion date: 2019-10-28
Enrollment: 613 participants; Allocation: NA; Intervention model: PARALLEL

Brief summary:
This will be an open-label, multicenter, 30-day, unsupervised AUS among targeted (at-risk) adult and adolescent consumers designed to mimic an OTC-like environment. More specifically, "at-risk" consumers, as discussed with the FDA, will comprise elderly consumers (\>65 years of age), consumers with an increased risk of gastrointestinal (GI) bleeding or cardiovascular (CV) adverse events, consumers who experience severe pain, low literacy subjects, and adolescents (12-17 years of age). The total number of subjects expected to enroll into the study is approximately 820. Sites will be pharmacies in diverse geographic locations around the US. Prospective adult subjects will be recruited via general population and targeted risk condition advertising (although participants will not be informed as to specific health conditions for which they are being recruited), while adolescents will be recruited using targeted, outbound pre-recruiting telephone calls. Subjects (or the parents/guardians of prospective adolescent subjects) responding to the advertisements or recruitment calls will be initially screened by telephone, and eligibility will subsequently be verified in-person at the pharmacy site.

Detailed description:

Arms: arm 1: Ibuprofen 600 mg Immediate Release/Extended Release Tablets
Interventions: intervention 1: Ibuprofen 600 mg Immediate Release/Extended Release Caplet
Intervention descriptions: intervention 1: Ibuprofen 600 mg Immediate Release/Extended Release Tablet to be adminstered orally (i.e., one caplet every 12 hours, not to exceed 2 caplets per day) for pain.

Protocol documents:
Prot_000.pdf: 
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MULTICENTER ACTUAL USE AND COMPLIANCE STUDY OF IBUPROFEN 
600 MG IMMEDIATE RELEASE/EXTENDED RELEASE TABLETS AMONG 
TARGETED (AT-RISK) CONSUMERS IN A SIMULATED OVER-THE-COUNTER 
ENVIRONMENT
Investigational Product Number:
PF-00344559
Investigational Product Name:
Ibuprofen 600 mg Immediate 
Release/Extended Release Tablets
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
B4371011
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and 
Rationale
Original protocol
18-April-2018
Not applicable (N/A)
Amendment 1
Protocol/Final v2.0
12-September-2018
Schedule of Activities: The schedule 
of activities table updated.
Section 1 and Protocol Summary: 
Purpose of June 20, 2018 FDA 
Type C meeting added.
Section 2 and Protocol Summary: 
Secondary endpoint regarding 
subjects who use product more than 
10 consecutive days added. 
Section 2.1, 9.2.1, and Protocol 
Summary: Expanded clarification 
and justification for the primary 
endpoint selection added.
Section 3: Study Schematic updated.
Section 3 and Protocol Summary: 
“At-risk” consumers added; 
Procedure to ask parent/guardian and 
adolescent subject at Enrollment 
Visit to help determine which of 
them will be responsible to 
administer the study medication and 
subsequently participate in 
remaining study added; Description 
that electronic-diary platform will 
capture concomitant medications 
added.
Section 3.1: Introduction regarding 
“Ask a Doctor Before Use” and 
elevated cardiovascular and 
gastrointestinal bleeding factors 
added.
Section 4.1: Clarification of certain 


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inclusion criteria added.
Section 4.2: Addition of exclusion 
criteria regarding subject/household 
employment.
Section 6.5: Resupply Pharmacy 
Visit added.
Section 6.2: Mention of specific risk 
conditions in proposed recruitment 
advertising language removed. 
Section 6.3: REALM-SF will be 
used as literacy screening tool for 
adults at Pre-Screening Telephone 
Call rather than REALM-Test, which 
will instead be moved to the 
Enrollment Visit.
Section 6.4: 
Items 1& 2: Subject identity 
verification and confirmation of 
parent/guardian presence for 
adolescent subjects added; Item 4: 
Clarification regarding medical 
condition questions added.
Item 9: Adolescent subjects will sign 
to indicate assent added.
Item 11: Test results entered into 
ASCVD 10-Year Risk Calculator 
added.
Item 12: Allow subjects with “Ask a 
Doctor Before Use” conditions to 
continue to the pharmacy site (rather 
than excluding at Pre-Screening 
Telephone Call), make a selection 
decision and collect reasons why 
they desired to purchase prior to 
excluding them from the study.
Item 13: Attempts by subjects to 
purchase more than 5 packages of 


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study medication during study will 
be described in the study report.
Item 15: Concomitant medication 
collection (within relevant time 
windows before and after study 
medication use) in the electronic 
diary with rationale added.
Item 16: Pre-paid mailer to return 
study product and/or electronic-diary 
added.
Section 6.6.1: Clarification regarding 
who will complete EOS interview 
added; Procedures discussed with 
subjects at conclusion of EOS 
telephone interview added.
Section 6.6.2: Nurse 
identification/verification of last 
administration date of study 
medication added. 
Section 6.7: Clarification of 
reimbursement for study medication 
purchase added.
Section 7.1: Reading grade level 
scoring and descriptions regarding 
the REALM-SF, REALM, and 
REALM Teen tests added. 
Section 7.4: Clarification of blood 
pressure assessment administration 
added. 
Section 7.5: Clarification regarding 
the 10-year risk for atherosclerotic 
cardiovascular disease assessment 
added. 
Section 8.4.4: updated.
Section 9.2.1: At-risk population 
subgroups for primary endpoints 


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clarified. 
Section 9.2.3: At-risk population 
subgroups for secondary endpoints 
clarified. 
Section 9.3: Description of 
procedure to audio-record, transcribe 
and analyze verbatim responses from 
subjects to questions in the 
End-of-Study Interview added.
Section 9.3.1 and Protocol Summary: 
Description of identification of 
misuse clarified; Explanation of 
mitigating factors and the two types 
of mitigation (pre-specified and 
post-study) added; Mitigation plan
clarified.
Section 9.3.1: Figure 2 depicting 
overview of error classification 
scheme removed; Clarification of 
knowledge-based mistakes added; 
Memory recall mistake removed.
 
Section 11.1: Explanation of Data 
Management Plan added.
Amendment 2
06-March-2019
Incorporated changes from PACL 
No. 1. Section 6.4: updated price of 
study drug to $5.00. Section 13.2: 
language added to clarify how coded 
subject information may be used.
Protocol Summary, Study Design: 
Clarified instances of use of oral 
OTC and prescription pain 
medications to “oral” (updated 
throughout protocol). Updated 30-
Day Use Period to 30-Day Use Phase 
(updated throughout protocol). 
Modified timing of final telephone 
follow-up contact. Updated order of 
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identifying whether parent/guardian 
or adolescent is responsible for study 
procedures after the enrollment 
interview to before medication 
purchase.
Protocol Summary, Numbers and 
Types of Subjects: Updated 
numbers.
Schedule of Activities: Updated 
window of Follow-Up Phone 
Contact. Added “oral” to footnote g.
Section 3: Figure 1 updated.
Section 3.1: ASCVD risk upper 
bound changed to <20% (updated 
throughout protocol) and updated 
rationale provided.
Section 4.2: Clarified exclusion 
criteria language (No. 7, 10, 11, 12).
Section 4.4.1: Updated language 
concerning usage of birth control.
Section 6.4: Reordered visit 
steps/procedures.
Section 6.6.1: Removed language 
about dosing summary report being 
sent to subjects if withdrawn from 
the study. Clarified options to 
complete the EOS Interview (1 & 3).
Added that subjects will be reminded 
of the need to use birth control at the 
EOS call. Clarified that after a 
subject has started the EOS 
interview, no additional diary entries 
can be made.
Section 6.6.2: Updated call window 
for Follow-Up Phone Contact. 
Section 6.8.1: Clarified study 
procedures for subjects who request 


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to discontinue receipt of study 
treatment. Text moved from 
Section 6.8.2.
Section 6.8.2: Removed text about 
replacing subjects who withdraw 
from the study.
Section 7.5: Updated values entered 
into Risk Calculator. Updated 
ASCVD upper bound for inclusion 
in the CV Risk group and exclusion 
in the study.
Section 8.1.4: Updated time period 
for actively eliciting and collecting 
AEs and SAEs.
Section 8.4.4: Updated definition of 
medication error.
Section 9.1: Updated Individual 
Adult Group Sizes to address any 
risk groups failing to fill adequately.
Section 9.1: Updated numbers in 
Total Sample Size Requirements.
Abbreviations: Added PACL.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs/ethics 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
LIST OF FIGURES .................................................................................................................11
PROTOCOL SUMMARY.......................................................................................................12
SCHEDULE OF ACTIVITIES................................................................................................21
1. INTRODUCTION ...............................................................................................................24
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background and Rationale ......................................................................................25
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
2.1. Rationale for Primary Endpoint Selection ..............................................................27
3. STUDY DESIGN.................................................................................................................28
3.1. Risk Group Classifications......................................................................................30
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................32
4.1. Inclusion Criteria.....................................................................................................33
4.2. Exclusion Criteria....................................................................................................33
4.3. Randomization Criteria ...........................................................................................35
4.4. Lifestyle Requirements ...........................................................................................35
4.4.1. Contraception..............................................................................................35
4.5. Sponsor’s Qualified Medical Personnel..................................................................36
5. STUDY TREATMENTS.....................................................................................................37
5.1. Allocation to Treatment ..........................................................................................37
5.2. Breaking the Blind ..................................................................................................37
5.3. Subject Compliance.................................................................................................37
5.4. Investigational Product Supplies.............................................................................37
5.4.1. Dosage Form(s) and Packaging..................................................................37
5.4.2. Preparation and Dispensing........................................................................37
5.5. Administration.........................................................................................................38
5.6. Investigational Product Storage ..............................................................................38
5.7. Investigational Product Accountability...................................................................39
5.7.1. Return or Destruction of Investigational Product Supplies........................39
5.8. Concomitant Treatment(s).......................................................................................39
6. STUDY PROCEDURES .....................................................................................................39


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6.1. Study Sites...............................................................................................................39
6.2. Recruitment Methods ..............................................................................................39
6.3. Telephone Pre-Screening ........................................................................................40
6.4. Pharmacy Enrollment Visit .....................................................................................41
6.5. Resupply Pharmacy Visit........................................................................................45
6.6. 30-Day Use Phase ...................................................................................................45
6.6.1. End-of-Study Telephone Interview ............................................................45
6.6.2. Follow-Up Phone Contact (Up to Day 75).................................................48
6.7. Reimbursement for Study Medication Purchase.....................................................48
6.8. Subject Withdrawal or Early Termination ..............................................................48
6.8.1. Withdrawal of Consent:..............................................................................48
6.8.2. Lost to Follow-Up: .....................................................................................49
7. ASSESSMENTS..................................................................................................................49
7.1. Health Literacy Assessment....................................................................................49
7.2. Pregnancy Testing...................................................................................................50
7.3. Finger-Stick Cholesterol Test..................................................................................51
7.4. Blood Pressure Test.................................................................................................51
7.5. 10-Year Risk for Atherosclerotic Cardiovascular Disease (ASCVD) 
Assessment ................................................................................................................52
7.6. Rater Qualifications.................................................................................................52
8. ADVERSE EVENT REPORTING......................................................................................52
8.1. Requirements...........................................................................................................52
8.1.1. Additional Details on Recording Adverse Events on the CRF...................54
8.1.2. Eliciting Adverse Event Information..........................................................54
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................54
8.1.4. Time Period for Collecting AE/SAE Information......................................54
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................54
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF.................55
8.1.5. Causality Assessment .................................................................................55
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................55
8.2. Definitions...............................................................................................................55
8.2.1. Adverse Events...........................................................................................55


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8.2.2. Abnormal Test Findings .............................................................................56
8.2.3. Serious Adverse Events ..............................................................................57
8.2.4. Hospitalization............................................................................................57
8.3. Severity Assessment................................................................................................58
8.4. Special Situations ....................................................................................................59
8.4.1. Protocol-Specified Serious Adverse Events...............................................59
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................59
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................61
8.4.3.1. Exposure During Pregnancy......................................................61
8.4.3.2. Exposure During Breastfeeding ................................................62
8.4.3.3. Occupational Exposure .............................................................62
8.4.4. Medication Errors .......................................................................................62
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................63
9.1. Sample Size Determination.....................................................................................64
9.2. Dosing Compliance Analysis..................................................................................65
9.2.1. Analysis of the Primary Endpoint...............................................................65
9.2.2. Performance Threshold Selection and Rationale........................................66
9.2.3. Analysis of Secondary 
 Dosing Compliance Endpoints .........66
9.4. Safety Analysis........................................................................................................70
9.6. Interim Analysis ......................................................................................................71
9.7. Data Monitoring Committee ...................................................................................71
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................71
11. DATA HANDLING AND RECORD KEEPING .............................................................72
11.1. Case Report Forms/Electronic Data Record .........................................................72
11.2. Record Retention...................................................................................................72
12. ETHICS..............................................................................................................................73
12.1. Institutional Review Board/Ethics Committee......................................................73
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12.2. Ethical Conduct of the Study ................................................................................73
12.3. Subject Information and Consent..........................................................................73
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................74
13. DEFINITION OF END OF TRIAL...................................................................................75
13.1. End of Trial in All Participating Countries ...........................................................75
14. SPONSOR DISCONTINUATION CRITERIA ................................................................75
15. PUBLICATION OF STUDY RESULTS..........................................................................75
15.1. Communication of Results by Pfizer ....................................................................75
15.2. Publications by Investigators ................................................................................76
16. REFERENCES ..................................................................................................................78
ABBREVIATIONS .................................................................................................................79
LIST OF TABLES
Table 1.
REALM-SF Test Grade-Equivalent Reading Levels ...........................................50
Table 2.
REALM Test Grade-Equivalent Reading Levels.................................................50
Table 3.
REALM-Teen Test Grade-Equivalent Reading Levels........................................50
LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................30
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PROTOCOL SUMMARY
BACKGROUND 
AND RATIONALE
Pfizer has developed an ibuprofen 600 mg immediate 
release/extended release (IR/ER) tablet formulation (Advil® 12 
Hour) that approximates the early release characteristics of an 
ibuprofen 200 mg tablet with ER properties that are intended to 
maintain plasma concentrations adequate for analgesic efficacy 
over a 12-hour dosing interval.  Pfizer submitted a 
 
 to the United States (US) Food 
and Drug Administration (FDA) on 23 April 2014 for an ibuprofen 
600 mg IR/ER tablet for over-the-counter (OTC) use, with the 
proposed trade name of Advil 12 Hour.  Pfizer received a Complete 
Response Letter (CRL) on 23 February 2015 in which the Agency 
requested Pfizer to design a consumer program to: 1) evaluate 
subjects with low literacy to understand when and how they use the 
product; 2) identify individuals with medical conditions that may 
put them at greater risk for adverse effects when using nonsteroidal 
anti-inflammatory drugs (NSAIDs) and determine whether the 
labeling allows them to make appropriate decisions with regard to 
use of this product versus an IR product; 3) evaluate subjects with 
severe pain to determine if these individuals will deselect from 
using the product rather than taking more than the recommended 
dose when their pain is not relieved; and 4) understand additional 
measures that would discourage the behaviors of consumers who 
may override the label. 
Following these discussions with FDA, Pfizer conducted extensive 
qualitative consumer research to understand the baseline motivators 
and behaviors behind consumer use and misuse within the analgesic 
category, as well as follow-up interviews among a segment of the 
misusers in an earlier Advil 12 Hour Actual Use Study (AUS) 
(B4371008).  On 09 March 2017, Pfizer met with the FDA to 
discuss the label development program and additional consumer 
research that would be needed leading up to a resubmission.  In the 
meeting and official minutes, the FDA encouraged Pfizer to 
conduct a new AUS to characterize the misuse of Advil 12 Hour 
among those at increased risk, and to deeply understand the reasons 
for misuse.  The Agency also provided feedback regarding which 
at-risk subpopulations should be studied, including elderly 
consumers (>65 years of age), consumers with an increased risk of 
gastrointestinal (GI) bleeding or cardiovascular (CV) adverse 
events, consumers who experience severe pain, and low literacy 
subjects. Adolescents (12-17 years of age) should also be included 
for pediatric safety assessments, and the study should enroll a large 
proportion of frequent OTC analgesic users to increase the 
incidence of misuse.  On 20 June 2018, FDA granted a Type C 
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meeting to discuss the design of Pfizer’s proposed AUS.  
Specifically, Pfizer and FDA met once again to discuss and clarify 
issues surrounding the primary endpoint, subjects with “Ask a 
Doctor Before Use” conditions, methods to pre-select for low 
reading ability, collecting concomitant NSAID use information 
during the Use Phase, and other important topics relevant to this 
study and the program.  This protocol describes the AUS design 
and at-risk populations that will be employed to address the FDA’s 
specific requests and advice for this critical component of the 
consumer research program.
OBJECTIVES 
AND ENDPOINTS
The primary objective of this AUS is to evaluate compliance with 
the labeled dosing directions for Advil 12 Hour and to understand 
why misuse occurred and if it was a conscious decision by the 
subject.  A secondary objective is to evaluate the safety of Advil 12 
Hour in unsupervised actual use and how it relates to misuse. 
Accordingly, the following primary and secondary endpoints will 
be evaluated.
Primary Endpoint:

Proportion of subjects who exceed the maximum daily dose 
(1200 mg) on two or more calendar days during the use period.
Secondary Endpoints:

Proportion of subjects who exceed the maximum daily dose 
(1200 mg) on one or more calendar days during the use period.

Proportion of subjects who exceed the maximum daily dose 
(1200 mg) on one or more calendar days during the use period 
due to reasons categorized as unintentional misuse only (ie, 
subjects who did not understand the dosing instructions on the 
package).

The proportion of subjects who exceed the maximum amount 
per dose (600 mg) on 1 or more occasions.

The proportion of subjects who exceed the maximum amount 
per dose (600 mg) on two or more occasions.

The proportion of subjects who exceed the maximum daily dose 
on 10 or more calendar days.

The proportion of subjects who exceed the maximum daily dose 


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on 7 or more calendar days.
•
The proportion of subjects who take more than two doses (ie,
more than two dosing occasions) on a calendar day.
•
The proportion of subjects who re-dose in <12 hours, <10 hours 
and <8 hours on 1 or more occasions.
•
The proportion of subjects who use the product on more than 
10 consecutive days.
 
 
 
 
 
 
 
 
 
 
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Rationale for Primary Endpoint Selection:
The primary endpoint was selected based on input from the FDA, 
considerations of the study population, and the incremental CV and 
GI bleeding risk of misusing the study medication.  The FDA 
indicated that a primary endpoint of interest was the proportion of 
subjects who exceed the maximum daily dose (1200 mg) (ie, 
misuse) even once.  Pfizer has proposed the primary endpoint as the 
proportion of subjects who exceed the maximum daily dose on two 
or more calendar days, based on the justification of data from large, 
long-term clinical trials’ (ie, TARGET,3 CLASS,4 and 
PRECISION5) CV and GI safety outcomes in subjects receiving 
prescription doses of ibuprofen.  Based on these publications of 
controlled clinical trials on long-term use of prescription ibuprofen, 
it is conservatively estimated that each day of misuse would incur 
an incremental 0.0011% (1.1/100,000) risk of an -Antiplatelet 
Trialists’ Collaboration (APTC) non-hemorrhagic CV event, and an 
incremental 0.0014% (1.4/100,000) risk of upper GI bleeding 
compared to the estimated risk for 1200 mg ibuprofen per day.  
Therefore, two days of misuse for the proposed primary endpoint 
would not incur a clinically meaningful increase in the risk of a 
serious CV or GI outcome (2.2/100,000 and 2.8/100,000, 
respectively) compared to one day of misuse in an OTC population.  
Even if subjects were to misuse on 7 days, the incremental risks of 
a serious CV or GI outcome would be 0.0077% (7.7/100,000) and 
0.0098% (9.8/100,000), respectively, which qualify as “very rare” 
adverse events (less than 0.01% or 1/10,000) according to the 
World Health Organization (WHO) (International Conference on 
Harmonisation (ICH) Council for International Organizations of 
Medical Sciences (CIOMS) guidance).  For these reasons, Pfizer 
considers the proposed primary endpoint of the proportion of 
subjects who exceed the maximum daily dose on two or more 
calendar days among these at-risk study populations to be a highly 
sensitive endpoint to assess OTC suitability, and represents a 
minimal incremental clinical risk for those consumers who exceed 
this threshold frequency of misuse.
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STUDY DESIGN
This will be an open-label, multicenter, 30-day, unsupervised AUS
among targeted (at-risk) adult and adolescent consumers designed 
to mimic an OTC-like environment.  More specifically, “at-risk” 
consumers, as discussed with the FDA, will comprise elderly 
consumers (>65 years of age), consumers with an increased risk of 
gastrointestinal (GI) bleeding or cardiovascular (CV) adverse 
events, consumers who experience severe pain, low literacy 
subjects, and adolescents (younger than the age of majority in their 
state, hereafter referred to as “12-17 years of age,” although some 
sites may also designate 18-year-olds as younger than the age of 
majority, according to state requirements). Sites will be pharmacies 
in diverse geographic locations around the US.  Prospective adult 
subjects will be recruited via general population and targeted risk 
condition advertising--- (although subjects will not be informed as 
to specific health conditions for which they are being recruited), 
while adolescents will be recruited using targeted, outbound 
pre-recruiting telephone calls.  Subjects (or the parents/guardians of 
prospective adolescent subjects) responding to the advertisements
or recruitment calls will be initially screened by telephone, and 
eligibility will subsequently be verified in-person at the pharmacy 
site.
Adult subjects and the parents/guardians of adolescent subjects who 
qualify will answer questions related to the subject’s attitudes 
toward, and usage of, oral OTC and prescription pain medications, 
and will have the opportunity to purchase and use the study 
medication based only on their reading of the Drug Facts Label 
(DFL) and other information on the package.  Data regarding 
subjects’ use of the study medication will be captured in an 
electronic diary.  The electronic diary will also capture information 
on concomitant medications to elucidate concurrent use of NSAIDs
(see Section 6.4). Subjects (and either the parents/guardians of 
adolescent subjects or adolescent subjects) may return to the 
pharmacy site at any point during the 30-Day Use Phase to 
purchase additional study medication (up to 5 packages maximum
at any point during the study).  Finally, between Days 31 and 40, 
subjects (or the parents/guardians of adolescent subjects) will 
provide detailed explanatory information about the subject’s 
reasons for misuse, as well as information about adverse events
(AEs), in an end-of-study (EOS) telephone interview; the EOS 
telephone interview will be audio-recorded in order to capture 
subjects’ verbatim responses.  The EOS telephone interview will be 
followed by a self-administered Attitudes and Beliefs electronic 
questionnaire, and a final telephone follow-up contact (at least 28
(and up to 35) calendar days after the subject’s 30-Day Use Phase
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least 28 (and up to 35) calendar days after last recorded dose of 
investigational product) to capture any potential adverse events and 
to confirm appropriate contraception usage, after which 
participation will end. 
Note that for adolescent subjects 12-17 years of age, the initial 
telephone screening and pharmacy enrollment visit assessments 
(with the exception of the Rapid Estimate of Adolescent Literacy in 
Medicine (REALM-Teen) Test7 and instances where the 
investigator may exercise judgment to determine if the 
parent/guardian and/or adolescent subject should both be present 
for and respond to questions in the birth control verification 
discussion or other sensitive content areas) will be directed to and 
managed by the parent/guardian, who will answer for and on behalf 
of the adolescent subject, and must be present to enroll the 
adolescent into the study and purchase study medication.  However, 
to allow for real-world, naturalistic medication use behaviors 
between parents/guardians and adolescent subjects, the 
parent/guardian and adolescent subject will be asked before the
study medication purchase by the parent at the pharmacy 
enrollment visit to identify which of them usually administers the 
oral OTC pain reliever medications the adolescent takes, and that 
person will have the primary responsibility to administer the study 
medication and subsequently participate in remaining study 
assessments including completion of the electronic diary, the 
end-of-study (EOS) telephone interview and the self-administered 
Attitudes and Beliefs questionnaire.  In cases where the 
parent/guardian and the adolescent report they “both” usually 
administer oral OTC pain reliever medications the adolescent takes, 
the parent/guardian and adolescent will be asked to decide which of 
them will have primary responsibility for entering data and 
participating in all future assessments.  
STUDY 
TREATMENTS
This is an open label study.  Subjects or the parents/guardians of 
prospective adolescent subjects will purchase study medication, 
which will consist of Advil 12 Hour 600 mg IR/ER tablets 
(40 tablets per bottle), with a labeled dosing regimen of one 600 mg
IR/ER tablet every 12 hours, not to exceed 2 tablets in 24 hours 
(total daily dose = 1200 mg ibuprofen).  However, subjects will be 
free to take the medication (or not take it) according to their own 
(or in the case of the adolescent subject, the parent’s/guardian’s)
understanding and decisions based on the Drug Facts Label and 
other packaging instructions throughout the 30-Day Use Phase.
NUMBERS AND 
TYPES OF 
The total number of subjects expected to enroll into the study is 
820 (including approximately 720 adults and 100 adolescents).  


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SUBJECTS
Accordingly, the number of subjects expected to be screened by 
telephone is 14,409, of whom approximately 7,029 would meet all 
initial screening criteria and schedule an enrollment visit 
appointment.  Among these, it is expected that 3,046 would visit a 
participating pharmacy research site, and 820 would meet all 
eligibility criteria, purchase study medication and enter the Use 
Phase. Finally, among enrolled subjects it is expected 
approximately 700 would be available for the dosing compliance 
endpoint analysis (compliance-evaluable subjects are those that 
take at least one dose of study medication and record it in the 
electronic diary), including approximately 620 adults and 80 
adolescents.
Risk Group Classifications:
The adult portion of the study sample will consist entirely of 
subjects from the following special at-risk populations of interest, 
including:
1. Cardiovascular (CV) Risk.
2. Gastrointestinal (GI) Bleeding Risk.
3. History of Severe Pain.
4. >65 Years of Age.
Note that because of substantial overlap in these frequently 
co-morbid conditions, subjects from the at-risk groups are not 
recruited in any specific, fixed proportions.  Approximately 30% of 
each adult at-risk group (groups 1-4 above) will be classified as 
low- literacy based on the Rapid Estimate of Adult Literacy in 
Medicine (REALM) Test in order to evaluate dosing compliance 
and other important behaviors among subjects at increased risk due 
to low health literacy.  Among adult subjects, heavy oral OTC pain 
reliever users (ie, those who report taking an average of 30 or more 
doses per month on average in the 3 months preceding enrollment) 
will be enrolled in approximately a 2:1 ratio with moderate users 
(5-29 doses in the previous 3 months).
Additional Cohort of Interest:
Adolescent subjects will be included for pediatric compliance and 
safety assessments.


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5. Adolescent Subjects (12-17 years of age).
STATISTICAL 
METHODS
The Primary Endpoint (proportion of subjects who exceed the 
maximum daily dose, 1200 mg, on two or more days during the use 
period) will be calculated as:
Adult compliance-evaluable subjects exceeding 
1200 mg/day on ≥2 days, divided by the total number of 
adult compliance-evaluable subjects.
The complement of this number (1 – obtained proportion) will be 
calculated.  This is the correct performance rate.
The Primary Endpoint will be considered successfully met if the 
lower-limit of the two-sided 95% confidence interval (CI)
(calculated using the Wald Confidence Interval) for the correct 
performance rate is greater than the a priori performance standard 
of 90%.  Adolescent performance for the Primary Endpoint will be 
presented descriptively. No inferential analysis on adolescents will 
be performed (descriptive only) and hence this group will not be 
compared to the performance threshold.
Values for all other dosing compliance endpoints will be calculated 
in similar fashion but will not be compared to any pre-specified 
performance threshold.
Product misuse will be recorded by subjects in the electronic diary 
(which captures the date, time and number of tablets for each 
dosing occasion).  For subjects whose electronic diary entries show 
misuse of the study medication (Primary Endpoint: exceeding the 
maximum daily dose, 1200 mg, on two or more calendar days, and 
relevant secondary endpoints related to dosing), data from the 
subject’s full case report form (CRF) -(including the Enrollment 
Interview, electronic diary and EOS Interview) will be carefully 
reviewed to evaluate the benefit-risk balance, including potential 
mitigating factors.  Mitigating factors are circumstances or 
considerations that result in reclassification of misuses to 
“acceptable” status, meaning the risk-benefit balance is judged to 
be favorable in spite of misuse.  Two kinds of mitigation will be 
employed: pre-specified and post-study.  Pre-specified mitigating 
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factors for the primary and relevant secondary endpoints related to 
dosing include: responses showing clear consultation with or 
direction from a healthcare practitioner (HCP) regarding observed 
patterns of misuse--, and severe pain, pain that is different than 
usual, or being larger or needing better/faster pain relief that would 
have otherwise led to using an opioid or other Rx analgesic, 
according to the subject.  Because of wide variability in consumer 
behaviors and health conditions, not all mitigating factors can be 
pre-specified.  Therefore, if other behavioral or health factors are 
identified and judged in post-study analysis to substantially impact 
the benefit-risk balance, associated misuses may likewise be 
mitigated to “acceptable” status.  To ensure full transparency for 
reviewers, mitigation (both pre-specified and post-study) of 
individual misuses based on subjects’ responses, together with the 
accompanying medical justification or rationale, will be carefully 
documented in the study report.
Subgroup analyses will be performed on subjects 1) at increased GI 
risk; 2) at increased CV risk; 3) >65 years age; and 4) with severe 
pain for the primary endpoint and secondary endpoints.
Adverse event (AE) summaries will include all events which 
initially occurred or worsened following initiation of treatment. 
AEs will be summarized using the Medical Dictionary for 
Regulatory Activities (MedDRA), System Organ Class (SOC) and 
Preferred Term (PT) designations and classified according to their 
severity (mild, moderate, or severe) and relationship (related or not 
related) to the study product.  
 
 
 
 
 
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Visit Identifier
Telephone 
Screening
Enrollment 
Visit
Resupply
Pharmacy 
Visit
Day 30
End of Study 
Telephone 
Interviewj
Follow-Up 
Phone Contact 
(and Exit from 
Study)
Visit Window (Days)a
<1
1
1-30
30
31 (up to 40)
(up to 75)
Pre-Screening Telephone Call
X
Reading Level for Adults (REALM-SF Test)b
X
Identification Verified 
X
Enrollment Screening and Medical Conditions to Confirm 
Eligibility
X
Purchase Decision
X
Analgesic Use History
X
Demographics 
X
Reading Level for Adults (REALM Test) or Adolescents 
(REALM-Teen Test)b
X
Inclusion and Exclusion Criteriac
X
X
Read and Sign Informed Consent (and Assent for Minors)
X
Verification of Effective Birth Controld
X
X
Urine Pregnancy Test (if applicable)
X
X
Finger-Stick Cholesterol and Blood Pressure Testse
X
Subgroup Identification for At-Risk Populations
X
Purchase Study Medicationf
X
X
Subject Trained on Completion of Electronic Diary Entriesg
X
End of Study Pregnancy Test (if applicable) and Pre-Paid Mailer 
Provided
X
Use Study Medication / Complete Electronic Diary / Record 
Concomitant Medicationsh
X

X
Adverse Event and Medication Error Recording and Follow-Upi
X
X
X
X 
X
Electronic Diary Reviewj
X
Focused Questions on Product Misuse
X


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Visit Identifier
Telephone 
Screening
Enrollment 
Visit
Resupply
Pharmacy 
Visit
Day 30
End of Study 
Telephone 
Interviewj
Follow-Up 
Phone Contact 
(and Exit from 
Study)
Visit Window (Days)a
<1
1
1-30
30
31 (up to 40)
(up to 75)
Questions on Concomitant Analgesic Use (Concomitant 
Medication Use for Subjects Experiencing AEs)
X
Conduct End of Study Urine Pregnancy Test (if applicable)k
X
Attitudes and Beliefs (Self-Administered via the Electronic Diary 
Application at Completion of End of Study Telephone Interview)l
X
Return Unused Medication (and Electronic Diary device if 
applicable) Via Mailm
X
Exit from Study at Conclusion of Follow-Up Phone Contact
X
Subject is Reimbursed for Purchase Price of Study Medication 
Following Last Subject Outn
Abbreviations: 
= ongoing/continuous event
REALM-SF = Rapid Estimate of Adult Literacy in Medicine – Short Form
REALM = Rapid Estimate of Adult Literacy in Medicine
REALM-Teen = Rapid Estimate of Adolescent Literacy in Medicine
AE = Adverse Event
a.
Day relative to first purchase of study product on Day 1.
b.
REALM-SF Test will assess reading grade level at screening for adult subjects.  Adult subjects will have reading grade level confirmed via the REALM 
Test, and adolescent subjects will have reading grade level assessed via the REALM-Teen Test during the enrollment visit.
c.
These are evaluated programmatically in the EDC system (based on pre-specified, protocol-defined, automatic edit checks), some at the initial telephone 
screening, and then all required criteria at the enrollment visit, prior to subject entry into the Use Phase (before medication purchase).
d.
Conducted with male and female subjects.
e.
Conducted with adult subjects (18 years and older) only.
f.
Subjects (or the parents/guardians of adolescent subjects) will be allowed to purchase as much study medication as desired at the enrollment visit (up to 
5 packages) after reading and signing the informed consent form.  Subjects (or the parents/guardians of adolescent subjects or adolescent subjects) will also 
be allowed to purchase additional study medication (not to exceed a total of 5 packages for the study) from the pharmacy site if needed during the course of 
the 30-day study.
g.
Diary entries are to be completed by the subject or the adolescent subject’s parent/guardian if the adolescent subject does not usually self-administer oral 
OTC pain medication.  The electronic diary will also capture information on concomitant medications taken in the 24-hour period before or the 24-hour 
period after each dose of the study medication.
h.
As needed (determined by subject or the parents/guardians of adolescent subjects) from Day 1 to Day 30.


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i.
At any time during the 30-day study, subjects (or the parents/guardians of adolescent subjects) may contact the Investigator at the study site or may call the 
PEGUS 24-hour nurse line to report an AE.  During the End-of-Study Telephone Interview and the Follow-up Phone Contact, subjects will be queried about 
AEs.
j.
EOS Telephone Interview should take place shortly after Day 30 (ranging from Day 31 to Day 40) to ensure that all electronic diary entries have been 
transmitted, but at a time that reasonably allows for accurate subject recall about specific dosing instances.  Subjects will be questioned to gather information 
on AEs, concomitant medications for subjects who experienced adverse event(s), subjects’ use of the medication (and reasons for any deviations from the 
label directions), concomitant analgesic use, subject typical practices on following OTC dosing directions for analgesics, and any discussion the subject may 
have had with a physician or other healthcare professional about the study medication use.
k.
After the last dose of study medication, female subjects of childbearing potential and at risk of pregnancy will self-administer the end of study pregnancy test 
that was provided to them at the Day 1 visit and report the result to the trained nurse interviewer during the End-of-Study Telephone Interview.
l.
The Attitudes and Beliefs Questionnaire will be completed by subjects using the electronic-diary application within 10 days after completing the 
End-of-Study Telephone Interview.
m. Subjects will be instructed at End-of-Study Telephone Interview to discontinue all use of study medication and to use the provided mailing materials to 
return all unused study medication and electronic diary device (if applicable).
n.
Once all subjects have exited the study, subjects, or the adolescent subject’s parent/guardian will be reimbursed (at the same time) for the purchase price of 
study medication they purchased during the study.  To maintain the naturalism of the study, subjects will not be notified in advance, at any time, that
medication purchases will be reimbursed.


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1. INTRODUCTION
Pfizer has developed an ibuprofen 600 mg immediate release/extended release (IR/ER) tablet
formulation (Advil® 12 Hour) that approximates the early release characteristics of an 
ibuprofen 200 mg tablet with ER properties that are intended to maintain plasma 
concentrations adequate for analgesic efficacy over a 12-hour dosing interval.  Pfizer 
submitted a 
 to the United States (US) Food 
and Drug Administration (FDA) on 23 April 2014 for an ibuprofen 600 mg IR/ER tablet for 
over-the-counter (OTC) use, with the proposed trade name of Advil 12 Hour. Pfizer received 
a Complete Response Letter (CRL) on 23 February 2015 in which the Agency requested that 
Pfizer design a consumer program to: 1) evaluate subjects with low literacy to understand 
when and how they use the product, 2) identify individuals with medical conditions that may 
put them at greater risk for adverse effects when using nonsteroidal anti-inflammatory drugs 
(NSAIDs) and determine whether the labeling allows them to make appropriate decisions 
with regard to use of this product versus an IR product, 3) evaluate subjects with severe pain 
to determine if these individuals will deselect from using the product rather than taking more 
than the recommended dose when their pain is not relieved, and 4) understand additional 
measures that would discourage the behaviors of consumers who may override the label.
Following these discussions with FDA, Pfizer conducted extensive qualitative consumer 
research to understand the baseline motivators and behaviors behind consumer use and 
misuse within the analgesic category as well as follow-up interviews among a segment of the 
misusers in an earlier Advil 12 Hour Actual Use Study (AUS) (B4371008).  On 09 March 
2017, Pfizer met with the FDA to discuss the label development program and additional 
consumer research that would be needed leading up to a resubmission.  In the meeting and 
official minutes, the FDA encouraged Pfizer to conduct a new AUS to characterize the 
misuse of Advil 12 Hour among those at increased risk, and to deeply understand the reasons 
for misuse.  The Agency also provided feedback regarding which at-risk subpopulations 
should be studied including elderly consumers (>65 years of age), consumers with an 
increased risk of gastrointestinal (GI) bleeding or cardiovascular (CV) adverse events, 
consumers who experience severe pain, and low literacy subjects.  Adolescents (12-17 years 
of age) should also be included for pediatric safety assessments, and the study should enroll a 
large proportion of frequent OTC analgesic users to increase the incidence of misuse.  On 
20 June 2018, FDA granted a Type C meeting to discuss the design of Pfizer’s proposed 
AUS.  Specifically, Pfizer and FDA met once again to discuss and clarify issues surrounding 
the primary endpoint, subjects with “Ask a Doctor Before Use” conditions, methods to 
pre-select for low reading ability, collecting concomitant NSAID use information during the 
Use Phase, and other important topics relevant to this study and the program. This protocol 
describes the AUS design and at-risk populations that will be employed to address the FDA’s 
specific requests and advice for this critical component of the consumer research program.
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1.1. Mechanism of Action/Indication
The product is a bi-layer, 600 mg ibuprofen tablet in which one layer contains 200 mg of 
ibuprofen as immediate release (IR) and the other layer contains 400 mg as extended release 
(ER). This bi-layer tablet formulation approximates the early-release characteristics of an 
ibuprofen 200 mg IR tablet combined with ER properties that maintain plasma 
concentrations adequate to provide 12 hours of analgesic efficacy.
The clinical development program for Advil 12 Hour consisted of three pharmacokinetic 
(PK) studies comparing the formulation to 3 consecutive ibuprofen 200 mg doses, dosed 
every 4 hours, two dental pain extraction efficacy studies (one single and one multiple dose), 
and one AUS which included self-selection and compliance arms. These studies 
demonstrated that the product has a PK profile bioequivalent to that of 200 mg IR 
administered three times a day (TID) every 4 hours and provides sustained analgesic efficacy 
up to 12 hours following both single and multiple doses. The efficacy data support that the 
proposed product provides an onset of analgesia which is maintained for 12 hours.
The indications of Advil 12 Hour are “Pain reliever/Fever reducer.”  The uses identified in 
the proposed Drug Facts Label (DFL) are: for up to 12-hour relief of minor aches and pains 
due to: minor pain of arthritis, muscular aches, backache, menstrual cramps, toothache, 
headache, the common cold, and temporarily reduces fever.
1.2. Background and Rationale
Pfizer Consumer Healthcare (PCH) believes that an ibuprofen formulation that will provide a 
similar onset but longer duration of analgesic effect compared to currently marketed 
ibuprofen IR dosage forms will provide a benefit to consumers who dose more than once 
with an immediate release, short-acting analgesic to treat their painful condition.  Market 
research studies indicate that OTC consumers often need to treat their pain symptoms with 
multiple doses of analgesics.1,2
This study is being conducted to evaluate the extent to which consumers will appropriately 
use the ibuprofen 600 mg IR/ER tablets and comply with the dosing instructions (ie, 1 tablet 
every 12 hours, not to exceed 2 tablets per 24 hours) (total daily dose 
= 1200 mg ibuprofen). However, subjects will be free to take the medication (or not take it) 
according to their own (or in the case of the adolescent subject, the parent’s/guardian’s)
understanding and decisions based on the Drug Facts Label and other packaging instructions 
throughout the 30-Day Use Phase.
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). 
2. STUDY OBJECTIVES AND ENDPOINTS
The following primary and secondary endpoints will be evaluated.


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Primary Objective:
Primary Endpoint:
•
Evaluate compliance with the labeled dosing 
directions for Advil 12 Hour, and understand why 
misuse occurred and if it was a conscious decision by 
the subject.
•
Proportion of subjects who exceed the maximum 
daily dose (1200 mg) on two or more calendar days 
during the use period.
Secondary Objectives:
Secondary Endpoints:
•
Evaluate the safety of Advil 12 Hour in unsupervised 
actual use and how it relates to misuse.
•
Proportion of subjects who exceed the maximum 
daily dose (1200 mg) on one or more calendar days 
during the use period.
•
Proportion of subjects who exceed the maximum 
daily dose (1200 mg) on one or more calendar days 
during the use period due to reasons categorized as 
unintentional misuse only (ie, subjects who did not 
understand the dosing instructions on the package).
•
The proportion of subjects who exceed the maximum 
amount per dose (600 mg) on 1 or more occasions.
•
The proportion of subjects who exceed the maximum 
amount per dose (600 mg) on two or more occasions.
•
The proportion of subjects who exceed the maximum
daily dose on 10 or more calendar days.
•
The proportion of subjects who exceed the maximum 
daily dose on 7 or more calendar days.
•
The proportion of subjects who take more than two 
doses (ie, more than two dosing occasions) on a 
calendar day.
•
The proportion of subjects who re-dose in <12 hours, 
<10 hours and <8 hours on 1 or more occasions.
•
The proportion of subjects who use the product on 
more than 10 consecutive days.
 
 
 
 
 
 
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2.1. Rationale for Primary Endpoint Selection
The primary endpoint was selected based on input from the FDA, considerations of the study 
population, and the incremental CV and GI bleeding risk of misusing the study medication.  
The FDA indicated that a primary endpoint of interest was the proportion of subjects who 
exceed the maximum daily dose (1200 mg) (ie, misuse) even once.  Pfizer has proposed the 
primary endpoint as the proportion of subjects who exceed the maximum daily dose on two 
or more calendar days, based on the justification of data from large, long-term clinical trials’
(ie, TARGET,3 CLASS,4 and PRECISION5) CV and GI safety outcomes in subjects 
receiving prescription doses of ibuprofen.  Based on these publications of controlled clinical 
trials on long-term use of prescription ibuprofen, it is conservatively estimated that each day 
of misuse would incur an incremental 0.0011% (1.1/100,000) risk of an -Antiplatelet 
Trialists’ Collaboration (APTC)6 non-hemorrhagic CV event, and an incremental 
0.0014% (1.4/100,000) risk of upper GI bleeding compared to the estimated risk for 1200 mg 
ibuprofen per day.  Therefore, two days of misuse for the proposed primary endpoint would 
not incur a clinically meaningful increase in the risk of a serious CV or GI outcome
(2.2/100,000 and 2.8/100,000, respectively) compared to one day of misuse in an OTC 
population. Even if subjects were to misuse on 7 days, the incremental risks of a serious CV 
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or GI outcome would be 0.0077% (7.7/100,000) and 0.0098% (9.8/100,000), respectively, 
which qualify as “very rare” adverse events (less than 0.01% or 1/10,000) according to the 
World Health Organization (WHO) (International Conference on Harmonisation (ICH) 
Council for International Organizations of Medical Sciences (CIOMS) guidance).  For these 
reasons, Pfizer considers the proposed primary endpoint of the proportion of subjects who 
exceed the maximum daily dose on two or more calendar days among these at-risk study 
populations to be a highly sensitive endpoint to assess OTC suitability and represents a 
minimal incremental clinical risk for those consumers who exceed this threshold frequency 
of misuse.
3. STUDY DESIGN
This will be an open-label, multicenter, 30-day, unsupervised AUS among targeted (at-risk) 
-adult and adolescent consumers designed to mimic an OTC-like environment.  More 
specifically, “at-risk” consumers, as discussed with the FDA, will comprise elderly 
consumers (>65 years of age), consumers with an increased risk of gastrointestinal (GI) 
bleeding or cardiovascular (CV) adverse events, consumers who experience severe pain, low 
literacy subjects, and adolescents (younger than the age of majority in their state, hereafter
referred to as “12-17 years of age,” although some sites may also designate 18-year-olds as 
younger than the age of majority, according to state requirements). The total number of 
subjects expected to enroll into the study is approximately 820.  Sites will be pharmacies in 
diverse geographic locations around the US.  Prospective adult subjects will be recruited via 
general population and targeted risk condition advertising--- (although subjects will not be 
informed as to specific health conditions for which they are being recruited), while 
adolescents will be recruited using targeted, outbound pre-recruiting telephone calls.  
Subjects (or the parents/guardians of prospective adolescent subjects) responding to the 
advertisements or recruitment calls will be initially screened by telephone, and eligibility will 
subsequently be verified in-person at the pharmacy site.
Adult subjects and the parents/guardians of adolescent subjects who qualify will answer 
questions related to the subject’s attitudes toward, and usage of, oral OTC and prescription 
pain medications and will have the opportunity to purchase and use the study medication 
based only on their reading of the Drug Facts Label (DFL) and other information on the 
package.  Following the initial purchase decision, subjects (or the parent/guardian of 
adolescent subjects) will provide informed consent and complete additional evaluations for 
inclusion/exclusion as well as assessment of risk group classification(s) for adult subjects 
(see Section 3.1). Eligible subjects (or the parents/guardians of eligible adolescent subjects) 
are then permitted to purchase as much study medication as desired (up to 5 packages) at the 
start of the study.  Data regarding subjects’ use of the study medication will be captured in an 
electronic diary. 
 
 
 
 
 
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The electronic diary will also capture information on concomitant medications to elucidate 
concurrent use of NSAIDs (see Section 6.4).  Subjects (and either the parents/guardians of 
adolescent subjects or adolescent subjects, depending on which is responsible to make entries 
in the electronic diary and participate in all other assessments) may return to the pharmacy 
site at any point during the 30-Day Use Phase to purchase additional study medication (not to 
exceed a total of 5 packages for the study).  Finally, between Days 31 and 40, subjects (or the 
parents/guardians of adolescent subjects) will provide detailed explanatory information about 
the subject’s reasons for misuse, as well as information about adverse events (AEs), in an 
end-of-study (EOS) telephone -interview; the EOS telephone interview will be 
audio-recorded in order to capture subjects’ verbatim responses.  The EOS telephone 
interview will be followed by a self-administered Attitudes and Beliefs electronic 
questionnaire (to be completed within 10 days after the EOS telephone interview) and 
participation will end.
Note that for adolescent subjects 12-17 years of age, the initial telephone screening and 
pharmacy enrollment visit assessments (with the exception of the REALM-Teen Test7 and 
instances where the investigator may exercise judgment to determine if the parent/guardian 
and/or adolescent subject should both be present for and respond to questions in the birth 
control verification discussion or other sensitive content areas) will be directed to and 
managed by the parent/guardian, who answers for and on behalf of the adolescent subject,
and must be present to enroll the adolescent into the study and purchase study medication.  
The individual (parent/guardian or adolescent subject) identified as the one who usually 
administers the oral OTC pain reliever medications the adolescent takes will have the 
primary responsibility to administer the study medication and subsequently participate in 
remaining study assessments including completion of the electronic diary, the EOS telephone 
interview and the self-administered Attitudes and Beliefs electronic questionnaire.
Figure 1 is a visual representation (schematic) of the study.
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Figure 1.
Study Schematic
3.1. Risk Group Classificati
Of special interest for this stu
conditions from the proposed
and gastrointestinal bleeding 
of subjects who: 1) have a his
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PFIZER CONFIDENTIAL
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c
ions
udy are consumers with key “Ask a Doctor Befo
d DFL, especially those with factors for elevated
risk.  The adult portion of the study sample will
story taking oral OTC analgesics at least 5 doses
ore Use” 
d cardiovascular 
l consist entirely 
s/month on 


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average during the past 3 months, and 2) are from the following special at-risk populations of 
interest (which are not mutually exclusive):
1. Cardiovascular (CV) Risk: In order to ensure that subjects for this group to be 
included in the study are at increased risk for cardiovascular disease, a 10-year risk 
for atherosclerotic cardiovascular disease (ASCVD) assessment will be used for adult 
subjects. The 2013 American College of Cardiology (ACC)/American Heart 
Association (AHA) Prevention Guidelines Tool CV Risk Calculator, which is a 
companion tool to the 2013 ACC/AHA Guideline on the Assessment of 
Cardiovascular Risk, will be used for this calculation. Subjects in the 40-79-year age 
bracket will only be eligible for inclusion in the CV Risk Group if they have a score 
of 5% to <20% for 10-Year ASCVD risk.  The <20% upper threshold for 10-year
ASCVD risk is selected to be high enough to enable enrollment of older consumers
(who naturally have higher 10-year risk scores as a function of age regardless of other 
contributing factors) as requested by the FDA, while still conservatively excluding 
those with the highest levels of risk (ie, ensures subjects 40-79 years of age will have 
no more than a 1 in 5 estimated baseline risk for a first ASCVD event in 10 years).  It 
should be noted that a <20% upper limit for 10-Year ASCVD risk will result in no 
more than 0.082% additional baseline risk in 30 days (the length of the Use Phase)
for any individual subject in the study versus a 10% ASCVD upper limit, or about a 
1 in 1217 additional risk in 30 days.  This 0.082% additional baseline risk derives 
from the assumption that if the additional 10% ASCVD risk (by increasing from 10% 
to <20%) is evenly distributed across 10 years, any 30-day period (the length of the 
Use Phase) will represent 30 days/3650 days x 10% ASCVD risk in 10 years = 
0.082%.  All subjects will have their high-density lipoprotein (HDL) and total 
cholesterol levels assessed on-site using a finger-prick test and will have these values 
entered into the Risk Calculator (programmed in the electronic data capture (EDC)
System), along with the subject’s systolic blood pressure reading.  In order to avoid 
having subjects with significant concurrent cardiovascular disease who would be at 
unacceptably high risk for a CV adverse event (AE) enrolled into the study, subjects 
with the following clinical conditions, which place them at excessively high risk for 
ASCVD as defined by the 2013 ACC/AHA Guidelines on the Assessment of 
Atherosclerotic Cardiovascular Risk, will not be included in the study: clinically 
established coronary heart disease; cerebrovascular disease; peripheral artery disease; 
abdominal aortic aneurysm; and chronic kidney disease. Subjects who have 
experienced a prior non-fatal cardiovascular disease event (angina, heart failure, heart 
disease, heart attack or stroke/transient ischemic attack) or have had heart surgery or 
who currently have uncontrolled high blood pressure (either by self-report or 
measured systolic blood pressure higher than 180 mmHg or diastolic pressure higher 
than 120 mmHg at the time of the enrollment interview) will also be excluded from 
the study.
2. Gastrointestinal (GI) Bleeding Risk: Subjects for this group will be considered to 
be at moderate risk for gastrointestinal bleeding and eligible for inclusion in the study 
if they have at least one but no more than two of the following risk factors: age 
>65 years; a previous history of uncomplicated ulcer within one year of the study 


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enrollment date; concurrent use of oral corticosteroids; or concurrent use of a low 
dose aspirin regimen.8 Subjects with concurrent or recent (within 30 days) use of 
anticoagulants, a prior history of complicated peptic ulcer, or a GI bleeding event 
requiring hospitalization or blood transfusion will be excluded from the study. 
3. History of Severe Pain: Subjects who report at enrollment that they experienced 5 or 
more episodes of pain they rate as “severe” during the preceding month. 
4. >65 Years of Age: Subjects who report their age at the time of enrollment to be 
greater than 65 years of age. 
Note that these at-risk groups are not mutually exclusive.  Because of substantial overlap in 
these frequently co-morbid conditions, subjects from the at-risk groups are not recruited in 
any specific, fixed proportions.  Approximately 30% of each adult at-risk group (groups 
1-4 above) will be classified as low- literacy based on the Rapid Estimate of Adult Literacy 
in Medicine (REALM) Test9 in order to evaluate dosing compliance and other important 
behaviors among subjects at increased risk due to low health literacy.  Among adult subjects, 
heavy oral OTC pain reliever users (ie, those who report taking an average of 30 or more 
doses per month on average in the 3 months preceding enrollment) will be enrolled in 
approximately a 2:1 ratio with moderate users (5-29 doses in the previous 3 months).
Additional Cohort of Interest:
Adolescent subjects will be included for pediatric compliance and safety assessments.
1. Adolescent Subjects (12-17 years of age): Subjects who report their age at the time 
of enrollment to be 12-17 years.
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.  Eligibility questions that 
involve only straightforward collection of subjects’ self-reports may be administered by any 
trained and designated member of the investigator’s study team (including non-pharmacist 
study coordinators).  Exclusion criteria questions that require additional judgment or 
understanding to recognize potential risks or clinical issues, or that involve sensitive 
discussions (such as birth control verification) must be administered by a registered 
pharmacist (either the investigator or another pharmacist from the study team).
The specific criteria that must be evaluated by a study pharmacist (and not by a 
non-pharmacist member of the study team) are: Exclusion Criteria Numbers 6 through 
10 and 15 (see Section 4.2).


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4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Male or female 18 years of age or older, has history of using oral OTC analgesics at 
OTC dose levels, defined as taking at least 5 doses/month on average during the past
3 months, and qualifies for inclusion in at least one risk group category, including 
cardiovascular, gastrointestinal bleeding, history of severe pain (5 episodes in last 
month) or >65 years of age (see Groups 1-4 in Section 3.1).
OR
Male or female 12-17 years of age and has history of using oral OTC analgesics at 
OTC dose levels, defined as taking at least 5 doses/month on average during the past
3 months.
2. Evidence of a personally signed and dated informed consent document (ICD), and in 
the case of minor adolescent subjects (12-17 years of age or adolescent subjects 
residing in states where the age of majority is > than 18), an assent document,
indicating that the subject and where applicable a legally acceptable 
representative/parent(s)/legal guardian has been informed of all pertinent aspects of 
the study.
3. Willing and able to comply with scheduled visits, treatment plan, and other study 
procedures.
4. Willing (or in the case of adolescent subjects, the parent/guardian is willing) and able 
to purchase study medication.
5. Agrees the product purchased is for subject’s own use and not to be shared.
6. Willing (or in the case of adolescent subjects, the parent/guardian is willing) and able 
to provide contact information for follow-up purposes.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subject (or parent/guardian, if applicable) cannot read, speak, and/or understand 
English.
2. Trained or employed as a healthcare professional.
3. Subject or someone else in the household is employed by a pharmaceutical company, 
medical practice or hospital, pharmacy, managed care or health insurance 
organization or a contract research organization.


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4. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
potential subjects who are Pfizer employees, including their family members, directly 
involved in the conduct of the study.
5. Participation in other studies involving investigational drug(s) within 6 months prior 
to study entry and/or during study participation.
6. Known hypersensitivity to ibuprofen, aspirin, or any other NSAIDs.
7. Subjects with the following clinical conditions which place them at excessively high 
risk or have 20% 10-year risk for atherosclerotic cardiovascular disease (ASCVD), 
as defined by the 2013 ACC/AHA Guidelines on the Assessment of Atherosclerotic 
Cardiovascular Risk, will not be included in the study: clinically established coronary 
heart disease; cerebrovascular disease; peripheral artery disease; abdominal aortic 
aneurysm; and chronic kidney disease. Subjects who have experienced a prior 
non-fatal cardiovascular disease event (angina, heart failure, heart disease, heart 
attack, stroke/transient ischemic attack) or have had heart surgery or who currently 
have uncontrolled high blood pressure (either by self-report or by measured systolic 
blood pressure higher than 180 mmHg or diastolic pressure higher than 120 mmHg at 
the time of the enrollment interview), will also be excluded from the study. 
8. Subjects with concurrent or recent (within 30 days) use of anticoagulants, a prior 
history of complicated peptic ulcer, or a gastrointestinal bleeding event requiring 
hospitalization or blood transfusion. 
9. Other 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 (IP)
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.
10. Pregnant female subjects; breastfeeding female subjects; and male 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 28 days after the end of their 30-Day Use Phase or, for subjects who use 
the investigational product after Day 30, 28 days after the last recorded dose of 
investigational product.


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11. 18 years of age or older and classified as normal-literacy (REALM Test score 61) 
after the normal literacy group quotas (approximately 70% of adult subjects) are full 
or refuses to complete the REALM Test (note there is no corresponding literacy 
exclusion criterion for adolescent subjects based on REALM Teen score).
12. 18 years of age or older and classified as moderate (less frequent) oral OTC pain 
reliever user (<30 doses per month on average in the preceding 3 months) after the 
moderate user group quotas (approximately 33% of adult subjects) are full. 
13. Not capable of swallowing a vitamin-sized tablet.
14. Refuses to participate in required assessments (such as urine pregnancy, finger-stick 
cholesterol or blood pressure tests, or unable or unwilling to comply with electronic 
diary procedures).
The following additional exclusion criteria will be applied for adolescent subjects only 
(12-17 years of age):
15. Has developmental or learning disabilities that, in the judgment of the parent/guardian 
or the investigator, would interfere with study participation.
16. Another adolescent child from the family is already enrolled into the study, or 
parent/guardian does not agree that only one adolescent child from the family or 
household will be enrolled into the study.
4.3. Randomization Criteria
Not Applicable (N/A).  This is a single-treatment study.
4.4. Lifestyle Requirements
4.4.1. Contraception
In this study, male and female subjects who are of childbearing potential will receive 
ibuprofen, which has been associated with premature closure of the ductus arteriosus.
Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use a method of highly effective contraception throughout 
the study and for at least 28 days after the end of their 30-Day Use Phase or for subjects who 
use the investigational product after Day 30, for 28 calendar days after their last recorded 
dose.  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 list of permitted contraception methods (see below) and will confirm that the subject 
has been instructed in their 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 
a highly effective method of contraception consistently and correctly and document the 
conversation, and the subject’s affirmation, in the subject’s case report form (CRF).  In 
addition, the investigator or designee will instruct the subject to call immediately if the 


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selected contraception method is discontinued or if pregnancy is known or suspected in the 
subject or 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.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Abstinence, if this is the preferred and usual lifestyle of the subject (conditional upon 
agreement to use an acceptable method of birth control if subject becomes sexually 
active).
7. Same-sex partner (conditional upon agreement to use an acceptable method of birth 
control if subject becomes sexually active with a member of the opposite sex).
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 


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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.
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 is ibuprofen 600 mg IR/ER tablets (Advil 12 
Hour).
5.1. Allocation to Treatment
This is a single-treatment study; all eligible subjects or the parents/guardians of prospective 
adolescent subjects will be provided the opportunity to purchase and use ibuprofen 600 mg 
IR/ER tablets.
5.2. Breaking the Blind
Not Applicable (N/A).  This is an open-label study.
5.3. Subject Compliance
Subjects will use the medication based only on their reading of the Drug Facts Label (DFL) 
and other information on the package (ie, use of the study drug is not protocol-driven).  Data
regarding subjects’ use of the medication will be captured in an electronic diary -application 
either on the subject’s own device (eg, smart phone, tablet or personal computer) or on a 
smart phone provided for use in the study.  Subjects (or the parent/guardian of an adolescent 
subject) will be instructed by the study staff at the enrollment visit how to use the electronic 
diary to report their use of the medication throughout the 30-Day Use Phase.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Ibuprofen 600 mg IR/ER (provided with the proposed trade name Advil 12 Hour) will be 
provided as tablets for oral administration.  The 600 mg tablets will be supplied in 40 count 
packages and labeled according to local regulatory requirements.
5.4.2. Preparation and Dispensing
The investigational product will be dispensed at the end of the Enrollment Visit. A qualified 
staff member will dispense the investigational product via unique container numbers in the 
packages provided, recording dispensation in the Electronic Data Capture (EDC) system. 
The subjects or the parents/guardians of prospective adolescent subjects may purchase up to
a maximum of 5 total packages of the investigational product at any time during their 30-Day 


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Use Phase.  The subject/caregiver should be instructed to maintain the product in the package 
provided throughout the course of the Use Phase.
5.5. Administration
This is an observational study with no other protocol-directed dosing.  Subjects will use (or 
the parent/guardian of adolescent subjects will administer) the investigational product 
according to their own understanding of the directions on the DFL.  The DFL directs users to 
“swallow the tablet of investigational product whole – do not crush, chew, split or dissolve.”  
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational 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 SRSD 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.  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 
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.


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Temperatures occurring outside of the specified storage range of 20°-25°C (68°-77°F) will be 
recorded and reported to Pfizer.  IP will not be quarantined unless the reported temperature 
excursion is outside the documented stability range of 15°-30°C (59°-86°F).  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 and do not need to be reported.
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. All unused IP and/or empty study 
drug packaging must be returned to the contract research organization (CRO) by the subject 
at the end of the trial.  A pre-paid United States Postal Service (USPS) envelope will be 
provided to subjects at the end of the pharmacy enrollment visit for return of unused IP and 
empty packaging.
5.7.1. Return or Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the return or destruction of unused 
investigational product (eg, at the site). If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in compliance 
with applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
There are no prohibited prior treatments.  Subjects currently using anticoagulants will be 
excluded from the study prior to purchasing study medication (see Section 4.2).
6. STUDY PROCEDURES 
6.1. Study Sites
Approximately -30 retail pharmacies will be chosen as study sites.  These sites represent an 
environment or setting in which consumers customarily seek and purchase their 
over-the-counter medications, and trained study staff and pharmacist-Investigators will 
manage all subject enrollment and medication purchase interactions.  The sites will be 
selected from diverse areas of the US to provide geographic and demographic diversity.  
Some sites may be selected in areas of lower socio-economic status to improve recruitment 
of low- literacy subjects.  Each site will be required to have a private office or a suitable 
semi-private area where the study will be carried out confidentially and without distraction.  
The study area at the site will be equipped with all necessary computer equipment and a 
high-speed Internet connection to accommodate the electronic data capture (EDC) system.
6.2. Recruitment Methods
To ensure adequate recruitment for the specific targeted groups requested by the FDA, 
multiple recruitment methods are anticipated.


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
General Population Advertising (Pain Indication Only): General population 
advertisements, such as direct mail postcards, print, radio or targeted digital media to 
the geographic areas surrounding the study pharmacy sites will be used to generate 
interest.  The advertisements will feature a general pain indication (“Do you use 
over-the-counter pain relievers to treat aches and pains?”) with a toll-free number for 
prospective subjects to call.  These advertisements are expected to capture a 
substantial proportion of the needed elderly subjects (>65 years of age), and a portion 
of this advertising may be targeted to households with socioeconomic factors loosely 
correlated with lower-literacy and households with children 12-17 years of age.

Targeted Advertising: Because of the need to recruit adult subjects with 
highly-specific risk conditions (CV risk, GI bleeding risk, and severe pain sufferers), 
additional media advertisements, potentially including postcards, print, radio or 
targeted digital media, will be employed to target consumers who: 1) have pain
usually treated with oral OTC pain relievers, and 2) also have relevant risk factors for 
inclusion in the target group (for example, “Do you use over-the-counter pain 
relievers to treat aches and pains?  And, are you 65 years of age or older: …?” or “Do 
you suffer from severe pain?”).

Targeted Outbound Pre-Recruiting: Because adolescents are: 1) less likely than 
adults to use pain relievers on a regular basis, and 2) less likely to see standard 
recruitment advertising and consider themselves candidates for inclusion in a study, 
specialized recruitment vendors located near the pharmacy study sites will conduct 
outbound pre-recruiting telephone calls to parents/guardians from existing market 
research databases to identify those with adolescents who would be interested in 
participating.  Additional targeted outbound pre-recruiting (possibly including other 
direct methods) may also be used to supplement recruitment for low- literacy 
subjects.
6.3. Telephone Pre-Screening
Prospective subjects (or parents/guardians of subjects) who become aware of the study via 
recruitment advertising will respond to the advertisement by calling a telephone number or 
(if available) visiting a website address to see if they qualify to participate in the study.  Both 
the telephone number and the website address will route subjects to speak with a trained 
interviewer in the CRO call center, where potential subjects (or parents/guardians of minor
subjects) will be pre-screened for initial eligibility criteria (all data will be entered into the 
study EDC system). 
The parents/guardians of prospective adolescent subjects or other subjects identified by way 
of targeted outbound pre-recruiting will likewise be directed (by the recruiter) to visit a study 
website address or call the toll-free number at the CRO call center to see if they qualify to 
participate in the study. 


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Because a large proportion of each adult subgroup, approximately 30%, will need to be low
literacy (AUSs often have naturally occurring low- literacy incidence rates of approximately 
12-15%), evaluation of prospective adult subjects for literacy will be completed by telephone 
at the time of initial screening.  This will be accomplished using the Rapid Estimate of Adult 
Literacy in Medicine-Short Form (REALM-SF) Test, an abbreviated version of the REALM 
Test consisting of an excerpt of only 7 words from the full assessment that are demonstrated 
to have high correlation to results of the REALM Test when dichotomized to an 
8th/9th reading grade level split.10 Words from the REALM-SF will be made available to 
prospective subjects for the telephone pre-screening via a simple website address subjects 
can enter into the browser of their smartphone, tablet, or personal computer, or by other 
electronic or non-electronic means.  Once accessed, this list will display only the 7 words 
from the REALM-SF Test.  The interviewer will give instructions for completing the test 
verbally over the telephone, after which the prospective subject will read the words aloud,
and scoring of the REALM-SF words will be documented in the EDC system exactly as it 
would be if administered in- person.  REALM-SF scores of zero to 6 correspond to 3rd to 
8th grade reading levels (low health literacy), whereas a score of 7 corresponds to 9th grade or 
higher reading levels (normal health literacy).  This pre-screening for reading ability will 
help ensure adequate representation of poor readers within each of the adult at-risk groups 
without the significant inefficiency incurred by conducting the REALM Test only in-person 
at the sites.  Note that neither adolescent subjects, nor their accompanying parents/guardians, 
will be screened for literacy at the time of the initial telephone screening and scheduling call.  
Subjects who are qualified based on their REALM-SF score and other eligibility criteria will 
have an enrollment visit scheduled at the nearest pharmacy study site, and their contact 
information will be collected in the subject scheduling system. 
6.4. Pharmacy Enrollment Visit
Upon arrival at the pharmacy study site, subjects (or parents/guardians of prospective 
adolescent subjects) will participate in the following enrollment visit steps or procedures:
1. Identity for the subject (or the parent/guardian of adolescent subjects) will be verified 
from government-issued identification (ID) against contact information contained in the 
scheduling system.
2. For adolescent subjects 12-17 years of age, the study staff will confirm that the 
adolescent is accompanied by a parent or guardian.  Legal guardians will be required to 
provide proof of guardianship.  The initial telephone pre-screening and pharmacy 
enrollment visit assessments (with the exception of the REALM-Teen Test7 and instances 
where the investigator may exercise judgment to determine if the parent/guardian and/or
adolescent subject should both be present for and respond to questions in the birth control 
verification discussion or other sensitive content areas) will be directed to and managed 
by the parent/guardian, who will answer for and on behalf of the adolescent subject, and 
must be present to enroll into the study and purchase study medication.
3. Explicit consent to gather personal information will be elicited and documented.


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4. Next, the pre-screening questions answered initially by telephone will be re-asked by the 
study site personnel to ensure the subject currently meets all required initial eligibility 
criteria.  Questions at this stage will also collect information about the frequency of
subjects’ oral OTC pain reliever use in the 3 months prior to enrollment to define or 
identify heavy/frequent users (those taking 30 or more doses on average per month in the 
preceding 3 months) and the nature of subjects’ usual pain, including severity, to define 
or identify self-reported frequent, severe pain sufferers (5 or more episodes of severe pain 
in the preceding month).  Additional questions regarding medical conditions will also be 
asked at this stage to identify those with unacceptably high GI or CV risk (“Ask a Doctor 
Before Use” conditions).  Responses to these questions will also help identify subgroups 
for at-risk populations.
5. After verification of initial screening information, those who qualify (either the subject or 
the parent/guardian of adolescent subjects) will be given the Advil 12 Hour package and 
instructed to read the product information.  After reviewing the DFL and other 
information on the outside of the package, the subjects (or the parents/guardians of 
adolescent subjects) will be asked if they would like to purchase the product today for 
their own (or their child’s own) use for $5.00 per package of 40 tablets.
6. Adult subjects who decline to purchase will be asked the reasons why they did not want 
to purchase and will provide basic demographic information and complete the REALM 
Test, after which participation will end, and subjects will be compensated.  The 
parents/guardians of adolescent subjects who decline to purchase for their adolescent 
subject will be asked the reason why, provide basic demographic information and will 
complete the Rapid Estimate of Adolescent Literacy in Medicine (REALM-Teen) Test 
administered to descriptively characterize their health literacy level, after which 
participation will end, and the parents/guardians of the adolescent subject will be 
compensated.
7. Subjects (or parents/guardians of adolescent subjects) who decide to purchase the product 
will be asked to provide a brief history of the subject’s analgesic use, including brands 
taken of both oral OTC and prescription medications, followed by collection of basic 
demographic information and the REALM Test for adults and the REALM-Teen Test for 
adolescent subjects.  After the normal literacy group quotas (approximately 70% of adult 
subjects) are full, adult subjects who score as normal literacy on the REALM Test will 
end their participation at this point and be compensated.
8. Next, additional eligibility questions will be asked (see Exclusion Criteria 4, 9, and 13
(and if an adolescent subject, see 15 and 16) in Section 4.2). Inclusion and exclusion 
criteria are evaluated programmatically in the EDC system (based on pre-specified, 
protocol-defined, automatic edit checks), some at the initial telephone screening, and then 
remaining required criteria at the enrollment visit.  Exclusion criteria questions that 
require additional judgment or understanding to recognize potential risks or clinical 
issues, or that involve sensitive discussions (such as birth control verification), must be 
administered by a registered pharmacist (either the investigator or another pharmacist 
from the study team). 


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9. Subjects (or the parent/guardian of adolescent subjects) who are qualified will be asked to 
review and sign the informed consent document, which will be administered, signed and 
documented electronically.  Adolescent subjects (12-17 years of age, or older in states 
where the age of majority >18 years) will be asked to sign to indicate their assent.  As 
part of the informed consent process, adolescent subjects- will be instructed that if they 
do not wish to participate in order not to disclose to their parent/guardian that they are 
sexually active, they may opt-out without being required to disclose the reason.
10. After this, the adequacy of birth control methods will be verified, and females of 
childbearing potential will self-administer (or in the case of young adolescent female 
subjects, an accompanying parent/guardian may be allowed to assist) an in-stream 
urine-based pregnancy test to ensure they are not pregnant. 
11. At this stage, all subjects 18 or older will have a finger-stick cholesterol test (to measure 
total cholesterol and HDL) and blood pressure measurement.  Results from these tests 
will be entered with other previous data into the ASCVD 10-Year Risk Calculator in the 
EDC System (as described in Item 1 in Section 3.1). Next, all subjects will be asked to 
provide additional contact information necessary for study participation (which will be 
entered into an administrative database), after which subjects’ responses to all relevant 
health and other eligibility questions will be evaluated programmatically in the EDC 
System to determine if any exclusion criteria apply, or alternatively if the subject 
qualifies to continue to the study medication purchase transaction.
12. Adult subjects with excessively high CV or GI risk (screen failures, as defined in Items 7
and 8 in Section 4.2) who decide to purchase the product will provide basic demographic 
information, complete the REALM Test, and then answer questions about why they 
thought the medication would be appropriate for them to purchase even though they have 
an “Ask a Doctor Before Use” condition from the DFL (to enable descriptive analysis of 
the reasons).  All other subjects who do not qualify to purchase will provide basic 
demographic information and complete the REALM Test (adults) or REALM-Teen Test
(adolescents).  Following these questions, participation will end, and subjects (or the 
parents/guardians of adolescent subjects) will be compensated.
13. Subjects (or the parents/guardians of adolescent subjects) who qualify to purchase the 
study medication will be given access to an electronic medication use diary- application 
either on the subject’s (or, in the case of adolescent subjects, the parent’s/guardian’s) own 
device (eg, smart phone, tablet, or personal computer) or on a smart phone provided for 
use in the study.  Subjects (or parents/guardians of minor subjects) will be instructed by 
the study staff at the enrollment visit how to use the electronic diary to report their use of 
the study medication throughout the 30-Day Use Phase.
14. The electronic diary will also capture information on concomitant medications to 
elucidate concurrent use of NSAIDs (see Section 6.4).  To avoid sensitizing subjects to 
the purpose of concomitant medications data collected or influencing their behaviors 
surrounding concomitant NSAID use in any way, subjects will be instructed at the end of 
the enrollment visit to enter information for all concomitant medications (not limited to 


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NSAIDs) taken in the 24-hour period before or the 24-hour period after each dose of the 
study medication.  The concomitant medications form in the electronic diary application 
will present instructions to reaffirm the relevant time windows for concomitant 
medication reporting before and after each dose of the study medication, and subjects will 
see these instructions each time they proceed to enter a concomitant medication dose.  
However, the electronic diary application will not present proactive prompts or reminders
to subjects to make concomitant medication entries (to avoid inadvertently influencing 
their behaviors or perceptions of expectations for their behaviors during the study).  
Specifically, the electronic diary will elicit information about the medication name, date 
and time of dose and dose amount for each concomitant medication taken by the subject.  
To minimize the overall reporting burden, subjects will be instructed to enter dosing 
information for routine concomitant medications (regimens initially reported at 
enrollment) in the electronic diary only if they take them differently than normal.  
Otherwise, routine medications reported at enrollment, including NSAIDs, will be 
assumed to be ongoing, concomitant medications during the Use Phase.  The 24-hour 
windows before and after doses of the study medication reflect that:

The concomitant NSAIDs of interest are those taken in close enough temporal 
proximity to the study medication to result in additive NSAID over-exposure risk.

Most prescription and oral OTC NSAID pain relievers have meaningful plasma
concentration levels (and therefore dosing intervals) 24 hours, and therefore 
24 hours is the relevant window for concomitant medication collection before
study medication use.

The study medication, Advil 12 Hour, has a 12-hour dosing interval.  However, 
24 hours is conservatively selected as the relevant window for concomitant 
medication collection after study medication use: 1) to reduce the conceptual 
burden that would be imposed on subjects by having different windows before 
and after, and 2) to avoid prompting or suggesting “12 hours” to subjects in any 
way during the Use Phase, since this value corresponds to a key medication use 
compliance endpoint.
15. Subjects (or the parent/guardian of adolescent subjects) who qualify will purchase the 
study medication and are permitted to purchase as much study medication as desired (up 
to 5 packages) at the start of the study.  If they purchase less than 5 packages initially, 
they will be allowed to purchase additional study medication from the research site at a 
resupply visit, if desired, during the course of -their 30-Day Use Phase, not to exceed a 
total of 5 packages for the study.  While the parents/guardians of adolescent subjects 
must be present to enroll into the study and purchase study medication initially at the 
enrollment -visit, to ensure needed realism, adolescent subjects- who are assigned the 
responsibility to complete the electronic diary and participate in all future assessments
may purchase additional medication, unattended, during the course of their 30-Day Use 
Phase, up to the maximum of 5 packages.  Any attempts by subjects (or the 
parents/guardians of adolescent subjects) to purchase more than 5 packages of the study 
medication during the study will be recorded in the study database.


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16. Female subjects of childbearing potential and at risk of pregnancy will be provided an 
end of study pregnancy test (to self-administer after the last dose of study medication and 
report the result to the nurse interviewer during the End-of-Study Telephone Interview)
together with a pre-paid mailer to return the study product and study-issued electronic 
diary device (if one is provided), and the enrollment visit will end.  
6.5. Resupply Pharmacy Visit
For subjects who purchased less than 5 packages of study medication at their pharmacy 
enrollment visit, they may return to the pharmacy to purchase additional study medication at 
a resupply visit, if desired, during the course of their 30-Day Use Phase, not to exceed a total 
of 5 packages for the study. 
6.6. 30-Day Use Phase
After leaving the pharmacy research site, subjects will use the product as needed (determined 
by the subject or the parents/guardians of adolescent subjects), based on their own 
understanding of the DFL and packaging information (ie, use of the study medication is not 
protocol-driven) from Day 1 to Day 30 (Use Phase).  The electronic diary will be designed to 
send periodic (weekly, at 7-day intervals after study medication purchase) reminders to 
record any use of the product as soon as subjects take it.  These reminders will include
consistent messaging for all subjects. 
In the electronic diary, subjects (or the parents/guardians of adolescent subjects) will record 
each dose of medication taken, including date, time, and number of tablets for each dosing 
occasion and will also enter additional information about the pain they were treating (for 
example, type and severity) to help characterize their reasons for dose selection. They will 
also be asked situational questions (eg, where they were, who were they with, what were they 
doing) at the time of dosing and what they would have taken if they did not have the study 
medication to use.  The purpose of these situational questions is to: 1) help accurately 
characterize the reasons for subjects’ behaviors, as well as 2) provide context to aid subjects 
in remembering what they did and why later during the End-of-Study (EOS) Interview 
questions.  The electronic diary will also help capture information on concomitant 
medications to elucidate concurrent use of NSAIDs as described in Step 14 in Section 6.4.
At any time during the 30-Day Use Phase, subjects (or the parents/guardians of adolescent 
subjects) may contact the Investigator at the pharmacy site or may call the PEGUS 24-hour 
nurse line to report an adverse event.
6.6.1. End-of-Study Telephone Interview
After the end of the 30-Day Use Phase (Days 31 to 40), a nurse from the CRO will conduct 
an end-of-study (EOS) interview.  The telephone interview should take place shortly after 
Day 30 to ensure that all electronic diary entries have been transmitted, but at a time that 
reasonably allows for accurate subject recall about specific dosing instances. For adolescent 
subjects, either the parent/guardian or the adolescent subject will complete the EOS 
Interview, as designated by the question regarding who typically administers medications at 
the end of the Enrollment Visit. Subjects (and/or the parents/guardians of adolescent 


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subjects) will be questioned to gather information on AEs, concomitant medications for 
subjects who experienced adverse event(s), subjects’ use of the study medication (and 
reasons for any deviations from the label directions), concomitant analgesic use, subjects’
typical practices on following oral OTC dosing directions for analgesics, end-of-study 
pregnancy test results for female subjects of childbearing potential and at risk of pregnancy,
and any discussion the subject may have had with a physician or other healthcare 
professional about the study medication use (see DCI Section 22).  To facilitate a careful, 
in-depth behavioral assessment of subjects’ reasons for misusing Advil 12 Hour, the 
following procedures will be employed for this final interview in person or via telephone:

At the end of the 30-Day Use Phase, a simple tabular summary of all doses taken by 
the subject will be generated.  This dosing summary report may include information 
such as the date and time of dose, number of tablets, type of pain treated and pain 
severity for each dosing occasion recorded in the electronic diary.  The report may
highlight individual occasions on which misuse occurred, defined as taking: 1) more 
than 2 tablets per calendar day, 2) more than 1 tablet per dosing occasion (or distinct 
dosing occasions with identical date-time values), or 3) a dose <12 hours after the
most recent previous dose.  Individual electronic diary entries (dosing occasions) may 
be flagged for more than one type of misuse.

The dosing summary report will be provided to the subject (and/or the 
parent/guardian of adolescent subjects) for review and discussion before the time of 
the EOS Interview.  At enrollment or subsequently, subjects may elect for (or be 
assigned) 1 of 3 options to complete the EOS Interview:
1. Electronic diary data for the final interview will be provided to the subject (and/or 
the parent/guardian of adolescent subjects) in advance of the EOS interview 
(typically after Day 30 via email).  This is the recommended or preferred method.  
The diary data will be password protected to avoid inadvertently disclosing 
personal health information to anyone other than the subject.  Once the dosing 
summary report has been received by the subject, the nurse will call the subject by 
telephone (or alternatively, in some cases, may schedule an in-person 
appointment) to complete the EOS interview.  Alternatively, the subject (and/or 
the parent/guardian of adolescent subjects) can call the nurses directly during 
specific hours of the week. 
2. For subjects with no access to email or who prefer to be interviewed at the site, an 
appointment for the EOS interview may be scheduled at the pharmacy site.  
Appointment times will coincide with nurse hours at the CRO.  The subject will 
arrive at the pharmacy, return any unused study medication, using a computer at 
the site, and call the nurse by telephone from the site to complete the EOS 
Interview.
3. A printed paper copy of the dosing summary report will also be sent to the subject 
via regular mail, and the EOS Interview will be conducted by telephone.


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•
When the EOS Interview is initiated with the subject (or parent/guardian of the 
adolescent subject), if misuses are evident from the electronic diary, the interviewer 
will review the relevant information from the dosing summary report with attention to 
each prioritized, specific occasion or day with misuse.  
 
 
 
 
•
Subjects whose diaries indicate that study medication was taken but for whom no 
misuse occurred will skip questions regarding reasons for misuse, but will still 
participate in other relevant parts of the EOS Interview, including an assessment of 
adverse events and medication error recording and follow-up as well as concomitant 
analgesic use or concomitant medication use for subjects experiencing adverse events
and end-of-study pregnancy test results for female subjects of childbearing potential.  
Subjects whose diaries show no recorded uses of study medication will be asked 
questions regarding why the medication was not taken.  If the subject reports that 
study medication was taken but not recorded in the electronic diary, the interviewer 
will ask general questions (not occasion-specific) regarding what types of pain were 
treated, how the subject took the medication (typical number of tablets per day, 
tablets per dose and frequency of dosing) and whether the subject (or the 
parent/guardian of adolescent subjects) talked to a doctor or other HCP about Advil 
12 Hour during the study. 
Subjects will be instructed at the conclusion of the End-of-Study Telephone Interview to 
discontinue all use of study medication, use the provided mailing materials to return all 
unused study medication and electronic diary device (if applicable), and to report the results 
of their end-of-study pregnancy test (females of childbearing potential).  Unused study 
medication and other materials will be returned using a pre-addressed, postage-paid mailing 
envelope provided at enrollment. Subjects who are physically able to have children and who 
are sexually active will also be reminded (and provided the date) of the instruction to use 
birth control consistently and correctly at the conclusion of the End-of-Study Telephone 
Interview.
Once the subject has started the EOS Interview, subjects (and/or the parent/guardian of 
adolescent subjects) will no longer be able to make additional entries in their electronic diary 
and also will be provided with a form in the electronic dairy to self-administer (via mobile 
device) a final questionnaire about their attitudes and beliefs relating to pain reliever 
medications.  The Attitudes and Beliefs Questionnaire will be completed by subjects using 
the electronic-diary application within 10 days after completing the End-of-Study Telephone 
Interview.  This will include questions about usual oral OTC pain reliever dosing practices, 
the stability of subjects’ (or the parents/guardians of adolescent subjects) daily routines, size 
and orderliness of their households, subjects’ height and weight, and finally rating scales for
agreement with multiple statements about the reasons for various medication usage patterns 
or decision-making practices.
CCI


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6.6.2. Follow-Up Phone Contact (Up to Day 75)
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after the end of the subject’s 30-Day Use Phase or, for subjects who use the investigational 
product after Day 30, for at least 28 (and up to 35) calendar days after the last recorded dose 
of investigational product to capture any potential adverse events (see Section 8.1.4) and to 
confirm appropriate contraception usage (see Section 4.4.1).  The date of last administration 
of the investigational product will be identified by the nurse interviewer at the EOS 
Interview, who will verify with the subject whether the last administration corresponds with 
the date of the latest dosing occasion recorded in the diary or, if applicable, another date of 
administration that was not recorded by the subject.  Contact with the subject will be made
via a phone call, and study participation will end.
6.7. Reimbursement for Study Medication Purchase
Once all subjects have exited the study, all subjects will be reimbursed (at the same time) for 
the purchase price of study medication they purchased during the study.  To maintain the 
naturalism of the study, subjects will not be notified in advance, at any time that their 
medication purchases will be reimbursed.
6.8. Subject Withdrawal or Early Termination
6.8.1. 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.  If subjects who 
request to discontinue their participation are willing to complete follow-up procedures, the 
EOS telephone interview would be conducted as soon as possible and the Follow-Up Phone 
Contact will be conducted 28-35 calendar days after the date they request to discontinue.  
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 CRF 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.
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 8.1.3) 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. 


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If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.8.2. 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 two
documented phone calls, faxes, or e-mails as well as lack of response by the subject to 
one registered mail letter. All attempts should be documented. If it is determined that the
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death. 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.
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 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 all unused investigational product, 
request that the subject complete the EOS Interview, if applicable, and follow up with the 
subject regarding any unresolved adverse events (AEs).
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. Health Literacy Assessment
The REALM-SF Test will be used to estimate reading grade level for adult subjects during 
pre-screening.  The REALM-SF score corresponds to 4 grade-equivalent reading levels as 
shown in Table 1 below.  A score of 6 or less (a reading level of eighth grade or lower) will 
be used to identify subjects that potentially fall into the low literacy subgroup.


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Table 1.
REALM-SF Test Grade-Equivalent Reading Levels
REALM-SF Score
Grade-Equivalent Reading Level
0
Third and below
1-3
Fourth to sixth
4-6
Seventh to eighth
7
Ninth and above
The REALM Test will be used to confirm measured reading grade level for adult subjects at 
the enrollment visit and will be the measure of functional health literacy used for this study. 
The REALM score corresponds to 4 grade-equivalent reading levels as shown in Table 2
below.  A score of 60 or less (a reading level of eighth grade or lower) will define the 
low-literacy subgroup. 
Table 2.
REALM Test Grade-Equivalent Reading Levels
REALM Score
Grade-Equivalent Reading Level
0-18
Third and below
19-44
Fourth to sixth
45-60
Seventh to eighth
61-66
Ninth and above
The REALM-Teen Test will be used to measure reading grade level for all adolescent 
subjects.  The REALM-Teen score corresponds to 5 grade-equivalent reading levels as 
shown in Table 3 below.  No low-literacy subgroup will be defined for adolescents.  Instead, 
subjects’ reading levels will be presented descriptively.
Table 3.
REALM-Teen Test Grade-Equivalent Reading Levels
REALM-Teen Score
Grade-Equivalent Reading Level
0-37
Third and below
38-47
Fourth to fifth
48-58
Sixth to seventh
59-62
Eighth to ninth
63-66
Tenth and above
The health literacy tests will be scored in the EDC system.  Adult subjects may be excluded 
based on REALM Test score if literacy quotas have been reached (see Section 4.2).
7.2. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed on Day 1 before enrollment into the study (purchase of 
study medication) and at the end of the study (or as soon as possible after early-withdrawal)
to confirm the subject has not become pregnant during the study.  A pregnancy test kit will 
be provided to the subject at the pharmacy enrollment visit (or may be sent to the subject as a 
replacement towards the end of the study), so the subject can self-administer a pregnancy test 
following the last dose of study medication.


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Also, following the enrollment visit, an additional pregnancy test will be conducted for any 
female subjects who elect to return to the pharmacy for the first purchase of the study 
medication within 3 calendar days of the original enrollment visit (to ensure they have not 
become pregnant during the intervening days).  The result will be documented in the Data 
Collection Instrument (DCI).
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. 
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided approved by the sponsor in accordance with instructions provided in its 
package insert.  Subjects who have missed a menstrual period or who show an indeterminate
or positive result on the urine test may not further progress in the study until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test 
conducted at a certified laboratory).
In the case of a positive confirmed pregnancy, the subject will be withdrawn from
administration of investigational product and from the study. 
7.3. Finger-Stick Cholesterol Test
After informed consent but before enrollment into the study (purchase of study medication), 
subjects 18 years of age and older will be required to complete a finger-stick cholesterol test.  
The purpose of this assessment is to determine if subjects are at increased risk for 
cardiovascular disease to qualify for at-risk group inclusion (see Section 3.1).
The finger-stick cholesterol test will be conducted by a trained member of the study staff 
using a commercially-available analyzer (CardioChekPlus or similar).  Lipid panel results, 
including total cholesterol and HDL cholesterol, will be entered directly into the EDC 
System by study staff at time of the test.  Subjects who refuse to complete the test will be 
excluded from participation.
7.4. Blood Pressure Test
After informed consent but before enrollment into the study (purchase of study medication), 
subjects 18 years of age and older will be required to complete a blood pressure test.  The 
purpose of this assessment is to determine if subjects are at increased risk for cardiovascular 
disease to qualify for at-risk group inclusion and also to rule out those with unacceptably 
high risk for a CV adverse event (see Section 3.1).


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The blood pressure test will be conducted by a trained member of the study staff using a 
commercially-available blood pressure testing device.  Blood pressure results, including 
systolic and diastolic blood pressure values, will be entered directly into the EDC System by 
study staff at time of the test.  Subjects who refuse to complete the test will be excluded from 
participation.
Blood pressure will be assessed in a sitting position with both feet flat on the floor and back 
supported, after the subject has been seated for at least 10 minutes. Subjects should be 
instructed not to speak during measurements. The left (or if this is not possible, then the 
right) arm will be used for any given subject when measuring blood pressure. At the 
discretion of the trained member of the study staff, blood pressure measurements may be 
repeated to confirm the measurement (eg, due to subject movement, abnormal measurement, 
etc.). When repeated measurements are necessary, a total of 3 measurements, at least 
5 minutes apart, will be made, and the lowest systolic and diastolic values from these three 
measurements will be entered into the EDC System.
7.5. 10-Year Risk for Atherosclerotic Cardiovascular Disease (ASCVD) Assessment
The 2013 ACC/AHA Prevention Guidelines Tool CV Risk Calculator, which is a companion 
tool to the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk, will be 
used to calculate adult subjects’ 10-year risk for ASCVD.  A Risk Calculator will be 
programmed in to the EDC system to calculate each subject’s 10-year ASCVD risk.  Values 
entered into the Risk Calculator will include age, gender, race, total cholesterol, HDL 
cholesterol, systolic blood pressure, treatment for high blood pressure (yes/no), diabetes 
(yes/no), and current smoking status (yes/no).  Subjects in the 40-79-year age bracket will 
only be eligible for inclusion in the CV Risk Group if they have a score of 5% and <20% 
for 10-Year ASCVD risk (see Section 3.1).
7.6. Rater Qualifications
Not applicable.
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. 


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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 suspected causal relationship to the 
investigational product 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 8.2.3 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 
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.


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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.  In addition, each study 
subject/parent(s)/legal guardian 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 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 28 calendar days after the end of the subject’s 30-Day Use Phase or, for subjects 
who use the investigational product after Day 30, for at least 28 calendar days after the last 
recorded dose.
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.


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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.
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;


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
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

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.


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
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.
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;


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
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.
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
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.


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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
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections and will be handled as SAEs in 
the safety database. 
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.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a subject 
presents with clinical signs/symptoms, such LFT results should be managed and followed as 
described below.
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:


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
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.
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/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 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.


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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;

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).


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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), 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.
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, 
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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
Medication errors may result in this study from the administration or consumption of the 
investigational product by the wrong subject.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject;

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 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, is 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.


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9.1. Sample Size Determination
Overall Sample Size (Adult Risk Groups):
Overall sample size for the combined adult risk groups (cardiovascular risk, gastrointestinal 
bleeding risk, history of severe pain and >65 years of age) is driven primarily by power 
considerations.  The following assumptions are used to construct the sample size calculation:

Subject recruitment will be structured in a way to ensure that heavy pain reliever 
users (ie, those who report taking 30 or more doses on average per month in the 
3 months preceding enrollment) will represent approximately two-thirds (67%) of the 
overall adult sample.

Based on the Primary Endpoint (exceed >1200 mg per day on 2 or more days), the 
composite misuse rate (for combined heavy and moderate users in the study, in the 
proportions postulated above) is assumed to be of 6.6%, for a correct performance (ie,
correct daily dosing compliance) rate of 93.4%.

An a priori performance threshold of 90% is selected for the Primary Endpoint.  The 
lower limit of the 95% confidence interval (CI) for the obtained value for correct 
performance for the Primary Endpoint among the full adult Compliance-Evaluable 
Population must exceed this threshold value for success.

Power should be at least 85%.

Two-sided normal approximation z test for binomial proportion, alpha=.05.
Utilizing these assumptions, an overall sample of at least 620 compliance-evaluable adult 
subjects will yield 85% power to demonstrate superiority of the Primary Endpoint correct 
performance finding over the a priori performance threshold.
Individual Adult Group Sizes:
For each of the first 4 risk groups (adults with cardiovascular risk, gastrointestinal bleeding 
risk, history of severe pain or >65 years of age) it is expected that a minimum of 
approximately 180 subjects will be recruited and enrolled in order to yield at least 155 who 
are compliance-evaluable for the analysis.  Note, however, that because of substantial natural 
comorbidity (overlap) for these risk conditions, the at-risk groups are not mutually exclusive 
and many or most subjects will qualify for inclusion in more than one group, so that the sum 
of the individual subgroup counts will be expected to exceed the total adult subject count.  If 
any individual risk group fails to fill adequately, additional measures (such as more targeted 
recruitment advertising or excluding potential subjects who belong only to other, over-full 
risk groups) may be employed.  Any procedures used to manage risk group representation 
will be documented in the study report.


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Adolescent Group Size:
It is expected that the study will recruit a total of approximately 100 adolescent subjects to 
ensure approximately 80 will be evaluable for the endpoint analysis (note the 
enrolled-to-evaluable attrition rate for adolescents is expected to be somewhat larger than for 
adults).  For the Adolescent Group, a sample of 80 compliance-evaluable subjects is expected 
to be adequate to describe or characterize dosing compliance and other important behaviors 
as well as the underlying reasoning processes for this specific cohort of potential users of the 
ultimate approved product.
While reading grade level will be measured for adolescents (based on the REALM-Teen 
Test) and summarized descriptively, adolescent subjects will not be classified as low- or 
normal- literacy for the study. 
Similarly, adolescents entering the study will not be required to have any specific risk 
factors, history of severe pain or history of heavy pain reliever use. 
Total Sample Size Requirements:
The total number of subjects expected to enroll into the study is 820 (including 
approximately 720 adults and 100 adolescents).  Accordingly, the number of subjects 
expected to be screened by telephone is 14,409, of whom approximately 7,029 would meet 
all initial screening criteria and schedule an enrollment visit appointment.  Among these, it is 
expected that 3,046 would visit a participating pharmacy research site, and 820 would meet 
all eligibility criteria, purchase study medication and enter the Use Phase.  Finally, among 
enrolled subjects it is expected approximately 700 would be available for the dosing 
compliance endpoint analysis (compliance-evaluable subjects are those that take at least one 
dose of study medication and record it in the electronic diary), including approximately 
620 adults and 80 adolescents.
9.2. Dosing Compliance Analysis
9.2.1. Analysis of the Primary Endpoint
The analysis population for dosing compliance is composed of subjects that report at least 
one dose (dosing occasion with 1 or more tablets) of the study medication in the electronic 
diary application (Adult Compliance-Evaluable Population).  The Primary Endpoint 
(proportion of subjects who exceed the maximum daily dose, 1200 mg, on two or more days 
during the use period) will be calculated as:
Adult compliance-evaluable subjects exceeding 1200 mg/day on 2 days, divided by 
the total number of adult compliance-evaluable subjects.
The complement of this number (1 – obtained proportion) will be calculated.  This is the 
correct performance rate.


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Subgroup analysis for the primary endpoint will be performed on subjects within each of the 
at-risk populations: 1) increased CV risk; 2) increased GI risk; 3) a history of severe pain; 
and 4) >65 years age.  The correct performance rate for adolescent subjects will be presented 
descriptively; no inferential analysis on adolescent subjects will be performed.
9.2.2. Performance Threshold Selection and Rationale
The Primary Endpoint will be considered successfully met if the lower-limit of the two-sided 
95% CI (calculated using the Wald Confidence Interval) for the correct performance rate is 
greater than the a priori performance standard of 90%.  Adolescent performance for the 
Primary Endpoint will be presented descriptively. No inferential analysis on adolescents will 
be performed and hence it will not be compared to the performance threshold.
This performance threshold for the Primary Endpoint is selected to be highly conservative.  
Based on the power calculations noted in Section 9.1, a minimum of 93.4% of compliance 
evaluable subjects will need to exhibit correct performance to be successful for this endpoint.  
This high standard is to provide robust assurance regarding the utility of the proposed 
labeling refinements and the ability of consumers to correctly dose based on the directions 
for Advil 12 Hour.
9.2.3. Analysis of Secondary
Dosing Compliance Endpoints
Values for all other dosing compliance endpoints will be calculated in similar fashion to the 
Primary Endpoint (number of compliance-evaluable subjects exceeding the relevant dosing 
direction or dosing frequency, divided by the total number of adult compliance-evaluable 
subjects).  However, Secondary 
 Endpoint findings will not be compared to any 
pre-specified performance thresholds.  The SAP will provide a detailed description of the 
calculation methods for all endpoints. 
Subgroup analysis for the secondary endpoints will be performed on subjects within each of 
the at-risk populations: 1) increased CV risk; 2) increased GI risk; 3) a history of severe pain; 
and 4) >65 years age.
CCI
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9.4. Safety Analysis
Adverse event (AE) summaries will include all events which initially occurred or worsened 
following initiation of treatment.  AEs will be summarized using the Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT) 
designations and classified according to their severity (mild, moderate, or severe) and 
relationship (related or not related) to the study product.  
 
 
 
 
 
 
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9.6. Interim Analysis
No formal interim analysis will be conducted for this study. However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating pharmacokinetic (PK)/pharmacodynamic (PD) modeling, and/or to support 
clinical development.
9.7. Data Monitoring Committee 
Not applicable (N/A).
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the 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 study 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.
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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.
A Data Management Plan (DMP) will be created to describe the data management system 
and define procedures for security, user acceptance testing, data validation (edit 
specifications, queries and self-evident corrections), coding and database lock.
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. 


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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.
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.


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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 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.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the 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.
Coded subject information may be used to advance scientific research and public health in 
other projects that will occur in the future. At this time, Pfizer cannot anticipate the specific 
details of any future research projects. The privacy and confidentiality of subjects would be 
maintained. The subject would acknowledge this via the subject’s signature on the 
consent/assent document.
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. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as 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 
600 mg IR/ER ibuprofen at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects within 7 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.
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.


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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.
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.


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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.
Advil Dosing Behavior Study, 1996.
2.
Gallup Annual Monitor of Pain Relievers, 2002.
3.
TARGET Study Group.  Comparison of Lumiracoxib with Naproxen and Ibuprofen in 
the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), 
Cardiovascular Outcomes: Randomised Controlled Trial. Lancet. 2004 Aug 
21-27;364(9435):675-84.  
4.
Silverstein FE, et al. Gastrointestinal Toxicity with Celecoxib vs Nonsteroidal 
Anti-Inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS 
Study: A Randomized Controlled Trial. JAMA. 2000;284(10):1247-1255.
5.
The PRECISION Trial Investigators. Cardiovascular Safety of Celecoxib, Naproxen, or 
Ibuprofen for Arthritis. N Engl J Med 2016; 2519-2529.
6.
Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of 
antiplatelet therapy: I: prevention of death, myocardial infarction, and stroke. BMJ 
1994;308:81–106.
7.
Davis TC, Wolf MS, Arnold CL, Byrd RS, Long SW, Springer T, Kennen E, Bocchini 
JA. Development and validation of the Rapid Estimate of Adolescent Literacy in 
Medicine (REALM-Teen): a tool to screen adolescents for below-grade reading in 
health care settings. Pediatrics. 2006 Dec 1;118(6):e1707-14.
8.
Lanza FL, Chan FKL, Quigley EMM.  Guidelines for Prevention of NSAID-Related 
Ulcer Complications. Am J Gastroenterol 2009; 104:728-738.
9.
Murphy PW, Davis TC, Long SW, Jackson RH, and Decker BC. Rapid estimate of 
adult literacy in medicine (REALM): a quick reading test for patients. J of Reading 
1993;37(2)124-30. 
10.
Arozullah AM, Yarnold PR, Bennett CL, et al. Development and validation of a 
short-form, rapid estimate of adult literacy in medicine. Med Care 2007 November; 
45(11):1026-33. PMID: 18049342.
11.
Vaughn-Cooke, M., Nembhard, H. B., Ulbrecht, J., & Gabbay, R. (2015). Informing 
patient self-management technology design using a patient adherence error 
classification. Engineering Management Journal, 27(3), 124-130.


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ABBREVIATIONS
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ACC
American College of Cardiology
AE
adverse event
AHA
American Heart Association
ALT
alanine aminotransferase
APTC
-Antiplatelet Trialists’ Collaboration
ASCVD
atherosclerotic cardiovascular disease
AST
aspartate aminotransferase
AUS
Actual use study
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CRF
case report form
CRL
Complete response letter
CRO
Contract research organization
CSA
clinical study agreement
CSR
clinical study report
CT
Clinical trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
DCI
data collection instrument
DFL
Drug Facts label
DILI
drug-induced liver injury
DMC
data monitoring committee
DMP
data management plan
EC
ethics committee
EDC
Electronic data capture
EDP
exposure during pregnancy
EOS
end of study
ER
extended release
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HCP
Healthcare practitioner
HDL
high-density lipoprotein
IB
Investigator’s brochure


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Abbreviation
Term
IBU
ibuprofen
ICD
Informed consent document
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IR
immediate release
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
LFT
liver function test
LSLV
last subject last visit 
MedDRA
Medical Dictionary for Regulatory Activities
N/A
not applicable
NDA
new drug application
NSAIDS
nonsteroidal anti-inflammatory drugs
OTC
Over the counter
PACL
Protocol Administrative Change Letter
PCD
primary completion date
PCH
Pfizer Consumer Healthcare
PD
Pharmacodynamics(s)
PI
principal investigator
PK
pharmacokinetic
PT
preferred term
REALM
Rapid Estimate of Adult Literacy in Medicine
REALM-SF
Rapid Estimate of Adult Literacy in Medicine – Short Form
REALM-Teen
Rapid Estimate of Adolescent Literacy in Medicine
Rx
prescription
SAE
serious adverse event
SAP
statistical analysis plan
SOC
System organ class
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TID
Three times a day
ULN
upper limit of normal
URL
universal resource locator
US
United States
USPS
Unites States Postal Service
WHO
World Health Organization

SAP_001.pdf: 
Protocol B4371011 (PF-00344559) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol B4371011
MULTICENTER ACTUAL USE AND COMPLIANCE STUDY OF IBUPROFEN 600 
MG IMMEDIATE RELEASE/EXTENDED RELEASE TABLETS AMONG 
TARGETED (AT RISK) CONSUMERS IN A SIMULATED OVER THE COUNTER 
ENVIRONMENT
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
20 Jan. 2021


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimates.............................................................7
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................11
3.1. Primary Endpoint(s) ................................................................................................12
3.2. Secondary Endpoint(s) Dosing Compliance ...........................................................12
3.4. Baseline Variables...................................................................................................14
3.5. Safety Endpoints .....................................................................................................14
3.5.1. Adverse Events...........................................................................................14
3.5.2. Laboratory Data..........................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
5.2. General Methods .....................................................................................................16
5.2.1. Analyses for Binary Endpoints...................................................................16
5.2.2. Analyses for Categorical Endpoints ...........................................................16
5.2.3. Types of Data to be Analyzed ....................................................................16
5.3. Methods to Manage Missing Data ..........................................................................17
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Primary Endpoint(s) ................................................................................................17
6.1.1. Main Analysis.............................................................................................17
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6.2. Secondary Endpoint(s) ............................................................................................18
6.2.1. Proportion of subjects who exceed the maximum daily dose (1200 
mg) on one or more calendar days during the use period................................18
6.2.2. Proportion of subjects who exceed the maximum daily dose (1200 
mg) on one or more calendar days during the use period due to reasons 
categorized as unintentional misuse only (i.e., subjects who did not 
understand the dosing instructions on the package) ........................................18
6.2.3. The proportion of subjects who exceed the maximum amount per 
dose (600 mg) on 1 or more occasions ............................................................18
6.2.4. The proportion of subjects who exceed the maximum amount per 
dose (600 mg) on two or more occasions ........................................................18
6.2.5. The proportion of subjects who exceed the maximum daily dose on 
10 or more calendar days .................................................................................18
6.2.6. The proportion of subjects who exceed the maximum daily dose on 7 
or more calendar days ......................................................................................18
6.2.7. The proportion of subjects who take more than two doses (i.e., more 
than two dosing occasions) on a calendar day.................................................19
6.2.8. The proportion of subjects who re-dose in <12 hours, <10 hours, and 
<8 hours on 1 or more occasions .....................................................................19
6.2.9. The proportion of subjects who use the product on more than 10 
consecutive days ..............................................................................................19
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6.4. Subset Analyses.......................................................................................................21
6.5. Baseline and Other Summaries and Analyses.........................................................21
6.5.1. Baseline Summaries....................................................................................21
6.5.2. Study Conduct and Subject Disposition .....................................................21
6.5.3. Excessively High CV or GI risk .................................................................21
6.5.4. Study Treatment Exposure .........................................................................21
6.5.5. Concomitant Medications and Nondrug Treatments..................................22
6.6. Safety Summaries and Analyses .............................................................................22
6.6.1. Adverse Events...........................................................................................22
7. INTERIM ANALYSES.......................................................................................................22
8. REFERENCES ....................................................................................................................23
9. APPENDICES .....................................................................................................................24
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
LIST OF FIGURES
Figure 1.
Study Schematic .......................................................................................11
APPENDICES
Appendix 1. Target Medical Event List...................................................................................24
Appendix 2. Data Derivation Details.......................................................................................25
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Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................25
Appendix 2.2. Endpoint Derivations .......................................................................................25
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations................................................................................25
Appendix 3. Data Set Descriptions..........................................................................................25
Appendix 4. Statistical Methodology Details..........................................................................25
Appendix 5. List of Abbreviations...........................................................................................26


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol Amendment
Rationale
Specific Changes
1 / 20 Jan 2021
Amendment 2 Protocol/Final 
v3.0_06 Mar 2019
Not 
Applicable 
(N/A)
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B4371011.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
Pfizer has developed an ibuprofen 600 mg immediate release/extended release (IR/ER) tablet
formulation (Advil® 12 Hour) that approximates the early release characteristics of an 
ibuprofen 200 mg tablet with ER properties that are intended to maintain plasma 
concentrations adequate for analgesic efficacy over a 12-hour dosing interval.  Pfizer 
submitted a 
 to the United States (US) Food 
and Drug Administration (FDA) on 23 April 2014 for an ibuprofen 600 mg IR/ER tablet for 
over-the-counter (OTC) use, with the proposed trade name of Advil 12 Hour. Pfizer received 
a Complete Response Letter (CRL) on 23 February 2015 in which the FDA requested that 
Pfizer design a consumer program to: 1) evaluate subjects with low literacy to understand 
when and how they use the product, 2) identify individuals with medical conditions that may 
put them at greater risk for adverse effects when using nonsteroidal anti-inflammatory drugs 
(NSAIDs) and determine whether the labeling allows them to make appropriate decisions 
with regard to use of this product versus an IR product, 3) evaluate subjects with severe pain 
to determine if these individuals will deselect from using the product rather than taking more 
than the recommended dose when their pain is not relieved, and 4) understand additional 
measures that would discourage the behaviors of consumers who may override the label.
Following these discussions with FDA, Pfizer conducted extensive qualitative consumer 
research to understand the baseline motivators and behaviors behind consumer use and 
misuse within the analgesic category as well as follow-up interviews among a segment of the 
misusers in an earlier Advil 12 Hour Actual Use Study (AUS) (B4371008).  On 09 March 
2017, Pfizer met with the FDA to discuss the label development program and additional 
consumer research that would be needed leading up to a resubmission.  In the meeting and 
official minutes, the FDA encouraged Pfizer to conduct a new AUS to characterize the 
misuse of Advil 12 Hour among those at increased risk, and to deeply understand the reasons 
for misuse.  The Agency also provided feedback regarding which at-risk subpopulations 
should be studied including elderly consumers (>65 years of age), consumers with an 
increased risk of gastrointestinal (GI) bleeding or cardiovascular (CV) adverse events, 
consumers who experience severe pain, and low literacy subjects.  Adolescents (12-17 years 
of age) should also be included for pediatric safety assessments, and the study should enroll a 
large proportion of frequent OTC analgesic users to increase the incidence of misuse.  On 
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20 June 2018, the FDA granted a Type C meeting to discuss the design of Pfizer’s proposed 
AUS.  Specifically, Pfizer and the FDA met once again to discuss and clarify issues 
surrounding the primary endpoint, subjects with “Ask a Doctor Before Use” conditions, 
methods to preselect for low reading ability, collecting concomitant NSAID use information 
during the Use Phase, and other important topics relevant to this study and the program.  The 
study protocol describes the AUS design and at-risk populations that will be employed to 
address the FDA’s specific requests and advice for this critical component of the consumer 
research program.
2.1. Study Objectives, Endpoints, and Estimates
The following primary and secondary endpoints will be evaluated.
Primary Objective:
Primary Endpoint:

Evaluate compliance with the labeled dosing 
directions for Advil 12 Hour and understand why 
misuse occurred and if it was a conscious decision by 
the subject. 

Proportion of subjects who exceed the maximum 
daily dose (1200 mg) on two or more calendar days 
during the use period.
Secondary Objectives:
Secondary Endpoints:

Evaluate the safety of Advil 12 Hour in unsupervised 
actual use and how it relates to misuse. 

Proportion of subjects who exceed the maximum 
daily dose (1200 mg) on one or more calendar days 
during the use period. 

Proportion of subjects who exceed the maximum 
daily dose (1200 mg) on one or more calendar days 
during the use period due to reasons categorized as 
unintentional misuse only (i.e., subjects who did not 
understand the dosing instructions on the package).

The proportion of subjects who exceed the 
maximum amount per dose (600 mg) on 1 or more 
occasions.

The proportion of subjects who exceed the 
maximum amount per dose (600 mg) on two or 
more occasions.

The proportion of subjects who exceed the 
maximum daily dose on 10 or more calendar days.

The proportion of subjects who exceed the 
maximum daily dose on 7 or more calendar days.

The proportion of subjects who take more than two 
doses (i.e., more than two dosing occasions) on a 
calendar day.

The proportion of subjects who re-dose in 
<12 hours, <10 hours, and <8 hours on 1 or more 
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•
The proportion of subjects who use the product on 
more than 10 consecutive days.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2. Study Design
This will be an open-label, multicenter, 30-day, unsupervised AUS among targeted (at-risk) 
adult and adolescent consumers designed to mimic an OTC-like environment. More 
specifically, “at-risk” consumers, as discussed with the FDA, will comprise elderly 
consumers (>65 years of age), consumers with an increased risk of gastrointestinal (GI) 
bleeding or cardiovascular (CV) adverse events, consumers who experience severe pain, low 
literacy subjects, and adolescents (younger than the age of majority in their state, hereafter 
referred to as “12-17 years of age,” although some sites may also designate 18-year-olds as 
younger than the age of majority, according to state requirements).  The total number of 
subjects expected to enroll into the study is approximately 820 (including approximately 720 
adults and 100 adolescents).  For each of the first 4 risk groups (i.e., elderly consumers of 
>65 years of age, adults with GI bleeding risk, adults with CV adverse events risk, adults 
with history of severe pain), it is expected that a minimum of approximately 180 subjects will 
be recruited and enrolled, and within each risk group, approximately 30% will be low literacy
based on the Rapid Estimate of Adult Literacy in Medicine (REALM) Test1. Note, however, 
that because of substantial natural comorbidity (overlap) for these risk conditions, the at-risk 
groups are not mutually exclusive and many or most subjects will qualify for inclusion in 
more than one group, so that the sum of the individual subgroup counts will be expected to 
exceed the total adult subject count. Sites will be pharmacies in diverse geographic locations 
around the US.  Prospective adult subjects will be recruited via general population and 
targeted risk condition advertising (although subjects will not be informed as to specific 
health conditions for which they are being recruited), while adolescents will be recruited 
using targeted, outbound pre-recruiting telephone calls.  Subjects (or the parents/guardians of 
prospective adolescent subjects) responding to the advertisements or recruitment calls will be 
initially screened by telephone, and eligibility will subsequently be verified in-person at the 
pharmacy site.
Adult subjects and the parents/guardians of adolescent subjects who qualify will answer 
questions related to the subject’s attitudes toward, and usage of, oral OTC and prescription 
pain medications and will have the opportunity to purchase and use the study medication 
based only on their reading of the Drug Facts Label (DFL) and other information on the 
package. Following the initial purchase decision, subjects (or the parent/guardian of 
adolescent subjects) will provide informed consent and complete additional evaluations for 
inclusion/exclusion as well as assessment of risk group classification(s) for adult subjects 
(see Section 3.1).  Eligible subjects (or the parents/guardians of eligible adolescent subjects) 
are then permitted to purchase as much study medication as desired (up to 5 packages) at the 
start of the study.  Data regarding subjects’ use of the study medication will be captured in an 
electronic diary.  To allow for real-world, naturalistic medication use behaviors between 
parents/guardians and adolescent subjects, adolescent subjects and the parents/guardians of 
adolescent subjects will determine who will be responsible to administer the study 
medication and subsequently participate in remaining study assessments including 
completion of the electronic diary, the end-of-study (EOS) telephone interview, and the self-
administered Attitudes and Beliefs questionnaire based on their answer to this question at the 
end of the pharmacy Enrollment Visit: “Who usually decides how you (adolescent subject) 
will take OTC pain reliever medicines?”  If the answer is the parent/guardian, the 


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parent/guardian will be responsible for entering data and participating in all future 
assessments.  If the answer is the adolescent subject, the adolescent subject will be 
responsible for entering data and participating in all future assessments.  In cases where the 
parent/guardian and the adolescent report they “both” usually administer OTC pain reliever 
medications the adolescent takes, the parent/guardian and adolescent will be asked to decide 
which of them will have primary responsibility.    
The electronic diary will also capture information on concomitant medications to elucidate 
concurrent use of NSAIDs.  Subjects (and either the parents/guardians of adolescent subjects 
or adolescent subjects, depending on which is responsible to make entries in the electronic 
diary and participate in all other assessments) may return to the pharmacy site at any point 
during the 30-Day Use Phase to purchase additional study medication (not to exceed a total 
of 5 packages for the study).  Finally, between Days 31 and 40, subjects (or the 
parents/guardians of adolescent subjects) will provide detailed explanatory information about 
the subject’s reasons for misuse, as well as information about adverse events (AEs), in an 
end-of-study (EOS) telephone interview; the EOS telephone interview will be audio-recorded 
in order to capture subjects’ verbatim responses. The EOS telephone interview will be 
followed by a self-administered Attitudes and Beliefs electronic questionnaire (to be 
completed within 10 days after the EOS telephone interview) and a final telephone follow up 
contact (at least 28 (and up to 35) calendar days after the subject’s 30-Day Use Phase or, for 
subjects who use the investigational product after Day 30, at least 28 (and up to 35) calendar 
days after last recorded dose of investigational product) to capture any potential adverse 
events and to confirm appropriate contraception usage, after which participation will end.
Note that for adolescent subjects 12-17 years of age, the initial telephone screening and 
pharmacy enrollment visit assessments (with the exception of the Rapid Estimate of 
Adolescent Literacy in Medicine (REALM-Teen) Test2 and instances where the investigator 
may exercise judgment to determine if the parent/guardian and/or adolescent subject should 
both be present for and respond to questions in the birth control verification discussion or 
other sensitive content areas) will be directed to and managed by the parent/guardian, who 
will answer for and on behalf of the adolescent subject, and must be present to enroll the 
adolescent into the study and purchase study medication.  The individual (parent/guardian or 
adolescent subject) identified as the one who usually administers the OTC pain reliever 
medications the adolescent takes will have the primary responsibility to administer the study 
medication and subsequently participate in remaining study assessments including 
completion of the electronic diary, the EOS telephone interview and the self-administered 
Attitudes and Beliefs electronic questionnaire.
Figure 1 is a visual representation (schematic) of the study.


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Figure 1.
Study Schematic
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
The analysis population for dosing compliance is composed of subjects that report at least 
one dose (dosing occasion with 1 or more tablets) of the study medication in the electronic 
diary application (Adult Compliance-Evaluable Population). Only diary data during the 30-


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Day Use Phase will be included for the analysis population for dosing compliance. All diary 
data, entered during the Use Phase or outside of this window, will be relevant for safety 
reporting.
3.1. Primary Endpoint(s)
The Primary Endpoint (proportion of subjects who exceed the maximum daily dose, 1200 
mg, on two or more days during the use period) will be calculated as:
Adult compliance-evaluable subjects exceeding 1200 mg/day on ≥ 2 days, divided by 
the total number of adult compliance-evaluable subjects. 
The complement of this number (1-obtained proportion) will be calculated. This is the correct 
performance rate. 
3.2. Secondary Endpoint(s) Dosing Compliance 
Values for the following dosing compliance endpoints will be calculated in similar fashion to 
the Primary Endpoint (number of adult compliance-evaluable subjects exceeding the relevant 
dosing direction or dosing frequency, divided by the total number of adult 
compliance-evaluable subjects). The complement of this number (1-obtained proportion) will 
be calculated and will equal the total number of subjects with correct responses; however,
these findings will not be compared to any pre-specified performance thresholds. 

Proportion of subjects who exceed the maximum daily dose (1200 mg) on one or more 
calendar days during the use period. 

Proportion of subjects who exceed the maximum daily dose (1200 mg) on one or more 
calendar days during the use period due to reasons categorized as unintentional misuse 
only (i.e., subjects who did not understand the dosing instructions on the package).

The proportion of subjects who exceed the maximum amount per dose (600 mg) on 1 or 
more occasions.

The proportion of subjects who exceed the maximum amount per dose (600 mg) on two 
or more occasions.

The proportion of subjects who exceed the maximum daily dose on 10 or more calendar 
days.

The proportion of subjects who exceed the maximum daily dose on 7 or more calendar 
days.

The proportion of subjects who take more than two doses (i.e., more than two dosing 
occasions) on a calendar day.

The proportion of subjects who re-dose in <12 hours, <10 hours and <8 hours on 1 or 
more occasions.


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•
The proportion of subjects who use the product on more than 10 consecutive days.
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3.4. Baseline Variables
Cholesterol test results for all adult subjects will be recorded before enrollment into the 
study, including total cholesterol and HDL cholesterol.
A blood pressure (BP) test for all adult subjects will be conducted, and the results will be 
recorded before enrollment into the study, including systolic BP (mmHg) and diastolic BP
(mmHg).
Subjects’ 10-year atherosclerotic cardiovascular disease (ASCVD) risk will be calculated for
all adult subjects (between the ages of 40 and 79 years old) before enrollment into the study.
3.5. Safety Endpoints
Section 3.3.3 displays safety compliance endpoints specified in the protocol.  The incidence 
of adverse events (AEs) will be evaluated. 
3.5.1. Adverse Events
All observed or volunteered events regardless of suspected causal relationship to the 
investigational product will be reported. All AEs will be summarized by the Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred 
Term (PT). 
The time period for actively eliciting and collecting AEs and serious AEs (SAEs) (“active 
collection period”) for each subject begins from the time the subject provides informed 
consent, which is obtained before the subject’s participation in the study (i.e., before 
undergoing any study related procedure and/or receiving investigational product), through 
and including a minimum of 28 calendar days after the end of the subject’s 30-Day Use 
Phase or, for subjects who use the investigational product after Day 30, for at least 28 
calendar days after the last recorded dose of investigational product.
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers. No Tier-1 events (pre-specified events of clinical importance) have been 
identified in the Safety Review Plan (SRP) for this product. However, for this study AEs 
included in the Targeted Medical Event (TME) list of the SRP (see Appendix 1) will be used 
to summarize these types of AEs. Different analyses will be performed for different tiers (see 
Section 6.6.1).
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Tier 1 events: These are prespecified events of clinical importance and are maintained in a 
list in the product’s SRP. For this study, TME in the SRP are considered as Tier-1 events. 
Tier 2 events: These are events that are not Tier-1 but are “common.” A MedDRA PT is 
defined as a Tier-2 event if there are at least 2% in any treatment group.
Tier 3 events: These are events that are neither Tier-1 nor Tier-2 events.
3.5.2. Laboratory Data
Not applicable. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Vendor’s (PEGUS) standard operating procedures (SOPs). The populations 
of interest are defined as follows:
Population
Description
Screening
Potential subjects who respond to the recruitment advertising, 
call the toll-free number, and begin the screening process. 
Enrollment
Subjects who upon fulfilling the phone screen interview (and 
meet study inclusion criteria), schedule a face-to-face interview 
at the pharmacy site, appear at their scheduled interview, and 
make a purchase decision. 
Purchasers
Subjects who purchase the study medication.
Adult Compliance–
Evaluable
The analysis population for dosing compliance is composed of 
subjects that report at least one dose (dosing occasion with 1 or 
more tablets) of the study medication in the electronic diary 
application. 
Adolescent Users
Subjects less than age of majority (based on state of residence) 
that report at least one dose (dosing occasion with 1 or more 
tablets) of the study medication in the electronic diary 
application.
Safety
All subjects who sign informed consent and purchase the 
product. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The primary endpoint analysis will be the Wald test of binary endpoints which will be 
performed to calculate the two-sided 95% confidence interval (CI). The Primary Endpoint 


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will be considered successfully met if the lower limit of the two-sided 95% CI (calculated 
using the Wald Confidence Interval) for the correct performance rate in the Adult 
Compliance-Evaluable Population is greater than the a priori performance standard of 90%.  
Adolescent performance for the Primary Endpoint will be presented descriptively.  No 
inferential analysis on adolescents will be performed and hence it will not be compared to the 
performance threshold.
5.2. General Methods
5.2.1. Analyses for Binary Endpoints
For all binary endpoints, frequency and proportion will be calculated. Additionally, a 95% CI 
will be calculated for the primary endpoint based on Wald and Exact tests, the latter being a 
secondary analysis method.
5.2.2. Analyses for Categorical Endpoints
For categorical endpoints, descriptive statistics will be provided (number and %).
5.2.3. Types of Data to be Analyzed
Data regarding subjects’ use of the study medication is to be captured in an electronic diary, 
including the date, time, number of tablets taken, and other information for each dosing 
occasion. Per the protocol, the primary and secondary endpoint results are to be calculated 
from diary data and as well as clarified or mitigated diary data, which will lead in some cases 
to the generation of four sets of statistical tables as described below.
Analysis Set 
Number
Brief Description
Detailed Description
1
Original Data
Data exactly as recorded by subjects into their 
electronic diary.
2
Clarified Data
Data clarified by the nurses during the EOS interview 
under very specific pre-specified conditions when 
subjects spontaneously identified dosing occasion-
specific entry errors in their original electronic diary
data.
3
Corrected/Mitigated Data –
Incorrect or Impossible Diary 
Entries
Clarified data (Set 2) plus misuses mitigated for 
additional diary entries judged to be incorrect or 
impossible based on subjects’ clear verbatim responses
in the EOS interview.


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4
Mitigated Data – Pre-Specified 
Factors
Corrected data (Set 3) plus circumstances or 
considerations resulting in reclassification of misuses to 
“acceptable” status, meaning the risk-benefit balance is 
judged to be favorable by the subject despite misuse.
Pre-specified mitigations (see Protocol Mitigation Plan 
under Section 9.3.1) include:
1.
Clear consultation with or direction from a 
healthcare practitioner (HCP).
2.
Subjects who indicate they would have taken an 
opioid or other Rx analgesic if they had not taken 
another dose.
3.
Subjects who indicated they would have misused 
acetaminophen or other OTC analgesics.
4.
Subjects who re-dose earlier due to scheduling 
restrictions in order to prevent pain from
returning.
Analysis Set 3 incorporates both the subject-initiated data entry clarifications (implemented 
by the nurses at the EOS Interview) and post-study mitigations for diary entries determined 
to be incorrect or impossible. Analysis Set 3 therefore represents the subjects’ actual dosing 
behaviors, with self-reported errors and self-evident diary entry errors removed. Analysis Set 
4 builds on Analysis Set 3 by adding pre-specified mitigation factors to put occasions of 
misuse into context.
5.3. Methods to Manage Missing Data
All missing data will be considered missing, and no statistical procedures will be employed 
to estimate or impute missing data.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The primary endpoint (proportion of subjects who exceed the maximum daily dose, 1200 mg, 
on two or more days during the use period) will be calculated as:
Adult compliance evaluable subjects exceeding 1200 mg/day on ≥2 days, divided by 
the total number of adult compliance evaluable subjects.
The complement of this number (1 – obtained proportion) will be calculated.  This is the 
correct performance rate.
6.1.1. Main Analysis
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
A 95% two-sided CI for the primary endpoint will be calculated using the Wald test. The 
Primary Endpoint will be considered successfully met if the lower limit of the two-sided 95% 
CI (calculated using the Wald Confidence Interval) for the correct performance rate is greater 
than the a priori performance standard of 90%.


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Additional calculations will be performed using a 2-sided Exact Test for the 95% CIs for 
both primary and secondary endpoints only. 
No sensitivity analyses will be performed.
6.2. Secondary Endpoint(s)
Like the primary endpoint, secondary endpoints will be calculated as the number of adult 
compliance-evaluable subjects meeting the specified definition divided by the total number 
of adult compliance evaluable subjects, and the complement of this number will be the 
correct performance rate.  Secondary endpoint findings will not be compared to any pre-
specified performance thresholds.
6.2.1. Proportion of subjects who exceed the maximum daily dose (1200 mg) on one or 
more calendar days during the use period
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
6.2.2. Proportion of subjects who exceed the maximum daily dose (1200 mg) on one or 
more calendar days during the use period due to reasons categorized as unintentional 
misuse only (i.e., subjects who did not understand the dosing instructions on the 
package)
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
6.2.3. The proportion of subjects who exceed the maximum amount per dose (600 mg) 
on 1 or more occasions
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
6.2.4. The proportion of subjects who exceed the maximum amount per dose (600 mg) 
on two or more occasions
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
6.2.5. The proportion of subjects who exceed the maximum daily dose on 10 or more 
calendar days
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
6.2.6. The proportion of subjects who exceed the maximum daily dose on 7 or more 
calendar days
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.


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6.2.7. The proportion of subjects who take more than two doses (i.e., more than two 
dosing occasions) on a calendar day
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
6.2.8. The proportion of subjects who re-dose in <12 hours, <10 hours, and <8 hours on 
1 or more occasions
Frequency and proportion for each re-dose scenario category will be calculated based on the 
Adult Compliance-Evaluable Population.
6.2.9. The proportion of subjects who use the product on more than 10 consecutive days
Frequency and proportion will be calculated based on the Adult Compliance-Evaluable 
Population.
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6.4. Subset Analyses
Subgroup analysis for the primary and secondary endpoints will be performed based on 
normal and low literacy subgroups, adolescent users, and subjects within each of the at-risk 
populations: 1) increased CV risk; 2) increased GI risk; 3) a history of severe pain; and 4) 
>65 years age. The correct performance rates for these subsets will be presented descriptively
including 95% confidence intervals. No inferential analyses will be performed, and hence 
these results will not be compared to the performance threshold.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Cholesterol test results including total cholesterol and HDL cholesterol will be summarized 
with descriptive statistics based on the Purchasers, Adult Compliance-Evaluable Population, 
Safety Population, and within each at-risk subpopulation.
BP test results including systolic BP (mmHg) and diastolic BP (mmHg) will be summarized 
with descriptive statistics based on the Purchasers, Adult Compliance-Evaluable Population, 
Safety Population, and within each at-risk subpopulation.
Subject’s 10-year ASCVD risk will be summarized with descriptive statistics based on the 
Purchasers, Adult Compliance-Evaluable Population, Safety Population, and within each at-
risk subpopulation.
6.5.2. Study Conduct and Subject Disposition
A summary of the disposition of subjects (including Screening, Enrollment, Purchasers, 
Adult Compliance-Evaluable Population, Adolescent Users, and Safety Population) and 
reasons for exclusion from these populations will be provided (e.g., the reason that a subject 
was screened or participated in the enrollment interview but not a purchaser).  The number 
and percentage of subjects included in each analysis population will be summarized.
6.5.3. Excessively High CV or GI risk
Self-reported reasons why subjects with excessively high CV or GI risk decided to purchase 
the product will be presented descriptively for the study report.
6.5.4. Study Treatment Exposure
Study treatment exposure will be counted from the first day in Use Phase to last day in Use 
Phase (Day 1 to Day 30), or up to the date subject discontinues. Summary statistics will be 
provided for treatment exposure for the Adult Compliance-Evaluable Population, Adolescent 
Users, and Safety Population, including packages of study medication purchased.
The analysis will also descriptively summarize medication purchase behaviors, as well as any 
self-reported reasons why subjects attempted to purchase more than 5 packages of study 
medication during the study and subjects who attempt to purchase more than 5 packages will 
be described based on any relevant characteristics.


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6.5.5. Concomitant Medications and Nondrug Treatments
Concomitant medications will be summarized using the preferred drug name from 
WHODrug for the Safety Population.  
Concomitant non-drug treatment or procedures will be listed.
6.6. Safety Summaries and Analyses
Adverse event (AE) summaries will include all events which initially occurred or worsened 
following initiation of treatment. AEs will be summarized using the Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT) 
designations and classified according to their severity (mild, moderate, or severe) and 
relationship (related or not related) to the study product. 
 
 
 
 
6.6.1. Adverse Events
AEs will additionally be summarized using a 3-tier approach. No Tier-1 events (pre-specified 
events of clinical importance) have been identified in the SRP for this product. However, for 
this study AEs included in the TME list of the SRP (see Appendix 1) will be used to 
summarize these types of AEs as follows:
Tier-1:  pre-specified AEs of clinical importance, which are maintained in a list in the 
product’s SRP (see Appendix 1 for the complete list of TME AEs. For this study TMEs in 
the SRP are considered as Tier-1 events);
Tier-2: AEs that are not Tier-1 but are “common.” A MedDRA PT is defined as a Tier-2 
event if its frequency is at least 2% in any treatment group;
Tier-3: AEs that are neither Tier-1 nor Tier-2 events.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events.  Except for select events in unique situations, studies do not routinely employ 
formal adjudication procedures for the purpose of event classification.  As such, safety 
analysis is generally considered as an exploratory analysis and its purpose is to generate 
hypotheses for further investigation.  The 3-tier approach facilitates this exploratory analysis.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. However, as described in 
Section 9.6 of the protocol this is an open-label study, and the sponsor may conduct 
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unblinded reviews of the data during the course of the study, among other possible purposes,
to support clinical development.
8. REFERENCES
1.
Murphy PW, Davis TC, Long SW, Jackson RH, and Decker BC. Rapid estimate of 
adult literacy in medicine (REALM): a quick reading test for patients. J of Reading 
1993;37(2)124-30. 
2.
Davis TC, Wolf MS, Arnold CL, Byrd RS, Long SW, Springer T, Kennen E, Bocchini 
JA. Development and validation of the Rapid Estimate of Adolescent Literacy in 
Medicine (REALM Teen): a tool to screen adolescents for below grade reading in 
health care settings. Pediatrics. 2006 Dec 1;118(6):e1707 14.


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9. APPENDICES
Appendix 1. Target Medical Event List 
Target Medical Event Term
Code
Level (PT, SMQ1)
Cardiac failure
10007554
PT
Cerebral artery occlusion
10008089
PT
Deafness
10011878
PT
Gastrointestinal haemorrhage
10017955
PT
Hypersensitivity
10020751
PT
Hypertension
10020772
PT
Hypoacusis
10048865
PT
Myocardial infarction
10028596
PT
Overdose
10033295
PT
Pruritus
10037087
PT
Rash
10037844
PT
Renal failure
10038435
PT
Acute generalised exanthematous pustulosis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Bullous haemorrhagic dermatosis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Cutaneous vasculitis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Dermatitis bullous
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Dermatitis exfoliative
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Dermatitis exfoliative generalised
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Drug reaction with eosinophilia and systemic symptoms
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Epidermal necrosis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Erythema multiforme
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Erythrodermic atopic dermatitis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Exfoliative rash
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Oculomucocutaneous syndrome
20000020
Severe cutaneous adverse reactions SMQ1 narrow
SJS-TEN overlap
20000020
Severe cutaneous adverse reactions SMQ1 narrow


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Target Medical Event Term
Code
Level (PT, SMQ1)
Skin necrosis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Stevens-Johnson syndrome
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Target skin lesion
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Toxic epidermal necrolysis
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Toxic skin eruption
20000020
Severe cutaneous adverse reactions SMQ1 narrow
Source: Ibuprofen Safety Surveillance Review plan V14 Dated 30 Jan 2019 
PT = Preferred Term; SMQ = Standard Medical Query  
Appendix 2. Data Derivation Details
[Reference should be made to final Programming Specifications and Other Descriptions]
Appendix 2.1. Definition and Use of Visit Windows in Reporting
[Reference should be made to final Programming Specifications and Other Descriptions]
Appendix 2.2. Endpoint Derivations
[Reference should be made to final Programming Specifications and Other Descriptions]
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical Analyses/Populations
[Reference should be made to final Programming Specifications and Other Descriptions]
Appendix 3. Data Set Descriptions
[Reference should be made to final Programming Specifications and Other Descriptions]
Appendix 4. Statistical Methodology Details
[Reference should be made to final Programming Specifications and Other Descriptions]


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Appendix 5. List of Abbreviations
Abbreviation
Term
AE
adverse event
APTC
Antiplatelet Trialists’ Collaboration
ASCVD
atherosclerotic cardiovascular disease
AUS
actual use study
BP
blood pressure
CI
confidence interval
CSR
clinical study report
CRL
complete response letter
CV
cardiovascular
DFL
drug facts label
EOS
end-of-study
ER
extended release
FDA
Food and Drug Administration (United States)
GI
gastrointestinal
IR
immediate release
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
N/A
not applicable
NDA
New Drug Application
NSAID
nonsteroidal anti-inflammatory drug
OTC
over-the-counter
PT
preferred term
REALM
Rapid Estimate of Adult Literacy in Medicine
REALM-Teen
Rapid Estimate of Adolescent Literacy in Medicine
Rx
prescription
SAE
serious adverse event
SAP
statistical analysis plan


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Abbreviation
Term
SMQ
standard medical query
SOC
system organ class
SOP
standard operating procedure
SRP
safety review plan
TME
targeted medical event
US
United States