Conditions: Fever
Keywords: ibuprofen; acetaminophen; induced fever; fever
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 290
Healthy volunteers: yes

Brief summary:
This is a single dose study that will evaluate the efficacy and safety of a Fixed Dose Combination Ibuprofen 250 mg/ Acetaminophen 500 mg tablet in healthy male patients with fever. Results for the Fixed Dose Combination product will be compared to the individual components Ibuprofen 250 mg and Acetaminophen 500 mg and also compared to placebo.

Detailed description:

Arms:
arm 1: Single dose of 2 caplets of Ibuprofen 125 mg / Acetaminophen 250 mg by mouth arm 2: Single dose of 2 caplets of IBU 125 mg by mouth arm 3: Single dose of 1 APAP 500 mg caplet + 1 placebo caplet by mouth arm 4: Single dose of 2 caplets of Placebo by mouth

Interventions: intervention 1: Ibuprofen 250 mg / Acetaminophen 500 mg intervention 2: Ibuprofen 250 mg intervention 3: Acetaminophen 500 mg intervention 4: Placebo
Intervention descriptions: intervention 1: Ibuprofen 250 mg / Acetaminophen 500 mg intervention 2: Ibuprofen 250 mg intervention 3: 1 APAP 500 mg caplet intervention 4: Placebo tablet

Protocol document:
Prot_000.pdf: 
PF-06438867
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Final Protocol Amendment 6, 21 Sept 2017
Page 1
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, FULL 
FACTORIAL, SAFETY AND EFFICACY STUDY COMPARING THE 
ANTIPYRETIC EFFECTS OF A SINGLE ORAL DOSE OF IBUPROFEN (IBU)
250 MG/ ACETAMINOPHEN (APAP) 500 MG CAPLETS TO IBU 250 MG AND 
APAP 500 MG CAPLETS IN HEALTHY MALE VOLUNTEERS WITH FEVER 
INDUCED BY AN ENDOTOXIN
Compound:
PF-06438867
Compound Name:
Ibuprofen/Acetaminophen (IBU/APAP)
United States (US) Investigational New 
Drug (IND) Number:
112,538
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
B5061002
Phase:
3


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Final Protocol Amendment 6, 21 Sept 2017
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 6
21 September
2017
The following changes were made:

The primary analysis set will be modified 
intent to treat (mITT) population.  This 
population will exclude all randomized 
subjects prior to amendment 4.  The study 
was initiated with higher doses of endotoxin
which were then lowered under amendment 4.

Revised per protocol analysis set to include 
subjects in mITT population

 

20 additional subjects were added to ensure a 
total of 270 subjects in the mITT analysis set.

Added, as a covariate, time from the first RSE 
full dose to randomization in the analysis 
model.
Amendment 5
04 April 2017
The following change was made following FDA 
communication received on 31 March 2017
recommending the use of IV acetaminophen instead 
of IV ketorolac as rescue medication

Rescue medication changed from IV 
ketorolac to IV acetaminophen (500 mg dose) 
and added the option for investigator or 
qualified individual to institute appropriate 
medical interventions at the discretion of the 
investigator including administration of IV 
ibuprofen (up to 400 mg dose) to subjects 
whose temperature continues to rise after 
administration of rescue IV acetaminophen.

Minor revisions and clarifications to ensure 
consistency in different sections were made.
CCI


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Amendment 4
28 March 2017
The following changes were made to the dosing 
algorithm of endotoxin
Figure 1. Determination of RSE Full Dose;

Test dose of RSE changed from 1 ng/kg to 
0.5 ng/kg

Full dose of RSE changed from 2ng/kg and 
1ng/kg to 1.5 ng/kg, 1ng/kg and 0.5 ng/kg 
based on subject fever response and 
presentation of systemic symptoms after 
administration of RSE test dose
Administration of ondansetron changed from 
approximately 30 minutes after test dose to 
approximately 45-60 minutes after RSE test dose 
administration;
At any time after administration of endotoxin before 
randomization, subject will not be randomized if he 
develops two or more systemic RSE-related adverse 
events where both are rated as severe;
Temporary hold on randomization included as 
example of when subject can be allowed to rescreen
Minor revisions and clarifications to ensure 
consistency in different sections were made.
Amendment 3
30 January 2017
Use of CorTemp® Wireless Ingestible Temperature 
Sensor discontinued. The following changes to the 
study protocol were therefore effected.

Subject temperature will be monitored via the 
standardized electronic digital thermometer.

Removed verification of non-interference with 
CorTemp® sensor.

Removed 48 hour phone call to subjects.

Removed exclusion criteria 13 (subjects who may 
undergo MRI).
The following changes were made to dosing 
algorithm of RSE:


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
Full dose of RSE changed from 3ng/kg and 
2ng/kg to 2ng/kg and 1ng/kg plus an additional 
1ng/kg for subjects who do not respond to full 
dose after 60-90 minutes of monitoring at the 
discretion of the investigator.

Added 100 minute and 110 minute time points for 
temperature recordings.

Administration of prophylactic antiemetic 
changed from 30 minutes before RSE test dose by 
mouth to approximately 30 minutes after RSE test 
dose intravenously to maximize efficacy.

Figure 1 revised to reflect above changes for RSE 
dosing.
The following 3 changes were made to the Rescue 
Medication section:

Subject temperature for rescue changed from 
103.5 core temperature to >102.5 oral 
temperature.

Added consideration of subjects overall clinical 
presentation to conditions for administrating 
rescue medication.

Added the option for investigator or qualified 
individual to institute appropriate medical 
interventions at the discretion of the investigator 
including administration of IV acetaminophen (up 
to 500 mg/dose) to subjects whose temperature 
continues to rise after administration of rescue 
ketorolac.

Removed time window for temperature time 
points that are one hour apart. Maximum time 
points are 30 minutes apart.

Removed statement that one vial of RSE will be 
reconstituted for each subject

Typographical and grammatical error changes 
clarifications were made throughout the 
document


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Final Protocol Amendment 6, 21 Sept 2017
Page 5

Minor revisions and clarifications to ensure 
consistency in different sections were made
Amendment #2
26 October 2016

Subject temperature for randomization changed 
from ≥99.5OF (oral), ≥100.5 OF (core) to 100.5 OF 
(oral) 101.5 OF (core) as per FDA 
advice/information letter dated 26 Aug 2016.

Deleted the following statement; ‘Post treatment 
vital signs and its change from baseline will be 
summarized by treatment groups’ from section
9.4 due to duplication.

Typographical and grammatical error changes 
clarifications were made throughout the 
document.

Minor revisions and clarifications to ensure 
consistency in different sections were made.
The following changes were made based on statistical 
and operational reconsiderations:

Removed statement estimating study duration;

Sample size for randomized subjects increased 
from 230 to 270;

Added weighted sum of temperature differences 
from baseline to 2 hours (WSTD0-2) and to 
4 hours (WSTD0-4) as secondary efficacy 
endpoints;

The primary analysis set definition revised to 
include all randomized subjects who were dosed 
with study medication and had a baseline 
assessment;

 
 

Added New reference #14;

 
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Amendment #1
26 May 2016
The following changes were made based on 
comments and recommendations before, during and 
after the Site Initiation Visit (10-May 2016):

Subjects screening window changed from 14 to 
28 days prior to administration of study 
medication;

The study duration changed from approximately 
7 to 10 months;

24 hour safety phone call revised to include 
question asking subjects if they have had a bowel 
movement;

Study site will conduct a follow-up phone call to 
applicable subjects 48 hours after the 24 hour 
phone call to ascertain whether they have had a 
bowel movement since the previous call;

Ingestion of CorTemp thermometer sensor 
changed from with breakfast to approximately 
1 hour prior to breakfast;

Clarification in Inclusion criteria 2: Where 
applicable an average of the 3 consecutive 
temperatures will be used to determine eligibility 
for subjects with temperatures that fall outside 
protocol requirements;

Inclusion criteria 3: BMI changed from 32 to 37;

Contraception requirements revised to exclude 
female partner requirement;

Third party unblinded staff will be allowed to 
administer RSE to subjects;

Breakfast Lunch and Dinner will be provided to 
subjects on Day 0;

Site will be required to use, whenever possible, 
the same qualified individual to conduct the 
physical examination for any one subject;


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
Site will be allowed to use the same type of blood 
pressure cuff;

Clarification that QTcF is used for assessing QTc 
Interval for Database;

Revision to indicate that the source data from the 
CorTemp thermometer may be requested by 
Pfizer and used for a separate exploratory 
analysis;

Revision to remove Protocol Specified Adverse 
Event of Fever. All SAEs will be reported by the 
Investigator as described in Section 8;

The title of Section 8.6.1. was revised from 
Protocol-Specified Adverse Events to Protocol 
Specified Serious Adverse Events;


Typographical and grammatical error changes 
clarifications were made throughout the 
document;

Minor revisions and clarifications to ensure 
consistency in different sections were made;

Figure 1 revised to include a question which 
instructs site to withdraw subjects who whose
temperature is > 99.5F after RSE test dose and 
before the full dose.
Original
Protocol
18 March 2016
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
LIST OF FIGURES .................................................................................................................11
APPENDICES .........................................................................................................................11
PROTOCOL SUMMARY.......................................................................................................12
SCHEDULE OF ACTIVITIES................................................................................................16
1. INTRODUCTION ...............................................................................................................20
1.1. Mechanism of Action/Indication.............................................................................20
1.2. Background and Rationale ......................................................................................20
1.2.1. Study Rationale...........................................................................................20
1.2.2. Rationale for Endotoxin Induced Fever Model ..........................................21
1.2.3. Safety Data..................................................................................................21
1.2.4. Dose Rationale............................................................................................22
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................22
2.1. Objectives................................................................................................................22
2.2. Endpoints.................................................................................................................22
3. STUDY DESIGN.................................................................................................................23
4. SUBJECT SELECTION......................................................................................................25
4.1. Inclusion Criteria.....................................................................................................25
4.2. Exclusion Criteria....................................................................................................26
4.3. Randomization Criteria ...........................................................................................28
4.4. Lifestyle Guidelines ................................................................................................28
4.4.1. Contraception..............................................................................................28
4.4.2. Meals and Dietary Restrictions...................................................................28
4.4.3. Alcohol, Tobacco and Caffeine ..................................................................29
4.4.4. Activity .......................................................................................................29
4.5. Sponsor’s Qualified Medical Personnel..................................................................30
5. STUDY TREATMENTS.....................................................................................................30
5.1. Allocation to Treatment ..........................................................................................30
5.2. Breaking the Blind ..................................................................................................31
5.3. Subject Compliance.................................................................................................31
5.4. Investigational Product Supplies.............................................................................31
5.4.1. Dosage Form(s) and Packaging..................................................................31


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5.4.2. Preparation and Dispensing........................................................................32
5.5. Administration.........................................................................................................32
5.6. Investigational Product Storage ..............................................................................33
5.7. Investigational Product Accountability...................................................................34
5.7.1. Destruction of Investigational Product Supplies ........................................34
5.8. Reference Endotoxin...............................................................................................34
5.9. Concomitant Treatment(s).......................................................................................34
5.10. Rescue Medication ................................................................................................35
6. STUDY PROCEDURES .....................................................................................................36
6.1. Screening.................................................................................................................36
6.2. Study Period ............................................................................................................37
6.2.1. Day 0...........................................................................................................37
6.2.2. Day 1...........................................................................................................38
6.3. Post-study Subject Interview and Follow-Up .........................................................41
6.4. Subject Withdrawal.................................................................................................41
7. ASSESSMENTS..................................................................................................................42
7.1. Physical Examinations ............................................................................................43
7.2. Vital Sign Measurements ........................................................................................43
7.3. Respiratory Rate......................................................................................................43
7.4. Electrocardiogram (ECG)........................................................................................44
7.5. Laboratory Tests......................................................................................................44
7.6. Endotoxin Administration and Monitoring.............................................................46
7.7. Temperature Recording/Monitoring .......................................................................47
7.8. Global Evaluation....................................................................................................48
8. ADVERSE EVENT REPORTING......................................................................................48
8.1. Adverse Events........................................................................................................48
8.2. Reporting Period .....................................................................................................49
8.3. Definition of an Adverse Event...............................................................................49
8.4. Medication Errors....................................................................................................50
8.5. Abnormal Test Findings..........................................................................................50
8.6. Serious Adverse Events...........................................................................................51
8.6.1. Protocol-Specified Serious Adverse Events...............................................51
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................52


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8.7. Hospitalization ........................................................................................................53
8.8. Severity Assessment................................................................................................54
8.9. Causality Assessment..............................................................................................54
8.10. Exposure During Pregnancy..................................................................................54
8.11. Occupational Exposure .........................................................................................56
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................56
8.13. Eliciting Adverse Event Information ....................................................................56
8.14. Reporting Requirements........................................................................................56
8.14.1. Serious Adverse Event Reporting Requirements .....................................56
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................57
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................57
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................57
9.1. Sample Size Determination.....................................................................................58
9.2. Efficacy Analysis ....................................................................................................58
9.2.1. Primary Analysis Set ..................................................................................58
9.2.4. Analysis of the Primary Endpoint...............................................................59
9.2.4.1. Protection for Multiple Comparisons........................................59
9.2.5. Analysis of Secondary Endpoints...............................................................59
9.4. Safety Analysis........................................................................................................61
9.5. Data Monitoring Committee ...................................................................................61
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................61
11. DATA HANDLING AND RECORD KEEPING .............................................................62
11.1. Case Report Forms/Electronic Data Record .........................................................62
11.2. Record Retention...................................................................................................62
12. ETHICS..............................................................................................................................63
12.1. Institutional Review Board/Ethics Committee......................................................63
12.2. Ethical Conduct of the Study ................................................................................63
12.3. Subject Information and Consent..........................................................................63
12.4. Subject Recruitment ..............................................................................................64
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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................64
13. DEFINITION OF END OF TRIAL...................................................................................64
13.1. End of Trial in United States.................................................................................64
14. SPONSOR DISCONTINUATION CRITERIA ................................................................64
15. PUBLICATION OF STUDY RESULTS..........................................................................64
15.1. Communication of Results by Pfizer ....................................................................64
15.2. Publications by Investigators ................................................................................65
16. REFERENCES ..................................................................................................................67
LIST OF TABLES
Table 1.
Study Treatments..................................................................................................31
Table 2.
Laboratory Tests ...................................................................................................45
Table 3.
Sample Calculation for RSE Syringes..................................................................72
LIST OF FIGURES
Figure 1.
Determination of RSE Full Dose..........................................................................24
Appendix 1. Abbreviations......................................................................................................69
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PROTOCOL SUMMARY
BACKGROUND/RATIONALE
Ibuprofen (IBU) and acetaminophen (APAP) are the two most widely used non-prescription 
over-the-counter (OTC) analgesic/ antipyretic drugs both in the United States and globally.  
The objective of this currently proposed program is to develop a fixed-dose combination 
(FDC) of IBU plus APAP with efficacy superior to either agent alone, without increasing the 
risk of side effects. Combining two different antipyretic agents with different mechanisms of 
action, such as IBU and APAP, may provide superior efficacy and may also lower the total 
amount of each independent agent, thus lowering the risk of side effects associated with 
higher doses when taken as a single medication. 
OBJECTIVES AND ENDPOINTS

The objective of this study is to evaluate the safety and antipyretic efficacy of single, 
oral doses of IBU/APAP 250 mg/500 mg caplets versus APAP 500 mg caplets, IBU 
250 mg caplets, and placebo in subjects in whom pyrexia has been induced by the 
intravenous administration of a Reference Standard Endotoxin (RSE).

The primary endpoint for this study is the weighted sum of temperature differences 
from baseline (the time of dosing with study medication) to 8 hours (WSTD0-8);
weights being equal to the time elapsed between each two consecutive time points.
STUDY DESIGN
This study is a single-center, 8-hours, single-dose, inpatient, double-blind, randomized, 
placebo-controlled, full-factorial, parallel arm, safety and efficacy study in healthy male 
subjects 18 to 55 years of age (inclusive). Approximately 290 subjects will be enrolled in 
this study.
The study is comprised of a screening visit and a study treatment period. The screening visit 
will occur within 28 days prior to the study treatment period. Subjects will remain at the 
research center during the study treatment period for approximately 36 hours over 2 days.  
Subjects will enter the study center on Day 0 and will remain in-house until after the 
completion of all study procedures on Day 1, at the investigator’s discretion. Site personnel 
will conduct a safety follow up within 24 hours of discharge via a telephone call to the 
subject and again 14 calendar days after the last dose of study medication to ascertain if any 
Serious Adverse Events (SAEs) have occurred.
Fever will be induced in healthy male volunteers using RSE and temperature measurements 
will be taken throughout the study to monitor the subject’s fever. Once subjects have 
received a dose of RSE, their oral temperature will continue to be monitored at the discretion 
of the investigator approximately every 5 minutes using an oral standardized electronic,
digital thermometer. Subject temperatures from test dose till randomization will be recorded 
in the source document.
All endpoints for this study will be based on oral temperature measurements using a 
standardized electronic, digital thermometer.  Oral temperatures will be recorded at the 
following times: 


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Final Protocol Amendment 6, 21 Sept 2017
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
At screening and Day 0 to ensure the subjects are afebrile and eligible to participate 
in the study;

Prior to administration of the test dose of RSE. This will be referred to as the
“normal” temperature;

Approximately 60 and 90 minutes (90 minutes if increase in temperature is 
<1°F and subject experiences <2 systemic symptoms) after the test dose of RSE in 
order to determine the full dose of RSE that the subject will receive.  After 
approximately 60 or 90 min (90 min if increase in temperature is <1°F and subject 
experiences <2 systemic symptoms)  of receiving the test dose of RSE, subjects who
tolerate the test dose of RSE will receive a full dose of RSE;

After the full dose of RSE when the subject has reached an oral temperature of 
100.5°F. The subject’s oral temperature will need to be 100.5°F in order to be 
randomized to study medication.  If the subject’s oral temperature is not 
100.5°F, additional oral temperature measurements will be taken and recorded in the 
source document approximately every 5 minutes until the subject reaches this 
temperature or is given an additional dose of RSE. The time between the subject 
reaching an oral temperature of 100.5F and being dosed should not exceed 
10 minutes;

Immediately prior to study medication dosing after the subject has reached an oral 
temperature of 100.5°F and has been randomized. This will be referred to as the 
“baseline” temperature;

At 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 and 110 minutes post dose and at 2, 2.5, 3, 
3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours post dose;

At the discretion of the investigator, additional oral temperatures may be taken by the 
investigator or delegated site staff members more frequently to monitor the subject’s 
oral temperature. If the subject’s temperature exceeds 102.5oF, subjects may receive 
rescue medication. An oral temperature will be taken and recorded prior to rescue 
medication administration.
Safety evaluations including adverse event (AE) monitoring, vital signs (blood pressure and 
pulse rate), and respiratory rate will be monitored throughout the study. At the end of the 
8-hour post dose period or at the time of rescue medication (within 5 minutes) subjects will 
complete a global evaluation of study medication using a categorical rating scale where 
applicable, and then will be discharged from the study site. 
STUDY TREATMENTS
Treatment Group
Treatment 
Treatment Description
A
IBU 250 mg/ APAP 500 mg 
2 IBU 125 mg/ APAP 250 mg caplets
B
APAP 500 mg 
1 APAP 500 mg caplet + 1 placebo caplet
C
IBU 250 mg 
2 IBU 125 mg caplets 
D
Placebo 
2 placebo caplets


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STATISTICAL METHODS
The sample size calculation was partly based on the data from a previous induced fever study 
(Whitehall-Robins Protocol ED-93-03).  In that study, subjects with normal body 
temperature took study medication 30 minutes prior to receiving Endotoxin. The estimated 
variability (root mean square error RMSE) of the weighted sum of temperatures difference 
over 0-8 hours was 3.372, and treatment difference between APAP and Placebo was 3.57.
Literature review and simulations were additionally conducted to assess the treatment effect 
and variability.14
In this study, we assume a treatment difference of 1.77 and 1.88 units in WSTD0-8 (weighted 
sum of temperature differences) for APAP/IBU vs IBU and APAP/IBU vs. APAP, 
respectively, and a variability (RMSE) of 3.406.  A sample of 78 subjects per active 
treatment group will be required to provide about 85% joint power to achieve statistical 
significance at two-sided 0.05 level.  Furthermore, this sample size for each active group and 
26 subjects in placebo group (3:3:3:1 allocation ratio) will provide about 85% power to 
detect a treatment difference of 2.35 units in WSTD0-8 for the comparison of each active 
treatment to placebo. 
Therefore, a total of approximately 270 subjects are to be randomized into the study after 
adjusting for additional 3.7% subjects who are randomized but not dosed or with no 
post-baseline data for analysis.
Additional 20 subjects (two randomization blocks) will be randomized for a total of 
290 subjects.  This addition ensures a total of approximately 270 subjects in the modified 
intent to treat (mITT) analysis population which will include only subjects randomized after 
protocol amendment 4.  Seventeen subjects (replaced by the added 20 subjects) not included 
in the mITT were dosed with a different RSE dosing algorithm than the RSE current dosing 
algorithm before amendment 4.  These subjects were dosed with much higher test and full
doses of endotoxin.
All statistical tests will be performed at a two-sided 0.05 level of significance.
The primary efficacy endpoint, the weighted sum of temperature difference from baseline 
over 0-8 hours (WSTD0-8) will be analyzed using an analysis of covariance (ANCOVA)
model with treatment group term and covariates baseline temperature and time from the first 
RSE full dose to randomization using mITT.  Additional analyses will be conducted based on 
the intent to treat (ITT) analysis set.
Time from the first RSE full dose to randomization is added to the model as subjects 
demonstrated significant variations in time from RSE first full dose to randomization (ie,
reaching threshold temperature of 100.5).
All measures relating to weighted sum of temperature difference from baseline, or 
temperature difference from baseline at individual post-dose time point will be analyzed by 
ANCOVA model with treatment group term and covariates baseline temperature and time 
from the first RSE full dose to randomization.


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Time to rescue medication will be analyzed using a proportional hazards model with 
treatment group term in the model.
The time to return to “normal temperature” (time until fever clearance) will be analyzed 
using interval-censored survival analysis approach, since the exact time to fever clearance 
will not be observed.
Safety (adverse events [AE]/serious adverse events [SAE]) data will be summarized by 
treatment groups.  Post treatment vital signs and change from baseline values will be 
summarized by treatment groups.  Number and percent of subjects with abnormal 
electrocardiogram (ECG) exam at end of study will be summarized by treatment groups.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Visit Identifier
1
2
Visit Window
Screening: Day -28 to Day 0
Day 0
Prior to RSE Test Dose Day 1
RSE 
Period
Study Treatment Period
Within 24 hrs of Discharge
Early Termination
14 Calendar Days After Last Dose(+3days)
RSE Test Dose Administration
60 - 90 min after RSE Test Dose
RSE Full Dose Administration *
0 hrs
10, 20, 30, 40, & 50 min
60 min
70 min
80 min
90 min
100 min
110 min
2 hrs
2.5 hrs
3 hrs
3.5 hrs
4 hrs
4.5 hrs
5 hrs
5.5 hrs
6 hrs
6.5 hrs
7 hrs
7.5 hrs
8 hrs
Informed Consent
X
Inclusion/Exclusion 
criteria
X
X
Demographics
X
Medical History
X
X
Prior Treatmentsa
→
→
→
→
→
→
Concomitant 
Treatments(s)a
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Physical Examinationb
X
X
X
Safety Laboratory 
Testsc
X
X
History of Drug, 
Alcohol, & Nicotine 
Use
X


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Visit Identifier
1
2
Visit Window
Screening: Day -28 to Day 0
Day 0
Prior to RSE Test Dose Day 1
RSE 
Period
Study Treatment Period
Within 24 hrs of Discharge
Early Termination
14 Calendar Days After Last Dose(+3days)
RSE Test Dose Administration
60 - 90 min after RSE Test Dose
RSE Full Dose Administration *
0 hrs
10, 20, 30, 40, & 50 min
60 min
70 min
80 min
90 min
100 min
110 min
2 hrs
2.5 hrs
3 hrs
3.5 hrs
4 hrs
4.5 hrs
5 hrs
5.5 hrs
6 hrs
6.5 hrs
7 hrs
7.5 hrs
8 hrs
Temperature 
Recordingd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Admit to Study Unit
X
Blood Pressure & 
Pulse Ratee
X
X
X
X
X
X
X
X
X
X
X
X
X
Single, 12-lead ECGf
X
X
X
X
Respiratory Rateg
X
X
X
X
X
X
X
X
Contraception Check
X
X
Dinner
X
Lunch
X
X
Breakfast
X
X
Antiemetic dose 
administeredh
X
Endotoxin Test Dose
X
Monitor for Allergy / 
Systemic Responsei
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
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Visit Identifier
1
2
Visit Window
Screening: Day -28 to Day 0
Day 0
Prior to RSE Test Dose Day 1
RSE 
Period
Study Treatment Period
Within 24 hrs of Discharge
Early Termination
14 Calendar Days After Last Dose(+3days)
RSE Test Dose Administration
60 - 90 min after RSE Test Dose
RSE Full Dose Administration *
0 hrs
10, 20, 30, 40, & 50 min
60 min
70 min
80 min
90 min
100 min
110 min
2 hrs
2.5 hrs
3 hrs
3.5 hrs
4 hrs
4.5 hrs
5 hrs
5.5 hrs
6 hrs
6.5 hrs
7 hrs
7.5 hrs
8 hrs
Endotoxin Full Dose 
X
Randomization/ 
Treatment 
Administration
X
Lunchj
X
Global Evaluationk
X
X
Adverse Event 
Monitoringl
→
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→
→
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→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Discharge from Study 
Unitm
X
Follow up-calln, o
X
X
Abbreviations: RSE= Reference Standard Endotoxin; ECG= electrocardiogram; IV= intravenous; hrs= hours; min= minutes; AE= Adverse Events; SAE= Serious Adverse Events
a.
Treatments taken within 28 days before the first dose of study treatment will be documented as prior treatments and will be assessed at Screening and Day 0.
Treatments taken after the first dose of study treatments will be documented as concomitant treatments and will be assessed after dosing on Day 1. 
b.
Full physical exam will be performed at Screening and on Day 0.  Brief physical exam will be performed at early termination. 
c.
Safety Laboratory Tests will be performed at Screening and on Day 0 according to Section 7.5 of the protocol. Test results will need to be available prior to 
RSE test dose administration to ensure subjects are free of occult infection and eligible to partake in the study. 


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d.
During Screening and on Day 0, an oral temperature will be taken to verify that the subject is afebrile. Prior to the test dose of RSE administration, subject’s 
oral temperature will be recorded as their ‘normal’ temperature. Subject’s temperature will also be recorded 60 and 90 minutes (90 minutes if increase in 
temperature is <1 °F and subject experiences <2 systemic symptoms) after the test dose of endotoxin in order to determine their full dose of endotoxin. After 
administration of a full dose of RSE, subjects will be monitored using the standardized, electronic digital thermometer until their oral temperature reaches 
100.5F. The subject’s oral temperature will need to be 100.5°F in order to be randomized to study medication.  If the subject’s oral temperature is not 
100.5°F, additional oral temperature measurements will be taken every 5 minutes until the subject reaches this temperature or is given an additional dose of 
RSE.  Within 10 minutes of reaching this temperature, subjects will be randomized and their oral temperature will be recorded immediately prior to dosing 
with study medication (this will be known as their ‘baseline’ temperature).  Oral temperatures will also be recorded at 10, 20, 30, 40, 50, 60, 70, 80, 90, 
100 and 110 minutes after dosing and at 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours after dosing.  The following time windows will be allowed for 
each of the time points; the widths of ±3 minutes for time points that are 10 minutes apart and ±5 minutes for time points that are 30 minutes apart.  An oral 
temperature will be taken and recorded in the CRF prior to subjects receiving rescue medication. 
e.
Vital signs (Supine blood pressure and pulse rate) will be collected at Screening, Day 0, Day 1 prior to test dose of RSE, Day 1 prior to the full dose of RSE, 
Day 1 prior to additional 1 ng/kg dose of RSE if applicable and then every hour after dosing up until 8 hours after dosing and/or at early termination. 
f.
Single, 12-lead ECGs will be collected at Screening, Day 1 prior to test dose of RSE administration, at the end of the 8-hour monitoring period and/or early 
termination. 
g.
Respiratory Rate will be collected every hour after dosing up until 8 hours after dosing. 
h.
A prophylactic dose of antiemetic (ondansetron 8 mg IV) will be given approximately 45 - 60 min after test dose of RSE administration.
i.
After the 0.5 ng/kg test dose administration of RSE, subjects will be monitored for approximately 60 - 90 minutes (90 minutes if increase in temperature is 
<1 °F and subject experiences <2 systemic symptoms) to verify the absence of a medically significant allergic or exaggerated systemic response.  Subjects 
who tolerate the test dose will receive a full dose of RSE (see Figure 1 for RSE full dose details) and will be monitored or given additional dose of RSE until 
their body reaches an oral temperature of 100.5 F on an oral thermometer.  Subjects will continue to be monitored to verify the absence of a medically 
significant allergic or exaggerated systemic response. 
j.
Lunch will be served at the investigator’s discretion, approximately 4 hours after dosing.  Lunch will consist of low-fat, room temperature food (ie, 
sandwiches) and room temperature water. 
k.
Global Evaluation will be completed at 8-hours post-dose, at the time of rescue medication administration (within 5 minutes) or at the time of subject 
withdrawal (if applicable).
l.
Serious adverse events will be reported starting at screening after informed consent has been signed and non-serious adverse events will be recorded starting 
on Day 1 after dosing.  AEs and SAEs related to endotoxin will be collected after endotoxin administration on Day 1. 
m. Subjects will be discharged from study unit at the investigator’s discretion after all study procedures are complete. 
n.
Study site personnel will conduct a safety follow-up within 24 hours of discharge via a telephone call to the subject to ascertain if any AEs or SAEs have 
occurred.
o.
Study site personnel will conduct a safety follow-up 14 calendar days after last dose via a telephone call to the subject to ascertain if any SAEs have 
occurred.
*
Subjects may be administered an additional 1 ng/kg bolus dose of endotoxin at the discretion of the investigator if applicable (Subject’s vitals will be taken 
and recorded immediately prior to receiving the additional dose of RSE).


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1. INTRODUCTION
IBU and APAP are the two most widely used non-prescription OTC analgesic/ antipyretic 
drugs both in the United States and globally.  The objective of this currently proposed 
program is to develop a FDC of IBU plus APAP with efficacy superior to either agent alone, 
without increasing the risk of side effects. Combining two different antipyretic agents with 
different mechanisms of action, such as IBU and APAP, may provide superior efficacy and 
may also lower the total amount of each independent agent, thus lowering the risk of side 
effects associated with higher doses when taken as a single medication. Both drugs have 
been extensively studied, and their efficacy and safety profiles in humans are 
well-established.
1.1. Mechanism of Action/Indication
FDC IBU/APAP is an analgesic/antipyretic formulation that is being developed for OTC use.  
The FDC is intended to have the same indications as each individual medication: the relief of 
minor aches and pains due to headache, toothache, backache, menstrual cramps, the common 
cold, muscular aches, minor pain of arthritis and the temporary reduction of fever. 
Ibuprofen, a “traditional” non-steroidal anti-inflammatory drug (NSAID), decreases the 
synthesis of pain- and inflammation-promoting prostaglandins via non-selective inhibition of 
cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2).1 The mechanism of action of 
APAP, which has no significant anti-inflammatory activity, is not clear.  However, it may 
involve COX inhibition in the central nervous system and activation of central serotonergic 
pathways.2,3 IBU and APAP do not share metabolic pathways, which diminishes the 
likelihood of drug-drug interactions.  Pharmacokinetic studies have demonstrated that there 
are no alterations in drug levels when the two analgesics are administered together, which is 
consistent with a lack of drug-drug interactions.4,5
1.2. Background and Rationale
1.2.1. Study Rationale
For the majority of subjects who do not achieve fever reduction with lower doses of 
currently-marketed OTC antipyretic medications, or are intolerant to higher doses, no single 
antipyretic agent can completely reduce fever. Combining two different antipyretic agents 
with different mechanisms of action, such as IBU and APAP, may provide superior efficacy 
and may also lower the total amount of each independent agent, thus lowering the risk of side 
effects associated with higher doses when taken as a single medication. In addition, a 
combination antipyretic with superior efficacy may reduce the need for additional doses of 
other antipyretics, thereby reducing the total amount of antipyretic consumed and leading to 
improved consumer safety. 
The current study is therefore designed to evaluate the efficacy of a fixed dose combination 
of IBU and APAP in reducing fever induced with RSE.


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1.2.2. Rationale for Endotoxin Induced Fever Model
An induced fever model was selected for this study. Fever is known to be associated with 
chronic and acute infections and inflammation in which antibiotics, amongst other 
medications, are generally required.  Use of antibiotics and other medications in addition to 
the study treatment could affect study results as they would likely decrease the pain or fever 
associated with the infection.  Using only an antipyretic/analgesic to treat the infection, and 
not an antibiotic, would also not be appropriate as it would not treat the underlying cause of 
the infection.  Therefore, a traditional fever study is not appropriate for evaluating the 
antipyretic efficacy of an antipyretic/analgesic combination treatment. 
Gram negative bacterial lipopolysaccharide (typically from E. coli), endotoxin is known to 
trigger inflammation and various other responses including fever.  The immune response to 
endotoxin is predictable and reproducible which offers an opportunity to evaluate therapeutic 
agents. Endotoxin results in a well characterized, transient acute fever response.  The model 
has been widely used for decades as a system to study new therapeutic agents for fever and 
inflammation.  Worldwide, thousands of subjects have received controlled endotoxin doses 
and serious adverse events have been rarely observed.  A monophasic rise in core body 
temperatures starts by 1 hour post-RSE dose, peaks at approximately 4 hours, with increases 
of 2-4°F above baseline, and returns to baseline by 8-12 hours post-RSE dose.  The 
endotoxin is cleared rapidly from blood.6
Endotoxin induced fever was therefore selected as the best approach to evaluate the 
antipyretic efficacy of the FDC. 
1.2.3. Safety Data
IBU and APAP have demonstrated antipyretic efficacy and are nonprescription medications 
widely used for the reduction of fever.  The main safety concern with IBU use, primarily at 
higher prescription doses over extended periods of time, is gastrointestinal toxicity.7 APAP 
over-dosage may cause potentially fatal hepatic failure.8 Based on safety concerns related to 
APAP, the Food and Drug Administration (FDA) has recommended reducing the maximum 
single adult dose of APAP in OTC products from 1,000 mg to 650 mg, and lowering the 
current maximum total daily dose APAP from 4,000 mg to 3,250 mg.9 However, since there 
is no overlap in metabolic pathways with IBU and APAP, and the dose in this study will be 
less than the recommended maximum single adult dose for each product, there is no 
anticipated increase in the risk of adverse events. 
IBU/APAP combinations at OTC levels have been studied in humans, including single and 
multiple dose pharmacokinetic studies, single and multiple dose oral surgery studies, and a 
multiple dose knee pain study.  These studies show that the adverse event (AE) profile of an 
IBU/APAP combination product at the doses proposed in this document is not materially 
different than the AE profile of the individual mono-components at their maximum dose 
level.10-13


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1.2.4. Dose Rationale
The dose to be evaluated in this study is a single oral dose of FDC IBU 250 mg/APAP 
500 mg (administered as two caplets of IBU 125 mg/APAP 250 mg).  The anticipated dosing 
interval for the FDC is three times per day, which will provide a maximum daily dose of 
750 mg IBU/1500 mg APAP. This is well below the current allowed OTC maximum dose of 
IBU 1200 mg and APAP 4000 mg, respectively, as well as the FDA’s Analgesics Advisory 
Committee recommendation of reducing the maximum single adult dose of APAP in OTC 
products from 1,000 mg to 650 mg, and lowering the current maximum total daily dose 
APAP from 4,000 mg.9
Since there is no overlap in metabolic pathways in the two mono-components, and the dose 
of each drug will be lower than current OTC dose or anticipated future prescription dose 
limits, there is no anticipated increase in the risk of adverse events in this fixed dose 
combination product in comparison to that of each individual ingredient.
Complete information for this FDC IBU/APAP compound may be found in the single 
reference safety document (SRSD), which for this study is the Investigator Brochure (IB).  
The SRSD for the active comparator agents are the IBU (Advil®) IB and the APAP 
(Tylenol®) OTC Drug Facts Label.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives

The objective of this study is to evaluate the safety and antipyretic efficacy of single, 
oral doses of IBU/APAP 250 mg/500 mg caplets versus APAP 500 mg caplets, IBU 
250 mg caplets, and placebo in subjects in whom pyrexia has been induced by the 
intravenous administration of a RSE.
2.2. Endpoints
In the following, baseline is defined as the time of dosing with study medication.
Primary Endpoints:

Weighted sum of temperature differences from baseline (the time of dosing with 
study medication) to 8 hours (WSTD0-8), weights being equal to the time elapsed 
between each two consecutive time points.
Secondary Endpoints:

Weighted sum of temperature differences from baseline to 2 hours (WSTD0-2);

Weighted sum of temperature differences from baseline to 4 hours (WSTD0-4).

Weighted sum of temperature differences from baseline to 6 hours (WSTD0-6);

Time to return to “normal temperature” (time until fever clearance);

Time to rescue medication;


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
Weighted sum of temperature differences during the last two hours of observation 
(6-8 hours) (WSTD6-8).
 

Safety evaluated by AE monitoring.
3. STUDY DESIGN
This study is a single-center, 8-hours, single-dose, inpatient, double-blind, randomized, 
placebo-controlled, full-factorial, parallel arm, safety and efficacy study in healthy male 
subjects 18 to 55 years of age (inclusive). Approximately 290 subjects will be enrolled in 
this study.
The study is comprised of a screening visit and a study treatment period. The screening visit 
will occur within 28 days prior to the study treatment period.  Subjects will remain at the 
research center during the study treatment period for approximately 36 hours over 2 days.  
Subjects will enter the study center on Day 0 and will remain in-house until after the 
completion of all study procedures on Day 1, at the investigator’s discretion. Site personnel 
will conduct a safety follow up within 24 hours of discharge via a telephone call to the 
subject.  Site personnel will also conduct a follow-up call 14 calendar days after the last dose 
of study medication to ascertain if any SAEs have occurred.
The night prior to dosing on Day 0, subjects will report to the study site to complete several 
study procedures and will undergo urine and blood testing to ensure they are afebrile, free of 
occult infection and healthy. Afebrile is defined as a mean oral temperature between 
97.4°F and 98.8°F that does not vary by more than 0.4 F° from the lowest to highest on three 
repeated assessments during a 30 minute period. 
On Day 1, fever will be induced in healthy male volunteers using RSE and temperature 
measurements will be taken throughout the study to monitor the subject’s fever.  Once 
subjects have received a dose of RSE, their oral temperature will continue to be monitored at 
the discretion of the investigator approximately every 5 minutes using an oral standardized 
electronic, digital thermometer and recorded in the source document. All endpoints for this 
study will be based on oral temperature measurements using a standardized electronic, digital 
thermometer. 
CCI


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Figure 1.
Determination of RSE Full Dose
At any time after administration of endotoxin before randomization, subject will not be 
randomized if he develops two or more systemic RSE-related adverse events where both are 
rated as severe.
The study will consist of the following blinded treatments: 
Study Treatments
Treatment Group
Treatment 
Treatment Description
A
IBU 250 mg/ APAP 500 mg 
2 IBU 125 mg/ APAP 250 mg caplets
B
APAP 500 mg 
1 APAP 500 mg caplet + 1 placebo caplet
C
IBU 250 mg 
2 IBU 125 mg caplets
D
Placebo 
2 placebo caplets


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Safety evaluations including adverse event (AE) monitoring, vital signs (blood pressure and 
pulse rate), and respiratory rate will be monitored throughout the study. At the end of the 
8-hour treatment period or at the time of rescue medication (within 5 minutes), subjects will 
complete a global evaluation of study medication using a categorical rating scale where 
applicable and then will be discharged from the study site. 
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Healthy male subjects who, at the time of screening, are between 18 and 55 years of 
age, inclusive.  Healthy is defined as no clinically relevant abnormalities identified by 
a detailed medical history, full physical examination, including blood pressure and 
pulse rate measurement, 12-lead ECG and clinical laboratory tests.
2. The subject must have a normal, stable body temperature at Screening and on Day 0.  
If the subject’s oral temperature is not between 97.4F and 98.8F, then 2 additional
oral temperature readings will be obtained within a 30 minute period and averaged.  
The average of these 3 consecutive temperature readings must be between 97.4F and 
98.8°F, with the highest value within 0.4 Fof the lowest temperature value.
3. Body Mass Index (BMI) of 17.5 to 37.0 kg/m2; and a total body weight 50 kg 
(110 lbs) at Screening.
4. The subject has demonstrably adequate veins, by visual inspection, for intravenous 
(IV) catheter insertion. 
5. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
6. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
7. Male subjects able to father children must agree to use a highly effective method of 
contraception throughout the study and for at least 28 days after the last dose of 
assigned treatment. 


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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Evidence or history of clinically significant laboratory abnormality, hematological, 
renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (excluding untreated, asymptomatic, seasonal allergies at the time of 
dosing) within the last 5 years that may increase the risk associated with study 
participation.
2. Subjects with any gastrointestinal disorders (eg, gastrectomy, tracheostomy, 
esophageal surgeries, short gut syndrome, peptic ulcer disease, known or suspected 
obstructive disease, previous gastrointestinal surgery, felinization of the esophagus, 
hypomotility of the gastrointestinal track) that could affect the absorption, 
metabolism, or excretion of the study medication.
3. Subjects at risk for excessive bleeding. 
4. Subjects with a history of nasal polyps, angioedema, or significant or actively treated 
bronchospastic disease.
5. Screening supine blood pressure 90 or 140 mm Hg (systolic) or 50 or 90 mm Hg 
(diastolic), following at least 5 minutes of supine rest.  If blood pressure (BP) 
is ≤90 or 140 mm Hg (systolic) or 50 or 90 mm Hg (diastolic), the BP should be 
repeated two more times and the average of the three consecutive BP values should 
be used to determine the subject’s eligibility.
6. Screening supine 12-lead ECG demonstrating QTc >450 msec or a QRS interval 
>120 msec at Screening and on Day 1 prior to RSE administration.  If QTc exceeds 
450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times 
and the average of the three consecutive QTc or QRS values should be used to 
determine the subject’s eligibility. 
7. The subject has a history of recurrent or acute or chronic infections of any type or any 
findings suggestive of occult infection, such as tuberculosis, sinusitis, urinary tract 
infection, respiratory tract or dental (abscess) infection, etc., or those with a positive 
QuantiFERON Tuberculosis, Hepatitis B surface antigen, Hepatitis C antibody, 
and/or Human immunodeficiency virus (HIV) test at Screening.  Also excluded are 
subjects with frequent (more than 3 outbreaks per year), recurrent oral or genital 
herpes, recurrent herpes zoster, or any infection otherwise judged by the investigator 
to have the potential for exacerbation by participation in the study.


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8. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.
9. Subjects who have experienced cold/flu symptoms (ie, runny nose, cough, and/or 
fever) within 2 weeks prior to the first administration of study treatments. 
10. The subject has a history of an allergic-type reaction or known hypersensitivity to
NSAIDS including ibuprofen, ondansetron, cyclooxygenase inhibitors, sulfonamides, 
APAP, endotoxins, lactose, tetanus vaccine, or other vaccines.
11. Subjects unable to swallow large capsules without gagging/choking. 
12. Subjects with a cardiac pacemaker or other implanted device.
13. A positive urine drug screen or alcohol breath test during Screening or on Day 0.
14. History of regular alcohol consumption exceeding 14 drinks/week (1 drink = 5 ounces 
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard 
liquor) within 6 months of Screening.
15. Subject is unwilling to abstain from tobacco or nicotine-containing product use 
during the treatment evaluation period.
16. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of study medication (whichever is 
longer) or administration of endotoxin within 3 months of receiving study medication. 
17. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to the first dose of study medication. 
18. History of sensitivity to heparin or heparin-induced thrombocytopenia.
19. Unwilling or unable to comply with the Lifestyle guidelines described in this 
protocol.
20. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study. 
21. Male subjects able to father children 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 at least 28 days after the last dose of investigational product.
22. Subjects who have previously been enrolled in this study. 


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23. Subjects with a reduction in heart rate to ≤50 beats per minute or deemed to be at 
high risk of syncope and/or hypotension per the clinical judgment of the investigator 
following a carotid sinus massage procedure.
4.3. Randomization Criteria 
Subjects will be randomized into the study provided they have satisfied all subject eligibility 
criteria.
All subjects must reach an oral temperature 100.5 °F within approximately 3 hours of
receiving the full (or additional) IV bolus dose of endotoxin in order to be randomized to 
study treatment. 
4.4. Lifestyle Guidelines 
Any severe fluctuations in site temperature or humidity should be reported to study monitor. 
4.4.1. Contraception
All subjects who are able to father children and are sexually active and at risk for pregnancy 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and his partner(s) from the permitted list of contraception methods (see 
below) and instruct the subject in its consistent and correct use.  Subjects need to affirm that 
they meet the criteria for correct use of at least 1 of the selected methods of contraception.  
The investigator or his/her designee will discuss with the subject the need to use highly 
effective contraception consistently and correctly according to the schedule of activities and 
document such conversation in the subject’s chart.  In addition, the investigator or his or her 
designee will instruct the subject to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the subject or the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Male condom or female condom used WITH a spermicide (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.
2. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
4.4.2. Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 4 hours prior to 
any laboratory evaluations.


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
On Day 0, breakfast, lunch and dinner will be provided in accordance to all study 
procedures. 

On Day 1, subjects will receive a standardized light, low-fat breakfast (in order to 
minimize the chances of subjects vomiting following RSE administration) of plain 
toast and approximately 8.0 oz.  of apple juice, or another non acidic juice, prior to 
receiving RSE.  Dairy products, carbonated drinks and juices with high acid content 
will be eliminated from the breakfast. 

During the rest of the study period, subjects can sip plain, room temperature water. 

Subjects will not be allowed to drink water within 2 minutes of an oral temperature 
measurement. 

Approximately 4 hours after dosing and after the 4 hour temperature reading, lunch 
may be served at the investigator’s discretion and will consist of room temperature 
food (ie, sandwiches) and room temperature water. 
4.4.3. Alcohol, Tobacco and Caffeine

Subjects will abstain from alcohol for 48 hours prior to admission to the Clinical 
Research Unit (CRU) and will continue to abstain from alcohol until after the final 
study evaluation is complete.  Subjects will be required to have negative alcohol 
breath test at Screening and Day 0.

Subjects will abstain from caffeine for 24 hours prior to the start of dosing until after 
the final evaluation on Day 1. 

Subjects must abstain from nicotine-containing products and smoking cessation 
products from Day 0 until after the final study evaluation on Day 1. 
4.4.4. Activity

No strenuous activity will be allowed while the subjects are in the clinical research 
unit (CRU). Only walking, sitting, and lying down will be allowed. 

After RSE administration, subjects will remain in their beds at a 45angle (unless 
study procedures require otherwise) until permitted to get out of bed with the 
Investigator’s permission.  If subjects need to void or briefly ambulate, they will need 
to notify site staff and will be assisted as needed. 

Subjects will not be allowed to assume a supine position during the first 4 hours 
following administration of randomized study treatment, unless study procedures 
require otherwise. 


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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 trial master file (TMF). 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigational 
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 investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. For sites other 
than a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
The investigator will assign subject numbers sequentially as subjects are screened for the 
study.  Subjects will be randomized after they have been administered endotoxin and reached 
an oral temperature of 100.5°F. Treatment assignments will be determined by a computer 
generated randomization schedule, generated and maintained by Pfizer and provided to the 
site. Pfizer will provide a randomization schedule to the third party person(nel) assigned to 
prepare and administer the study medication.  Only the third party person(nel) assigned to 
prepare and administer the study medication will have access to the randomization schedule 
and dispensing records during the study period. 
The randomization numbers, which are 5-digits,
, etc. 
will be used.
In accordance with the randomization numbers, subjects will randomly receive one of the 
study medications listed in Table 1 below, in a 3:3:3:1 ratio.
Study treatments will include single doses of the following medications taken orally: 
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Table 1.
Study Treatments
Treatment Group
Treatment Arm
Treatment Description
A
IBU 250 mg/ APAP 500 mg
2 IBU 125 mg/ APAP 250 mg caplets
B
APAP 500 mg
1 APAP 500 mg caplet + 1 placebo caplet
C
IBU 250 mg
2 IBU 125 mg caplets 
D
Placebo
2 placebo caplets
Study medication will be prepared for dosing by a third party who is otherwise not involved 
in the study, and subjects will be blindfolded with a sleep mask or similar object when taking 
their assigned study medication.
5.2. Breaking the Blind
The study will be subject- and investigator-blinded.  At the initiation of the study, the study
site will be instructed on the method for breaking the blind.  Blinding codes should only be
broken in emergency situations for reasons of subject safety.  Whenever possible, the 
investigator or sub-investigator consults with a member of the study team prior to breaking
the blind.  When the blinding code is broken, the reason must be fully documented and 
entered on the case report form.
In the event of a medical emergency that necessitates breaking the code, the third party 
personnel will consult the Study Treatment Dispensing Record to confirm which study 
treatment the subject received and will then report it to the Investigator.  This disclosure will 
only be broken in the event of an emergency for which knowledge of the subject’s 
double-blind investigational product will have a direct impact on treatment decisions.  Every 
effort will be made to discuss the decision to break the blind with the Pfizer Consumer 
Healthcare (PCH) monitor in advance.
When the blind is broken, the Investigator will notify the Sponsor’s Clinician and Medical 
Monitor within 24 hours after determining that it is necessary to unblind the treatment 
assignment and document the reason and date of the unblinding.  The event will also be 
recorded on the Case Report Form (CRF) and in the source document.  Any AE or SAE 
associated with breaking the blind must be recorded and reported as specified in this 
protocol.
5.3. Subject Compliance
RSE will be administered by a qualified investigative site person(nel).  Study treatment will 
be administered by a third party person(nel) and the oral cavity of each subject will be 
examined following dosing to assure the study medication was swallowed.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
IBU 250 mg/ 500 mg caplets, IBU 125 caplets, APAP 500 mg caplets, and placebo caplets 
for oral administration will be supplied by PCH (Richmond, VA).  Study product will be 
supplied in bulk along with individual, opaque, plastic dosing containers for unit dosing.  
Dosage form and packaging related to RSE can be found in Appendix 2.  Rescue 
medications, ondansetron, and supplies will be provided by the study site. 


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5.4.2. Preparation and Dispensing
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.
The Sponsor will supply study treatment in bulk and in an un-blinded fashion.  To maintain 
the double-blind status of the study treatments, the following dispensing and dosing 
procedures will be followed.  The site will identify a qualified third party and alternate(s) 
who are otherwise not involved in the study and will be responsible for dispensing and 
administering the study medication and/or RSE.  PCH (Richmond, VA) will provide 
randomization codes generated by Pfizer directly to the individual identified by the study 
site.  A documentation packet consisting of a Study Treatment Dispensing Record and 2-part 
double-blind labels will be provided to the assigned third party person(nel) only.  The codes 
will be kept in a secured area with access limited to only the assigned third party dispenser.  
Opaque plastic bottles and caps will also be supplied to the third party person(nel). 
The third party dispenser will prepare study medication for each subject in a designated 
dispensing room.  The study coordinator or designee will notify the third party dispenser 
once the subject has reached an oral temperature 100.5 °F.  The third party dispenser will 
assign the next available randomization number to the subject and will dispense the 
appropriate 2 caplets of study medication from the bulk supply container into an individual 
opaque plastic bottle according to the randomization schedule.  The appropriate double-blind 
label, with the same randomization number, will be affixed to the bottle and the identification 
tab will be attached to the Study Treatment Dispensing Record, which will then be fully 
completed. The Study Treatment Dispensing Record will remain in a secure locked area 
with access limited to the dispenser and the designated alternate(s).  A second qualified 
individual with no other study involvement will witness the preparation and dispensing 
process.  No other study person(nel) will be present in the designated dispensing room at the 
time of study drug dispensing.  No other individuals will be able to see the study drug in the 
bottle once the bottle cap is closed.  The third party dispenser will inform the study 
coordinator or designee once the study drug is dispensed and is ready to be administered to 
the subject.
5.5. Administration
The investigational product will be administered to the subject within 10 minutes of the 
subject reaching an oral temperature of 100.5 °F.  Immediately prior to administration of 
study medication, the subject’s oral temperature will be recorded by site person(nel) and the
subject will be blindfolded. The third party person(nel) will then enter the room and all other 
blinded study person(nel) will leave.
The third party person(nel) will then give the appropriate study medication to the blindfolded 
subject with approximately 8 ounces of room temperature water (time=0) while they are 
sitting up.  Subjects will swallow the study medication whole, and will not manipulate or 
chew the investigational product prior to swallowing.  No blinded study person(nel) will be 
present at the time of dosing.  The time of dosing will be documented by the third party 
person(nel). 
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Investigational product administration details will be recorded on the case report form (CRF).
5.6. Investigational Product Storage 
The third party person(nel) 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.  Other site person(nel) will ensure that rescue 
medication, antiemetic, and RSE are stored in a secured area with controlled access under 
required storage conditions and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  Storage conditions stated in the single reference safety document (SRSD) (eg, 
investigator’s brochure [IB] and OTC Drug Facts Label) will be superseded by the storage 
conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions will be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the sponsor approves the use of the investigational 
product after the temperature excursion. Use of the investigational product prior to sponsor 
approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
All materials for this study must be stored in an area free from environmental extremes and 
with restricted access.  A PCH representative will inspect the study product storage area and 
discuss the study product accountability system with the Principal Investigator before any 
agreements are concluded between the Principal Investigator and PCH. 
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5.7. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All study drugs will be accounted 
for using a drug accountability form/record. 
The designated third party person(nel), upon dispensing the study treatment, must record the 
information on a study treatment dispensing/return log.  For accounting purposes and 
assessing subject compliance, a representative of PCH (unblinded monitor) will review the 
study treatment dispensing/return log, inventory the study treatment, and inspect the storage 
facility at appropriate time intervals throughout the clinical investigation, depending on the 
length of the study.  The Principal Investigator must account for any significant discrepancy 
and/or deficiency.
All investigational study treatments shipped for this clinical trial will be returned to the 
Sponsor at the termination of the study.  At the conclusion of the study, the Principal 
Investigator or an appropriate designee, and a representative of PCH (unblinded monitor) 
will inventory all used and unused investigational study treatment.  The study treatment 
inventory record for returned study treatment will then be completed. 
All used investigational product (empty containers), as well as all unused study product will 
then be returned to:
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
 
5.9. Concomitant Treatment(s)
Ondansetron (8 mg IV) will be provided by the study site and stored in accordance to the 
product’s current approved product label. 
Except for rescue medications as defined in Section 5.10, ondansetron antiemetic, and the 
treatment of adverse events, no other medications or fever reducing treatments such as cold 
compress will be allowed during the course of the study.  Treatments taken within 28 days 
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before the first dose of study treatment will be documented as a prior treatments and will be 
assessed at screening and Day 0. Treatments taken after the first dose of study treatment will 
be documented as concomitant treatments and will be assessed after dosing on Day 1.
Concomitant medications for fever reduction administered after 8 hours post dosing of study 
product or after early termination will not be considered as rescue medication. All 
concomitant medications used during the study will be recorded with indication, daily dose, 
and start and stop dates of administration in the case report form.
5.10. Rescue Medication
Medical supportive care per established clinical practice will be provided to manage AEs 
associated with the use of RSE at the discretion of the investigator in addition to the 
administration of rescue medication.
IV acetaminophen and IV ibuprofen will be provided by the study site and stored in 
accordance to the product’s current approved product label. 
At the investigator’s discretion, the investigator or other qualified staff member may 
administer a single 500 mg dose, of IV acetaminophen.  The IV catheter will then be flushed 
with 0.9% normal saline (NS).  The following conditions for rescue medication 
administration may be considered:  

A subject requests rescue medication at any time during the study;

A subject’s oral temperature reaches 102.5 °F;

Subject’s overall clinical presentation such as but not limited to, the presence of 
chills, nausea and/or vomiting.
A temperature of 102.5 °F should not be used by itself and in isolation of the clinical 
condition of the subject to decide whether or not to administer IV acetaminophen.  The 
subject’s oral temperature will be taken and recorded prior to administration of rescue 
medication and recorded in the source document. The use of rescue medication will be 
recorded in the appropriate page of the CRF with the date, time, dose, and reason for use.  
Subjects taking rescue medication during the course of the evaluation period will remain in 
the study for the full 8 hour duration and continue to be monitored for a decrease in 
temperature. All subjects who were given rescue medication within 1 hour of dosing with 
investigational product will be considered discontinued.
In addition, should a subject’s oral temperature continue to rise after administration of rescue 
acetaminophen, and/or other clinically significant symptoms develop, appropriate medical 
interventions may be instituted at the discretion of the investigator (eg, administration of IV 
ibuprofen not to exceed a 400 mg/dose, frequent vital sign recordings, pulse oximetry, etc) 
These and other safety measurements may be conducted more frequently, if clinically 
indicated, or at the discretion of the investigator
Subjects will be released from the study center at the investigator’s discretion.


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6. STUDY PROCEDURES 
6.1. Screening
Subjects will be screened within 28 days prior to administration of the study medication to 
confirm that they meet the subject selection criteria for the study. Serious adverse events will 
be reported starting at Screening after informed consent has been signed and serious and 
non-serious adverse events will be recorded starting on Day 1 after dosing with study 
treatment. AEs and SAEs related to endotoxin will be collected on Day 1 after
administration of endotoxin. 
If the time between Screening and dosing exceeds 28 days as a result of unexpected delays 
(eg, delayed drug shipment, scheduling problems, temporary hold on randomization), then 
subjects will be allowed to rescreen once.
The following procedures will be completed during screening: 

Informed consent will be obtained from each subject in accordance with the 
procedures described in Section 12.3 on Subject Information and Consent. This will 
be recorded on the CRF;

Review Inclusion and Exclusion criteria. This will be recorded on the CRF;

Complete demographic information. This will be recorded on the CRF;

Review medical history within the past 5 years. This will be recorded on the CRF;

Review complete history of all prescription or nonprescription drugs, and dietary and
herbal supplements (ie, vitamins, minerals, herbs or other botanicals and amino acids)
taken within 28 days prior to the first dose. This will be recorded on the CRF;

Inform subjects of contraception requirement described in Section 4.4.1. This will be 
documented in the source document;

Obtain an oral temperature using a standardized electronic, digital thermometer to 
verify that the subject is afebrile. If the subject’s oral temperature is not between 
97.4F and 98.8F, then obtain 2 additional oral temperature readings within a 
30 minute period. The subject will only be eligible if the highest value is within 
0.4F of the lowest temperature value. The temperature or average of the three 
temperatures (if three are taken) will be recorded on the CRF;

Conduct full physical examination including weight and BMI. This will be recorded 
on the CRF;

Obtain history of drug, alcohol and nicotine use, which will be recorded in the source 
document;


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
Obtain supine blood pressure [BP] and pulse rate [PR]. This will be recorded on the 
CRF;

Conduct single, standard supine 12-lead electrocardiogram (ECG). This will be 
recorded on the CRF;

Conduct a carotid sinus massage to evaluate subject’s risk of syncope and/or 
hypotension.  This will be recorded in the source document;

Following at least a 4-hour fast, collect blood and urine specimens for safety laboratory 
tests (chemistry, hematology and urinalysis, urine drug test, alcohol breath test, 
QuantiFERON tuberculosis test, hepatitis B surface antigen test, hepatitis C antibody test, 
Human Immunodeficiency Virus (HIV) test, and some additional tests as listed in
Table 2. See Section 7.5 for a table of laboratory tests.
To prepare for study participation, subjects will be instructed on the use of the Lifestyle 
Guidelines and Concomitant Treatment(s) sections of the protocol.
6.2. Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to: 

Oral temperature should be taken first, followed by respiratory rate, vitals [BP and 
pulse], and then a single, 12 lead ECG. 
SAEs will be assessed after completion of informed consent and AEs will be assessed after 
dosing with study medication.  AEs and SAEs related to endotoxin will be collected on Day 
1 after administration of endotoxin.
6.2.1. Day 0
Subjects will be admitted to the study site on Day 0 and will stay overnight.  The following 
procedures will be completed after admission to the study site:

Obtain an oral temperature using a standardized electronic, digital thermometer to 
verify that the subject is afebrile. If the subject’s oral temperature is not between 
97.4F and 98.8F, then obtain 2 additional oral temperature readings within a 
30 minute period. The subject will only be eligible if the highest value is within 
0.4F of the lowest temperature value. The temperature or average of the three 
temperatures (if three are taken) will be recorded on the CRF.

Review changes to Inclusion Criteria and Exclusion Criteria since Screening. This 
will be recorded on the CRF;

Review changes in subject’s medical history since Screening. This will be collected 
on the CRF;


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
Review any new prescription and nonprescription drugs, and dietary and herbal
supplements taken since Screening. This will be recorded on the CRF;

Inform subjects of contraception requirement described in Section 4.4.1. This will be 
documented in the source document;

Blood and urine specimens will be collected for safety laboratory tests and to ensure 
the subjects are free of occult infection. The results to these laboratory tests need to 
be available prior to RSE test dose administration and must have no clinically 
significant findings, as judged by the investigator, in order for a subject to be dosed
and eligible to partake in the study. See Section 7.5 for a table of laboratory tests for 
more information. All lab test results will be recorded in source document;

Conduct a full physical examination including weight to calculate RSE dose. This 
will be recorded on the CRF;

Obtain supine blood pressure [BP] and pulse rate [PR]. This will be recorded on the 
CRF;

Breakfast, lunch and dinner will be provided in accordance to study procedures.
6.2.2. Day 1
Prior to RSE administration, the following procedures will be completed: 

Record changes to prior treatments since Day 0. This will be recorded on the CRF;

Obtain supine blood pressure [BP] and pulse rate [PR]. This will be recorded on the 
CRF;

Conduct single, standard supine 12-lead electrocardiogram (ECG). This will be 
recorded on the CRF.

Subjects will then be given a standardized low-fat light breakfast of plain toast and 
8.0 oz. of apple juice, or another non acidic juice. Dairy products, carbonated drinks 
and juices with high acid content will be eliminated from the breakfast. During the 
rest of the study period, subjects can sip plain, room temperature water;

Oral temperatures will be recorded (using a standardized electronic, digital 
thermometer) immediately prior to administration of RSE test dose. This temperature 
will be recorded as the subjects “normal” temperature in the CRF.
During RSE administration, the following procedures will be completed: 

AEs and SAEs related to endotoxin will be collected on Day 1 after administration of 
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
Subjects will be administered a test dose of endotoxin (0.5ng/kg body weight). The 
IV catheter used for RSE administration will be flushed with NS after RSE
administration is complete. The dose and time of administration will be recorded on 
the CRF;

Site staff will continuously monitor subjects for approximately 60 – 90 minutes
(90 minutes if increase in temperature is <1 °F and subject experiences <2 systemic 
symptoms) (Refer to Figure 1 and Table 3 to determine the subject’s full RSE dose)
to verify the absence of a medically significant allergic or exaggerated systemic 
response to the endotoxin (as described in Section 7.6). Subjects must remain in a 
semi-recumbent position (45angle from supine unless procedures require 
otherwise).  Any medically significant allergic or exaggerated systemic responses will 
be recorded on the CRF.

Subject’s oral temperature (using a standardized electronic, digital thermometer) will 
be documented at 60 or 90 minutes (90 minutes if increase in temperature is <1 °F 
and subject experiences <2 systemic symptoms) after receiving the test dose of 
endotoxin to determine the subject’s full dose of RSE. Refer to Figure 1 and 
Table 3 to determine the subject’s full RSE dose. This will be recorded on the CRF;

Subjects will be given a prophylactic dose of antiemetic (IV ondansetron 8 mg) after 
approximately 45 – 60 min of administering the test dose of RSE; 

Subject’s vitals will be taken and recorded immediately prior to receiving the full 
dose of RSE to ensure they do not have more than a moderate cardiovascular 
response to the test dose. Moderate response is defined as a medically significant 
decrease of mean blood pressure of more than 20% from baseline or an increase in 
heart rate of more than 50% from baseline or 40 bpm, whichever is less. This will be 
recorded on the CRF;

Subjects who tolerate the endotoxin test dose with no more than a moderate 
cardiovascular response will receive the full dose of endotoxin. See Figure 1 and 
Section 7.6 for more detail on determining the full dose of RSE. The IV catheter used 
for full RSE administration will be flushed with NS after RSE administration is 
complete. RSE dose and time administered will be recorded on the CRF;

Subjects will be monitored or given additional dose of RSE until their body 
temperature reaches an oral temperature of 100.5 F;

The subject’s oral temperature will need to be 100.5°F in order to be randomized to 
study medication.  If the subject’s oral temperature is not 100.5°F, additional oral 
temperature measurements will be taken every 5 minutes and recorded in the source 
document until the subject reaches this temperature or is given an additional dose of 
RSE.


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
Subjects whose oral temperature does not reach 100.5 oF (after approximately 
60 – 90 minutes of vital signs monitoring) after administration of the full bolus dose
of endotoxin may be administered an additional 1 ng/kg bolus dose of endotoxin at 
the discretion of the investigator (Subject’s vitals will be taken and recorded 
immediately prior to receiving the additional dose of RSE). Subject’s temperature 
will then be monitored every 5 minutes until their oral temperature reaches 100.5oF
within approximately 3 hours;  

Subjects will continue to be monitored to verify the absence of a medically significant 
allergic or exaggerated systemic response. At any time after administration of 
endotoxin before randomization, subject will not be randomized if he develops two or 
more systemic RSE-related adverse event where both are rated as severe. 
During randomization and dosing with study medication, the following procedures will 
be completed:

Once an oral temperature of 100.5 F is reached, subjects will be randomized to 
receive treatment as described in Section 5.1. The time between the subject reaching 
an oral temperature of 100.5F and being dosed should not exceed 10 minutes. This 
will be recorded on the CRF;

Following randomization and immediately prior to study medication dosing an oral 
temperature will be recorded.  This will be referred to as the “baseline” temperature. 
The time of dose administration will be documented. This will be recorded on the 
CRF.
After dosing with study medication, the following procedures will be completed: 

SAEs will be assessed after completion of informed consent and AEs will be assessed 
after dosing with study medication. AEs and SAEs related to endotoxin will be 
collected on Day 1 after administration of endotoxin;

Oral temperatures will be obtained using a standardized electronic, digital 
thermometer and will be recorded at 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 and 
110 minutes after dosing and at 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours 
after dosing.  Subjects will remain in bed during the times of body temperature 
measurements. See Section 9.3 for allowable windows to capture temperature. This 
will be recorded on the CRF;

Respiratory rate and vital signs [BP and pulse] will be collected every hour after 
dosing up until 8 hours after dosing. This will be recorded on the CRF;

Subjects will continue to be monitored to verify the absence of a medically significant 
allergic or exaggerated systemic response to the endotoxin (as described in
Section 7.6);


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
The investigator or delegated site staff members will continuously monitor the 
subject’s temperature using an oral standardized electronic, digital thermometer.  If 
the subject’s temperature exceeds 102.5oF, subjects may receive rescue medication as 
described in Section 5.10. Prior to administration of rescue medication, the subject’s 
oral temperature will be taken and recorded in the source document and CRF;

If a subject vomits within 2 hours of taking the study medication, he will be 
considered discontinued from the treatment period and this will be recorded as an AE. 
Once the subject is stable, in the opinion of the investigator, he may be discharged;

Lunch may be served at the investigator’s discretion, approximately 4 hours after 
dosing with study medication, after the temperature measurement. Lunch will consist 
of low-fat, room temperature food (ie, sandwiches) and room temperature water;  

Review concomitant treatments. This will be recorded on the CRF;

At the end of the 8-hour monitoring or at the time of rescue medication (within 
5 minutes), subjects will complete a Global Evaluation of study medication using a 
6-point categorical rating scale where applicable. This will be recorded on the CRF;

At the end of 8-hour monitoring, a single, 12-lead ECG will be taken.  This will be 
recorded on the CRF;

Subjects will be discharged at the investigator’s discretion once all study procedures 
are complete. 
6.3. Post-study Subject Interview and Follow-Up

Study site personnel will conduct a safety follow-up within 24 hours of discharge via 
a telephone call to the subject asking an open-ended question such as “How do you 
feel?” Any AEs from this follow-up call will be collected on the AE page of the CRF.

The investigator (or an appropriate designee at the investigator site) will contact the 
subject via telephone, 14 calendar (+3 days) days after the last dose of the study 
medication to ascertain if any SAEs have occurred. Reporting of SAEs discovered 
during this process must be completed as outlined in Section 8.1 in the protocol.

Every effort (three telephone contact attempts) should be made to contact the subject.
All attempts to contact the subject and information received during contact attempts 
must be documented. 
6.4. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.


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If a subject does not return for a scheduled visit, every effort (three telephone contact 
attempts followed by a certified letter) 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 medical record. In any circumstance, every effort should be made to document 
subject outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved adverse events (AEs). Early Termination procedures, at 
the investigator’s discretion, will include: 

Oral temperature;

Brief physical examination;

Single supine blood pressure and pulse rate measurements;

Single 12-lead ECG measurement;

Global Evaluation (if applicable; within 5 minutes of rescue).
Subjects must be withdrawn from the study under the following circumstances:

The subject develops a concomitant illness (discontinuation as deemed necessary by 
the Investigator), SAE, or hypersensitivity to the study product;

The subject requires any concomitant treatment, other than the rescue medication, 
during the course of the study that could confound the study results;

The subject becomes uncooperative or refuses to complete the study according to the 
study conditions outlines in this protocol;

If the subject vomits within 2 hours of taking study treatment;

If the subject requires rescue medication within 1 hour of dosing with study 
treatment;

If the subject’s temperature does not reach the threshold temperature;

If the subject does not tolerate endotoxin as described in Section 7.6.
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.
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 


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investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion.
7.1. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or nurse
practitioner as acceptable according to local regulation, times specified in STUDY 
PROCEDURES section of this protocol.  Whenever possible, the same qualified individual
should conduct the physical examinations for any subject.  A full physical examination will
include general appearance of the subject, head, ears, eyes, nose, mouth, throat, neck, skin, heart
and lung examinations, lymph nodes, abdomen, musculoskeletal, and neurological systems.
Weight and BMI will be recorded in the CRF. Height will be recorded in the source 
document. The brief physical examination will focus on general appearance, the respiratory 
and cardiovascular systems, and subject reported symptoms. 
Any untoward findings identified on physical exams conducted after the administration of the 
first dose of study medication will be captured as an adverse event, if those findings meet the 
definition of an adverse event.
For measuring weight, a scale with appropriate range and resolution is used and must be
placed on a stable, flat surface.
Subjects must remove shoes, bulky layers of clothing, and
jackets so that only light clothing remains. They must also remove the contents of their
pockets and remain still during measurement of weight. This information will be collected in 
the CRF.
7.2. Vital Sign Measurements
Blood pressure and pulse rate will be measured at times specified in STUDY PROCEDURES
section of this protocol.
Additional collection times, or changes to collection times of blood
pressure and pulse rate will be permitted, as necessary, to ensure appropriate collection of 
safety data.
Supine blood pressure will be measured with the subject’s arm supported at the level of the
heart, and recorded to the nearest mmHg after at least 5 minutes of rest.
Whenever possible, 
the same arm (preferably the dominant arm) should be used throughout the study.  Subjects 
should be instructed not to speak during measurements.
The same properly sized and calibrated blood pressure cuff or type, will be used to measure
blood pressure each time.  The use of automated devices for measuring BP and pulse rate are
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial
artery for at least 30 seconds and multiplied by two.
This information will be collected in 
the CRF.
7.3. Respiratory Rate
Respiratory Rate will be measured at times specified in STUDY PROCEDURES section of
this protocol. Respiratory rate will be measured after approximately 5 minutes of rest in 
supine position by observing and counting the respirations of the subject for 30 seconds and 
multiplied by 2. 


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When blood pressure is to be taken at the same time, respiration measurement will be done 
during the 5 minutes of rest and before blood pressure measurement.
7.4. Electrocardiogram (ECG)
Single, 12-lead ECGs should be collected at times specified in STUDY PROCEDURES
section of this protocol, as well as any additional times the investigator feels necessary. All
scheduled ECGs should be performed in a supine position and after the subject has rested
quietly for at least 10 minutes in a supine position.  For purposes of this study, the QTcF 
correction should be used for QTc assessments.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurement collected on Day 1 prior to RSE administration. If the 
QTc interval is increased by 45 msec from the baseline, or an absolute QTc value is 
500 msec for any scheduled ECG, then 2 additional ECGs will be collected, approximately 
2-4 minutes apart, to confirm the original measurement.  If either of the QTc values from 
these repeated ECGs remains above the threshold value (45 msec from the baseline; or is 
500 msec), then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner at the discretion of the investigator); or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified physician’s interpretation determines that the QTc values are in the acceptable 
range.
7.5. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical labs may be obtained at any time during 
the study to assess any perceived safety concerns.


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Table 2.
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and Creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
AST, ALT
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Urine drug screening
Alcohol breath test
HIV testingb
Hepatitis B surface 
antigenb
Hepatitis C antibodyb
QuantiFERON 
tuberculosisb
Additional Tests (Needed 
for Hy’s law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b Only during screening.

Minimum requirement for drug screening includes: cocaine, tetrahydrocannabinol 
(THC), opiates/opioids, benzodiazepines and amphetamines.

Subjects may undergo random urine drug screening at the discretion of the 
investigator.  Drug screening conducted prior to dosing must be negative for subjects 
to receive study medication. 

Any remaining serum/plasma from samples collected for clinical safety labs at 
baseline and at all times post-dosing may be retained and stored for the duration of 
the study.  Upon completion of the study, retained safety samples may be used for the 
assessment of exploratory safety biomarkers; samples to be used for this purpose will 
be packaged and shipped to Pfizer’s Biobank for storage.  These data will not be 
included in the clinical study report.  Samples will be retained in Pfizer’s Biobank for 
1 year following completion of the study.


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7.6. Endotoxin Administration and Monitoring
Subjects will be administered a test dose of endotoxin (0.5 ng/kg body weight) by a qualified 
individual and will then be monitored for approximately 60 – 90 (90 minutes if increase in 
temperature is <1 °F and subject experiences <2 systemic symptoms) minutes to verify the 
absence of a medically significant allergic or exaggerated systemic response to the 
endotoxin. Subjects who tolerate the endotoxin test dose with no more than a moderate 
cardiovascular response will receive a full dose of endotoxin. Moderate response is defined 
as a medically significant decrease of mean blood pressure of more than 20% from baseline 
or an increase in heart rate of more than 50% from baseline or 40 bpm, whichever is less. 
Subjects will then be administered a full dose of RSE at a dose of 1.5 ng/kg, 1 ng/kg or 
0.5 ng/kg as an IV bolus over 30-45 seconds into a forearm vein via an indwelling catheter. 
Subjects will receive 0.5 ng/kg endotoxin full dose if the subject shows more than a 1oF oral 
temperature increase (but less than 100.5 oF) and/or experiences two or more adverse events 
within approximately 60 minutes of receiving test dose. Subjects who do not show more 
than a 1oF oral temperature increase and/or do not experience two or more adverse events 
within approximately 60 minutes of receiving test dose will be monitored for an additional 
30 minutes. After the additional 30 minutes of monitoring (90 minutes in total) subjects will 
be administered a 1 ng/kg of full dose endotoxin if they show more than a 1oF increase in 
oral temperature (but less than 100.5oF) and/or experience two or more adverse events. 
Subjects who do not show a more than a 1oF oral temperature increase and/or do not 
experience two or more adverse events within approximately 90 minutes of receiving 
endotoxin test dose will be administered a 1.5 ng/kg dose of endotoxin. (See Figure 1 for an 
algorithm on determining the full dose of RSE). At any time after administration of 
endotoxin before randomization, subject will not be randomized if he develops two or more 
systemic RSE-related adverse events where both are rated as severe.
Subjects whose oral temperature does not reach 100.5 oF (after 60 – 90 minutes of
additional monitoring) after administration of the full endotoxin dose may be administered an 
additional 1 ng/kg bolus dose of endotoxin at the discretion of the investigator (Subject’s 
vitals will be taken and recorded immediately prior to receiving the additional dose of RSE). 
Subject’s temperature will then be monitored approximately every 5 minutes and 
documented in the source document until their oral temperature reaches 100.5oF within 
approximately 3 hours.
Refer to Figure 1 to help determine the full dose of RSE for each subject.
Site staff will continuously monitor subjects to verify the absence of a medically significant 
allergic or exaggerated systemic response to the endotoxin and observe for signs and 
symptoms of endotoxemia (ie, chills, fever, headache, body aches, hypotension, etc.).  The 
onset of these symptoms will generally occur approximately 1-2 hours after RSE
administration and usually begins with transient chills, followed shortly thereafter by fever 
and other associated flu-like symptoms over the next 4-6 hours.
 
 
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7.7. Temperature Recording/Monitoring
During Screening and on Day 0, an oral temperature will be obtained from each subject
(using a standardized electronic, digital thermometer) to ensure they are afebrile. Afebrile is 
defined as a mean temperature between 97.4°F and 98.8°F that does not vary more than 
0.4 Ffrom the lowest to highest on three repeated assessments within a 30 minute period.
On Day 1, fever will be induced in healthy male volunteers using RSE and temperature 
measurements will be taken throughout the study to monitor the subject’s fever. At the 
discretion of the investigator, additional oral temperatures will be taken more frequently to 
monitor the subject’s oral temperature. If the subject’s temperature exceeds 102.5oF subjects 
may receive rescue medication.  All endpoints for this study will be based on oral 
temperature measurements via a standardized electronic, digital thermometer. 
Oral temperatures will be recorded at the following times: 

At screening and Day 0 to ensure the subjects are afebrile and eligible to participate 
in the study;

Prior to administration of the test dose of RSE. This will be referred to as the
“normal” temperature;

Approximately 60 and 90 minutes (90 minutes if increase in temperature <1°F and 
subject experiences <2 systemic symptoms) after the test dose of RSE in order to 
determine what full dose of RSE the subject will receive (see 
Section 7.6 above for RSE dosing).  After approximately 60 or 90 min (90 min if 
increase in temperature <1°F and subject experiences <2 systemic symptoms) of 
receiving the test dose of RSE, subjects who tolerate the test dose of RSE will receive 
a full dose of RSE;

After the full dose of RSE when the subject has reached an oral temperature 
100.5°F. The subject’s oral temperature will need to be 100.5°F in order to be 
randomized to study medication.  If the subject’s oral temperature is not 100.5°F, 
additional oral temperature measurements will be taken approximately every 
5 minutes and recorded in the source document until the subject reaches this 
temperature or is given an additional dose of RSE. The time between the subject 
reaching an oral temperature of 100.5F and being dosed should not exceed 
10 minutes;

Immediately prior to study medication dosing after the subject has reached an oral 
temperature of 100.5 °F and has been randomized. This will be referred to as the 
“baseline” temperature;

At 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 and 110 minutes post dose and at 2, 2.5, 3, 
3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours post dose.  The following time windows 
will be allowed for each of the time points; the widths of ±3 minutes for time points 
that are 10 minutes apart, ±5 minutes for time points that are 30 minutes apart.


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
At the discretion of the investigator, additional oral temperatures may be taken by the 
investigator or delegated site staff members more frequently to monitor the subject’s 
oral temperature.  If the subject’s temperature exceeds 102.5oF, subjects may receive 
rescue medication.  An oral temperature will be taken and recorded prior to rescue 
medication administration.
Subjects will remain in bed during the times of temperature measurements. The investigator 
or delegated site staff members will continuously monitor the subject’s oral temperature 
using a standardized, digital thermometer. If this temperature exceeds 102.5oF subjects may
receive rescue medication as described in Section 5.10. An oral temperature will be taken 
and recorded in the source document and CRF prior to rescue medication is administered. 
 
 
 
 
 
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain adequate information both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
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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.
All AEs believed by the investigator to be related to endotoxin will be marked as of “other” 
causality in the AE page of the CRF.  Investigators are advised to enter that the AE is due to 
endotoxin in the causality description of “other”.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 14 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
visit.  AEs and SAEs related to endotoxin should be reported on the CRF from the time the 
subject has been administered the test dose of endotoxin.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;


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
Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page. If there are errors 
related to endotoxin, they will be captured as a protocol deviation.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or


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
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
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.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements). 
Endotoxin-related adverse events will be recorded in the AE section of the CRF as of “other” 
causality and that the AE is due to endotoxin in the causality description of “other”.


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8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches ≥3 × ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for Liver Function Test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.


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


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Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes 
of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:


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1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.
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).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.


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Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
As noted in the Protocol-Specified Serious Adverse Events section, should an investigator 
judge one of the identified protocol-specified SAEs to have a causal relationship with the 
investigational product, the investigator must report the event to the sponsor within 24 hours 
of investigator awareness, even if that event is a component of the endpoint.


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In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions will be carried out in 
accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for the summary and statistical analyses of the data collected in this 
study are 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 to the primary endpoint definitions and/or 
their analyses will also be reflected in a protocol amendment.
Pfizer Consumer Healthcare will perform statistical analyses of data.  All computations will 
be performed using SAS® version 9.2 or higher (SAS Institute, Cary, NC).  Statistically 
significant treatment differences will be declared if the probability of random occurrence 
among or between treatments, p, is 0.05 (two sided).  Treatment differences will be 
considered marginally significant if 0.05<p 0.10.  All tests will be two sided.


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9.1. Sample Size Determination
The sample size calculation was based on the data from a previous induced fever study 
(Whitehall-Robins Protocol Number ED-93-03).  In that study, subjects with normal body 
temperature took study medication 30 minutes prior to receiving Endotoxin. The estimated 
variability (root mean square error RMSE) of the weighted sum of temperatures difference 
over 0-8 hours was 3.372, and treatment difference between APAP and Placebo was 3.57. 
Literature review and simulations were additionally conducted to assess the treatment effect 
and variability for sample size.
In this study, we assume a treatment difference of 1.77 and 1.88 units in WSTD0-8 for 
APAP/IBU vs IBU and APAP/IBU vs. APAP, respectively, and a variability (RMSE) of 
3.406.  A sample of 78 subjects per active treatment group will be required to provide about 
85% joint power to achieve statistical significance at two-sided 0.05 level.  Furthermore, this 
sample size for each active group and 26 subjects in placebo group (3:3:3:1 allocation ratio)
will provide about 85% power to detect a treatment difference of 2.35 units in WSTD0-8 for 
the comparison of each active treatment to placebo. 
Thus, after adjusting for additional 3.7% who are randomized but not dosed or with no 
post-baseline data, a total of approximately 270 subjects are to be randomized into the study.  
All statistical tests will be performed at a two-sided 0.05 level of significance.
Additional 20 subjects (two randomization blocks) will be randomized.  This addition 
ensures a total of approximately 270 subjects in the modified Intent to treat (mITT) analyses 
population which will include only subjects randomized after protocol amendment 4.  
Seventeen subjects (replaced by the added 20 subjects) not included in the mITT were dosed 
with a different RSE dosing algorithm than the RSE current dosing algorithm before 
amendment 4.  These subjects were dosed with much higher test and full doses of endotoxin.
9.2. Efficacy Analysis
The statistical analysis methods will be detailed in the SAP, and are briefly summarized 
below. Subjects will be assigned to the randomized treatment group for efficacy summary 
and analysis regardless of the treatment received.
9.2.1. Primary Analysis Set
The primary analysis set is the modified intent to treat (mITT) subject population, defined as 
all randomized subjects who were dosed with the study medication and RSE per procedures 
specified in protocol post amendment 4 and had a baseline assessment.
 
 
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9.2.4. Analysis of the Primary Endpoint
The primary efficacy endpoint, the weighted sum of temperature difference from baseline 
over 0-8 hours (WSTD0-8) will be analyzed using an ANCOVA model with treatment group
term and covariates baseline temperature and time from the first RSE full dose to 
randomization using mITT.  Additional analyses will be conducted based on the ITT analysis 
set.
Time from the first RSE full dose to randomization is added to the model as subjects 
demonstrated significant variations in time from RSE first full dose to randomization (ie,
reaching threshold temperature of 100.5).
9.2.4.1. Protection for Multiple Comparisons
In order for the study to be deemed successful, the combination product should be 
significantly better than both active comparators for the primary endpoint. The type 1 error 
for the primary endpoint will be preserved by testing each hypothesis at 0.05 level of 
significance (two-sided) in the following order:
1. IBU/APAP vs placebo;
2. IBU/APAP vs IBU and IBU/APAP vs APAP;
3. IBU vs placebo;
4. APAP vs placebo;
5. IBU vs APAP.
1. A comparison will not be eligible for being declared significant unless the one 
preceding it is also significant.
2. All pairwise comparisons will be presented for the sake of clinical completeness 
even if they are not technically eligible for being declared significant.
9.2.5. Analysis of Secondary Endpoints
All measures relating to weighted sum of temperature difference from baseline, temperature 
difference from baseline at individual post-dose time point will be analyzed by ANCOVA 
model with treatment group term and covariates baseline temperature and time from the first 
RSE full dose to randomization.  Additional analyses may be conducted based on the ITT 
analysis set.
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Time to rescue medication will be analyzed using a proportional hazards model with 
treatment group term in the model.
The time to return to “normal temperature” (time until fever clearance) will be analyzed 
using interval-censored survival analysis approach, since the exact time to fever clearance 
will not be observed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.4. Safety Analysis
The safety analysis set comprises all subjects who dosed with study medication.  Subjects 
will be analyzed according to the treatment they received, regardless of the randomized 
treatment assigned.
Adverse event (AE) analyses will include all events which initially occurred, or worsened 
following treatment.  Adverse events will be summarized by the medical dictionary for 
regulatory affairs (MedDRA) system organ class (SOC) and preferred term and classified 
according to their severity (mild, moderate, or severe) and relationship (related or not related) 
to study product.  For the summary by severity, subjects who have multiple occurrences of 
the same AE will be classified according to the worst reported severity of the AE.  Similarly, 
for the summary by relationship to the study product, the AE will be classified according to 
the worst relationship.
Safety (adverse events [AE]/serious adverse events [SAE]) data will be summarized by 
treatment groups. 
Non- treatment emergent AEs will be summarized.
Post-treatment vital signs and their change from baseline values will be summarized by 
treatment groups. Number and percent of subjects with an abnormal ECG exam at the end of 
the study will be summarized by treatment groups. 
9.5. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on 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 study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.


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


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


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in United States
End of trial is defined as last subject last visit (LSLV), which is the date the investigator
reviews the last subject’s final safety data and determines that no further evaluation is
required for the subject to complete the trial.
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 
PF-06438867 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 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. 


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
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 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.


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The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Grosser T, Smyth E, FitzGerald GA. “Chapter 34. Anti-inflammatory, Antipyretic, and 
Analgesic Agents; Pharmacotherapy of Gout.” (Chapter). Bruner LL, Chamber BA, 
Knollman BC: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 
12e: http://www.accessmedicine.com/content.aspx?aID=16670422.
2.
Graham, GG, Scott KF. Mechanism of action of paracetamol. Am. J. Therap. 2005; 12: 
46-55.
3.
Anderson BJ. Paracetamol (acetaminophen): Mechanisms of action. Paediatr. Anaesth. 
2008; 18: 915-921.
4.
Wright CE, Antal EJ, Gillespie WR, Albert KS. Ibuprofen and acetaminophen kinetics 
when taken concurrently. Clin. Pharmacol. Ther. 1983; 34: 707-701.
5.
Tanner T, Aspley S, Munn A, Thomas T. The pharmacokinetic profile of a novel 
fixed-dose combination tablet of ibuprofen and paracetamol. BMC Clin. Pharmacol. 
2010; 10: 10 (http://www.biomedcentral.com/1472-6904/10/10).
6.
Suffredini AF, Noveck RJ. Human Endotoxin Administration as an Experimental 
Model in Drug Development. Clin Pharmacol Ther.2014 Oct; 96 (4): 418-422.
7.
Davies NM. Clinical pharmacokinetics of ibuprofen: The first 30 years. Clin. 
Pharmacokin. 1998; 34: 101-154.
8.
Tylenol® (Acetaminophen) Professional Product Information. McNeil Consumer 
Healthcare. 2010.
9.
The Acetaminophen Hepatotoxicity Working Group, Center for Drug Evaluation and 
Research, Food and Drug Administration, Department of Health and Human Services. 
Recommendations for FDA interventions to Decrease the Occurrence of Acetaminophen 
Hepatotoxicity. 26 Feb 2008. 
10.
Tanner T, Aspley S, Munn A, Thomas T. The pharmacokinetic profile of a novel 
fixed-dose combination tablet of ibuprofen and paracetamol. BMC Clin. Pharmacol. 
2010; 10: 10 (http://www.biomedcentral.com/1472-6904/10/10).
11.
Mehlisch DR, Aspley S, Daniels, SE, Bandy DP. Camparison of the analgesic efficacy 
of ibuprofen and paracetamol with ibuprofen or paracetamol alone in the management 
of moderate to severe acute postoperative dental pain in adolescents and adults: A 
randomized, double-blind, placebo-controlled parallel-group, single-dose, two-center 
modified factorial study. Clin Therap. 2010a; 32: 882-895.


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12.
Mehlisch DR, Aspley S, Daniels SE, Southerden KA, Christensen KS. A single-tablet 
fixed dose combination of racemic ibuprofen/paracetamol in the management of 
moderate to severe postoperative dental pain in adult and adolescent patients: A 
multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, 
factorial study. Clin. Therap. 2010b; 32: 1033-1049.
13.
Doherty M, Hawkey C, Goulder M, Gibb I, Hill N, Aspley S, Reader S. A randomized 
controlled trial of ibuprofen, paracetamol, or a combination tablet of 
ibuprofen/paracetamol in community derived people with knee pain. Ann Rheum Dis 
2011; 70: 1534 41.
14.
Kett, Daniel H., et al. "A randomized study of the efficacy and safety of intravenous 
acetaminophen vs. intravenous placebo for the treatment of fever." Clinical 
Pharmacology & Therapeutics 90.1 (2011): 32-39.


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
Analysis of covariance
APAP
acetaminophen
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
CDS
core data sheet
COX
cyclo-oxygenase
CRF
case report form
CRU
clinical research unit
CSA
Clinical study agreement
EC
ethics committee
ECG
electrocardiogram
E.coli
Escherichia coli
EDP
Exposure of partner during pregnancy
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDC
Fixed-dose combination
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
IB
investigator’s brochure
IBU
ibuprofen
ICH
International Conference on Harmonization
ID
identification
IND
investigational new drug application
INR
International normalized ratio
IRB
institutional review board
IUS
intrauterine system 
IV
intravenous
LFT
liver function test
LPD
local product document
LSLV
last subject last visit 
MedDRA
medical dictionary for regulatory affairs 
MITT
modified intent to treat
MRI
magnetic resonance imaging
N/A
not applicable
NMR
nuclear magnetic resonance
NS
normal saline 0.9%
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Abbreviation
Term
NSAID
non-steroidal anti-inflammatory drug
OTC
over-the-counter
PCH
Pfizer Consumer Healthcare
PR
pulse rate
PT
prothrombin time
RMSE
root mean square error
RSE
reference standard endotoxin
SAE
serious adverse event
SAP
statistical analysis plan
SOC
System Organ Class
SOP
standard operating procedure
SRSD
single reference safety document
THC
tetrahydrocannabinol
TMF
trial master file
ULN
upper limit of normal
US
United States
WSTD
weighted sum of temperature differences


PF-06438867
B5061002
Final Protocol Amendment 6, 21 Sept 2017
Page 71
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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PF-06438867
B5061002
Final Protocol Amendment 6, 21 Sept 2017
Page 72
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PF-06438867
B5061002
Final Protocol Amendment 6, 21 Sept 2017
Page 73
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PF-06438867
B5061002
Final Protocol Amendment 6, 21 Sept 2017
Page 74
 
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SAP_001.pdf: 
Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 1 
 
TMF Doc ID: 98.03 
  
 
 
Protocol B5061002 
 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, FULL 
FACTORIAL, SAFETY AND EFFICACY STUDY COMPARING THE 
ANTIPYRETIC EFFECTS OF A SINGLE ORAL DOSE OF IBUPROFEN (IBU) 250 
MG/ ACETAMINOPHEN (APAP) 500 MG CAPLETS TO IBU 250 MG AND APAP 
500 MG CAPLETS IN HEALTHY MALE VOLUNTEERS WITH FEVER INDUCED 
BY AN ENDOTOXIN 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
 2.0 
Date:  
01-Nov-2017 


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%DVHOLQH7HPSHUDWXUH9LWDO6LJQVDQG(&*
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5HVFXH0HGLFDWLRQ
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,QWHUYDO&HQVRUHG7LPHWR(YHQW'DWD)RUPDW
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'DWD)RUPDW
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3ULRU0HGLFDO&RQGLWLRQVDQG0HGLFDO+LVWRU\
6WXG\&RQGXFWDQG6XEMHFW'LVSRVLWLRQ
$OO6XEMHFWV'RVHGZLWK(QGRWR[LQ
6XEMHFW5DQGRPL]HGWR6WXG\0HGLFDWLRQ7UHDWPHQW
6WXG\0HGLFDWLRQ([SRVXUH
&RQFRPLWDQW0HGLFDWLRQVDQG1RQ'UXJ7UHDWPHQWV
5HVFXH0HGLFDWLRQ
6DIHW\6XPPDULHVDQG$QDO\VHV
$GYHUVH(YHQWV
/DERUDWRU\'DWD
9LWDO6LJQV
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3K\VLFDO([DPLQDWLRQ
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Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 5 
 
TMF Doc ID: 98.03 
 
1. VERSION HISTORY 
The initial version of the statistical analysis plan (SAP) dated on 23-Mar-2016 for study 
B5061002 is being amended. This SAP amendment is based on all the amendments made to the 
protocol up to Protocol Amendment 6 dated on 21-Sep-2017. Summary of major changes are 
presented below.  
Table 1 Summary of Major Changes in the SAP Amendment 
SAP Version 
Version 
Date 
Summary of Major Changes and Rationale 
1 
23-Mar-
2016 
Not applicable 
2 
01-Nov-
2017 
Changes made based on amendments to protocol: 
 
 
Additional efficacy endpoints of WSTD0-2, WSTD0-4, and WSTD0-
6 were added (per Protocol Amendment 2); 
 
Methods for reporting Endotoxin dosing data during Endotoxin 
administration period (per Protocol Amendments 3 and 4); 
 
Change of the primary analysis set from ITT to modified intent-to-
treat (mITT) analysis set (per Protocol Amendment 6); 
 
Add time from RSE first full dose to randomization as a covariate in 
the ANCOVA model (per Protocol Amendment 6); 
 
Various clarifications and minor revisions are made on, for example, 
baseline variables and safety summaries. 
 
 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B5061002.  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. 
Note: in this document any text taken directly from the protocol is italicized. 
 
2.1. Study Objectives 
The objective of this study is to evaluate the safety and antipyretic efficacy of single, oral doses 
of IBU/APAP 250 mg/500 mg caplets versus APAP 500 mg caplets, IBU 250 mg caplets, and 
placebo in subjects in whom pyrexia has been induced by the intravenous administration of a 
Reference Standard Endotoxin (RSE). 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 6 
 
TMF Doc ID: 98.03 
2.2. Study Design 
This study is a single-center, 8-hours, single-dose, inpatient, double-blind, randomized, placebo-
controlled, full-factorial, parallel arm, safety and efficacy study in healthy male subjects 18 to 55 
years of age (inclusive).  Approximately 290 subjects will be enrolled in this study. 
The study is comprised of a screening visit and a study treatment period. The screening visit will 
occur within 28 days prior to the study treatment period.  Subjects will remain at the research 
center during the study treatment period for approximately 36 hours over 2 days. Subjects will 
enter the study center on Day 0 and will remain in-house until after the completion of all study 
procedures on Day 1, at the investigator’s discretion.  Site personnel will conduct a safety follow 
up within 24 hours of discharge via a telephone call to the subject and again 14 calendar days 
after the last dose of study medication to ascertain if any Serious Adverse Events (SAEs) have 
occurred. 
Fever will be induced in healthy male volunteers using RSE and temperature measurements will 
be taken throughout the study to monitor the subject’s fever. Once subjects have received a dose 
of RSE, their oral temperature will continue to be monitored at the discretion of the investigator 
approximately every 5 minutes using an oral standardized electronic, digital thermometer. 
Subject temperatures from test dose till randomization will be recorded in the source document. 
All endpoints for this study will be based on oral temperature measurements using a 
standardized electronic, digital thermometer.  Oral temperatures will be recorded at the 
following times: 
 
 
At screening and Day 0 to ensure the subjects are afebrile and eligible to participate in the 
study; 
 
Prior to administration of the test dose of RSE. This will be referred to as the “normal” 
temperature; 
 
Approximately 60 and 90 minutes (90 minutes if increase in temperature is 
<1°F and subject experiences <2 systemic symptoms) after the test dose of RSE in order to 
determine the full dose of RSE that the subject will receive. After approximately 60 or 90 
min (90 min if increase in temperature is <1°F and subject experiences <2 systemic 
symptoms)  of receiving the test dose of RSE, subjects who tolerate the test dose of RSE 
will receive a full dose of RSE; 
 
 After the full dose of RSE when the subject has reached an oral temperature of 
100.5°F. The subject’s oral temperature will need to be 100.5°F in order to be 
randomized to study medication. If the subject’s oral temperature is not 
100.5°F, additional oral temperature measurements will be taken and recorded in the 
source document approximately every 5 minutes until the subject reaches this temperature or 
is given an additional dose of RSE.  The time between the subject reaching an oral 
temperature of 100.5F and being dosed should not exceed 10 minutes; 
 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 7 
 
TMF Doc ID: 98.03 
 Immediately prior to study medication dosing after the subject has reached an oral 
temperature of 100.5°F and has been randomized. This will be referred to as the “baseline” 
temperature;  
 
 At 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 and 110 minutes post dose and at 2, 2.5, 3, 3.5, 4, 
4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours post dose;   
 
 At the discretion of the investigator, additional oral temperatures may be taken by the 
investigator or delegated site staff members more frequently to monitor the subject’s oral 
temperature.  If the subject’s temperature exceeds 102.5oF, subjects may receive rescue 
medication.  An oral temperature will be taken and recorded prior to rescue medication 
administration. 
 
Safety evaluations including adverse event (AE) monitoring, vital signs (blood pressure and 
pulse rate), and respiratory rate will be monitored throughout the study.  At the end of the 
8-hour post dose period or at the time of rescue medication (within 5 minutes) subjects will 
complete a global evaluation of study medication using a categorical rating scale where 
applicable, and then will be discharged from the study site. 
 
2.2.1. Study Treatments 
The study will consist of the following blinded treatments:  
Study Treatments 
Treatment Group 
Treatment  
Treatment Description 
A 
IBU 250 mg/ APAP 500 mg  
2 IBU 125 mg/ APAP 250 mg caplets 
B 
APAP 500 mg  
1 APAP 500 mg caplet + 1 placebo caplet 
C 
IBU 250 mg  
2 IBU 125 mg caplets  
D 
Placebo  
2 placebo caplets 
 
 
2.2.2. Schedule of Activities  
The schedule of baseline, efficacy, safety, and treatment activities across the study visits are 
listed in the following tables.   For details of schedule visit activities, refer to protocol sections   
including “Schedule of Activities”.   


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 8 
 
TMF Doc ID: 98.03 
Schedule of Activities: 
 
Visit Identifier 
1 
2 
Visit Window 
Screening: Day -28 to Day 0 
Day 0 
Prior to RSE Test Dose Day 1 
RSE 
Period 
Study Treatment Period 
Within 24 hrs of Discharge 
Early Termination 
14 Calendar Days After Last Dose(+3days) 
RSE Test Dose Administration 
60 - 90 min after RSE Test Dose 
RSE Full Dose Administration * 
0 hrs 
10, 20, 30, 40, & 50 min 
60 min 
70 min 
80 min 
90 min 
100 min 
110 min 
2 hrs 
2.5 hrs 
3 hrs 
3.5 hrs 
4 hrs 
4.5 hrs 
5 hrs 
5.5 hrs 
6 hrs 
6.5 hrs 
7 hrs 
7.5 hrs 
8 hrs 
Informed Consent 
X 
Inclusion/Exclusion 
criteria 
X 
X 
Demographics 
X 
Medical History 
X 
X 
Prior Treatmentsa 
→ → → → → → 
Concomitant 
Treatments(s)a 
→ → → → → → → → → → → → → → → → → → → → → 
Physical Examinationb 
X 
X 
X 
Safety Laboratory 
Testsc 
X 
X 
History of Drug, 
Alcohol, & Nicotine 
Use 
X 
 
 
 
 
 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 9 
 
TMF Doc ID: 98.03 
Visit Identifier 
1 
2 
Visit Window 
Screening: Day -28 to Day 0 
Day 0 
Prior to RSE Test Dose Day 1 
RSE 
Period 
Study Treatment Period 
Within 24 hrs of Discharge 
Early Termination 
14 Calendar Days After Last Dose(+3days) 
RSE Test Dose Administration 
60 - 90 min after RSE Test Dose 
RSE Full Dose Administration * 
0 hrs 
10, 20, 30, 40, & 50 min 
60 min 
70 min 
80 min 
90 min 
100 min 
110 min 
2 hrs 
2.5 hrs 
3 hrs 
3.5 hrs 
4 hrs 
4.5 hrs 
5 hrs 
5.5 hrs 
6 hrs 
6.5 hrs 
7 hrs 
7.5 hrs 
8 hrs 
Temperature 
Recordingd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admit to Study Unit 
X 
Blood Pressure & 
Pulse Ratee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Single, 12-lead ECGf 
X 
X 
X 
X 
Respiratory Rateg 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception Check 
X 
X 
Dinner 
X 
Lunch 
X 
X 
Breakfast 
X 
X 
Antiemetic dose 
administeredh 
X 
Endotoxin Test Dose 
X 
Monitor for Allergy / 
Systemic Responsei 
→ → → → → → → → → → → → → → → → → → → → → → → → 
 
 
 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 10 
 
TMF Doc ID: 98.03 
 
Visit Identifier 
1 
2 
Visit Window 
Screening: Day -28 to Day 0 
Day 0 
Prior to RSE Test Dose Day 1 
RSE 
Period 
Study Treatment Period 
Within 24 hrs of Discharge 
Early Termination 
14 Calendar Days After Last Dose(+3days) 
RSE Test Dose Administration 
60 - 90 min after RSE Test Dose 
RSE Full Dose Administration * 
0 hrs 
10, 20, 30, 40, & 50 min 
60 min 
70 min 
80 min 
90 min 
100 min 
110 min 
2 hrs 
2.5 hrs 
3 hrs 
3.5 hrs 
4 hrs 
4.5 hrs 
5 hrs 
5.5 hrs 
6 hrs 
6.5 hrs 
7 hrs 
7.5 hrs 
8 hrs 
Endotoxin Full Dose 
X 
Randomization/ 
Treatment 
Administration 
X 
Lunchj 
X 
Global Evaluationk 
X 
X 
Adverse Event 
Monitoringl 
→ → → → → → → → → → → → → → → → → → → → → → → → → → → → 
Discharge from Study 
Unitm 
X 
Follow up-calln, o, 
X 
X 
Abbreviations: RSE= Reference Standard Endotoxin; ECG= electrocardiogram; IV= intravenous; hrs= hours; min= minutes; AE= Adverse Events; SAE= Serious Adverse 
Events 
a. 
Treatments taken within 28 days before the first dose of study treatment will be documented as prior treatments and will be assessed at Screening and Day 
0. Treatments taken after the first dose of study treatments will be documented as concomitant treatments and will be assessed after dosing on Day 1. 
b. Full physical exam will be performed at Screening and on Day 0. Brief physical exam will be performed at early termination. 
c. 
Safety Laboratory Tests will be performed at Screening and on Day 0 according to Section 7.5 of the protocol. Test results will need to be available 
prior to RSE test dose administration to ensure subjects are free of occult infection and eligible to partake in the study. 
d. During Screening and on Day 0, an oral temperature will be taken to verify that the subject is afebrile. Prior to the test dose of RSE administration, 
subject’s oral temperature will be recorded as their ‘normal’ temperature. Subject’s temperature will also be recorded 60 and 90 minutes (90 minutes if 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 11 
 
TMF Doc ID: 98.03 
increase in temperature is <1 °F and subject experiences <2 systemic symptoms) after the test dose of endotoxin in order to determine their full dose of 
endotoxin. After administration of a full dose of RSE, subjects will be monitored using the standardized, electronic digital thermometer until their oral 
temperature reaches 100.5F. The subject’s oral temperature will need to be 100.5°F in order to be randomized to study medication. If the subject’s oral 
temperature is not 
100.5°F, additional oral temperature measurements will be taken every 5 minutes until the subject reaches this temperature or is given an additional dose 
of RSE. Within 10 minutes of reaching this temperature, subjects will be randomized and their oral temperature will be recorded immediately prior to 
dosing with study medication (this will be known as their ‘baseline’ temperature). Oral temperatures will also be recorded at 10, 20, 30, 40, 50, 60, 70, 80, 
90, 
100 and 110 minutes after dosing and at 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours after dosing. The following time windows will be allowed 
for each of the time points; the widths of ±3 minutes for time points that are 10 minutes apart and ±5 minutes for time points that are 30 minutes apart. 
An oral temperature will be taken and recorded in the CRF prior to subjects receiving rescue medication. 
e. 
Vital signs (Supine blood pressure and pulse rate) will be collected at Screening, Day 0, Day 1 prior to test dose of RSE, Day 1 prior to the full dose of 
RSE, Day 1 prior to additional 1 ng/kg dose of RSE if applicable and then every hour after dosing up until 8 hours after dosing and/or at early termination. 
f. 
Single, 12-lead ECGs will be collected at Screening, Day 1 prior to test dose of RSE administration, at the end of the 8-hour monitoring period and/or 
early termination. 
g. Respiratory Rate will be collected every hour after dosing up until 8 hours after dosing. 
h. A prophylactic dose of antiemetic (ondansetron 8 mg IV) will be given approximately 45 - 60 min after test dose of RSE administration. 
i. 
After the 0.5 ng/kg test dose administration of RSE, subjects will be monitored for approximately 60 - 90 minutes (90 minutes if increase in temperature is 
<1 °F and subject experiences <2 systemic symptoms) to verify the absence of a medically significant allergic or exaggerated systemic response. Subjects 
who tolerate the test dose will receive a full dose of RSE (see Figure 1 of protocol for RSE full dose details) and will be monitored or given additional 
dose of RSE until their body reaches an oral temperature of 100.5 F on an oral thermometer. Subjects will continue to be monitored to verify the 
absence of a medically significant allergic or exaggerated systemic response. 
j. 
Lunch will be served at the investigator’s discretion, approximately 4 hours after dosing. Lunch will consist of low-fat, room temperature food 
(ie, sandwiches) and room temperature water. 
k. Global Evaluation will be completed at 8-hours post-dose, at the time of rescue medication administration (within 5 minutes) or at the time of 
subject withdrawal (if applicable). 
l. 
Serious adverse events will be reported starting at screening after informed consent has been signed and non-serious adverse events will be recorded 
starting on Day 1 after dosing. AEs and SAEs related to endotoxin will be collected after endotoxin administration on Day 1. 
m. Subjects will be discharged from study unit at the investigator’s discretion after all study procedures are complete. 
n. Study site personnel will conduct a safety follow-up within 24 hours of discharge via a telephone call to the subject to ascertain if any AEs or SAEs 
have occurred. 
o. Study site personnel will conduct a safety follow-up 14 calendar days after last dose via a telephone call to the subject to ascertain if any SAEs 
have occurred. 
* 
Subjects may be administered an additional 1 ng/kg bolus dose of endotoxin at the discretion of the investigator if applicable (Subject’s vitals will be taken 
and recorded immediately prior to receiving the additional dose of RSE) 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 12 
 
TMF Doc ID: 98.03 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS 
The following definitions and conventions will be used in the derivation of endpoints described in 
Section 3: 
 Baseline temperature (and time) will be defined as the highest oral temperature assessment 
between randomization time and study medication dose time.  
 The time of administration of study medication will be considered time 0. 
 Temperature difference from baseline (at each assessment time point) is defined as the 
baseline temperature minus the post baseline temperature so that a higher positive value is 
indicative of a greater improvement. 
 The time-weighted sum of temperature difference (or deduction) from baseline over time 
interval t0 - tT will be derived as 
ti - ti-1) * xi, where t0 is the time of baseline 
assessment and x1, x2, . . . xn  are the temperature differences (or deduction) from baseline 
at scheduled post-treatment assessments time  t1, t2, . . . , tn. 
  ‘Normal temperature’ is defined as the last non-missing oral temperature measurement 
prior to or at the time  the subject takes the first RSE test dose.   
 The time of end of the study for a subject who is not discontinued is defined as the last 
time the subject performed the global assessment of study medication or last temperature 
assessment time whichever occurs last. 
 The time of end of the study for a subject with early withdrawal due to adverse events is 
defined as the onset time for the adverse event(s) that lead to the subject’s discontinuation. 
 The time of end of the study for a subject with early withdrawal due to other reasons (i.e. 
not adverse events) is defined as the time the subject performed the global assessment of 
study medication at discontinuation. 
 Subjects are allowed to receive rescue medication(s) at any time during the study for the 
treatment of fever.  The rescue medication is defined as medication(s) received for the 
treatment of fever during the time period from the administration of study medication to 
the time of end of the study. 
 
3.1. Primary Endpoint 
The primary endpoint for this study is the weighted sum of temperature difference from baseline 
to 8 hours (WSTD0-8), weights being equal to the time elapsed between each two consecutive 
time points. 
Weighted sum of temperature difference (or deduction) from baseline over 0-8 hours (WSTD0-8) 
will be derived using the temperature difference from baseline at each post study treatment 
assessment time point over 8 hours (i.e., baseline temperature minus analysis value of temperature 
derived per method of Section 5.3 at 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 and 110 minutes, and 
at 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours post-treatment scheduled time points).     


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 13 
 
TMF Doc ID: 98.03 
The primary efficacy endpoint will be analyzed by the method specified in Section 5.2.1 and 
summarized as described in Section 6.1.1. 
 
3.2. Secondary Endpoints 
The secondary efficacy endpoints are: 
 Weighted sum of temperature differences from baseline to 2 hours (WSTD0-2); 
 Weighted sum of temperature differences from baseline to 4 hours (WSTD0-4); 
 Weighted sum of temperature differences from baseline to 6 hours (WSTD0-6); 
 Time to return to “normal temperature” (time until fever clearance); 
 Time to rescue medication; 
 Weighted sum of temperature differences from baseline during the last two hours of 
observation (6-8 hours) (WSTD6-8). 
Weighted sum of temperature difference WSTD0-2, WSTD0-4, WSTD0-6 and WSTD6-8 will be 
derived as sum of temperature difference (or deduction) from baseline over time intervals of 0-2 
hours, 0-4 hours, 0-6 hours, and over 6-8 hours, respectively.    
 
These secondary efficacy endpoints will be analyzed by the method specified in Section 5.2.1 and 
summarized as described in Section 6.2.1. 
 
Time to Rescue Medication: Subjects can receive medication at any time during the study for the 
treatment of fever. The rescue medication is defined as medication received for the treatment of 
fever during the time period from the administration of study medication to the time of end of the 
study (as noted at the beginning of this section). The time to rescue medication will be computed 
as the minutes from the time of dosing study medication to the time a subject first takes a rescue 
medication (censoring is No), or to the end of the study time for  subjects that do not take any 
rescue medication prior to the end of the study (censoring is Yes).    
 
This secondary efficacy endpoint will be analyzed by the method specified in Section 5.2.2 and 
summarized as described in Section 6.2.3. 
 
Time to Return to Normal Temperature (Interval-Censored): The last temperature assessed prior 
to or on the time of RSE test dose is defined as “normal temperature” (as noted at the beginning 
of this section). For analysis purpose, return to normal temperature would be counted only if it 
occurs after the subject’s post-treatment temperature has already peaked. Interval censored time to 
return to “normal temperature” endpoint will be computed at discrete scheduled time points (Tj) 
of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 
420, 450, and 480 minutes after dosing of study medication (time 0).  For each subject, this 
endpoint will have two values of Ltime and Rtime defined as follows:  


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Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 16 
 
TMF Doc ID: 98.03 
covariate may also be categorized and adjusted for in other efficacy endpoint analyses 
where deemed appropriate. 
 Dosage (ng) of Endotoxin test dose, first full dose, and second full dose will be derived as 
dosage (in unit of ng) of first RSE dose (RSE test dose),  the second RSE dose (RSE first 
full dose), and possible the third RES dose (RSE second full dose) took by subjects prior 
to randomization.    
Total dosage of Endotoxin will be derived as the sum of all Endotoxin dosages administered 
prior to randomization per subject.  
 Number of subjects administered with RSE test dose, and first and second RSE full doses 
will be derived as number of subjects who take the first RSE dose (RSE test dose),  the 
second RSE dose (RSE first full dose), and the third RSE dose (RSE second full dose) 
prior to randomization.  And the corresponding 3 groups of subjects (i.e. taking only one, 
two, or all three doses) may be used, additionally, in Exposure to Endotoxin summaries.    
 
These Endotoxin administration relevant variables will be summarized as described in Section 
6.5.2.1 The corresponding listings will be also produced.  
 
3.4.3. Baseline Temperature, Vital Signs and ECG 
 
Baseline temperature and normal temperature (see Section 3) will be summarized as described in 
Section 6.5.1.2. The corresponding listings will be also produced.    
Baseline vital signs and baseline ECG will be those that will be assessed  prior to the Endotoxin 
test dose, and will be summarized as described in Section 6.5.1.3. 
 
3.4.4. Prior Medical Conditions and Medical History 
Prior medical conditions and medical history are those occurred prior to the administration of the 
Endotoxin test dose. These data will be summarized as described in Section 6.5.1.4. 
 
3.4.5. Concomitant Medications/Non-Drug Treatments (except Rescue Medication) 
All concomitant medications and/or non-drug treatments used/taken at any time post the 
administration of the Endotoxin test dose will be collected throughout the study. The following 
will be considered as concomitant medications and/or nondrug treatments:   
 
 Concomitant medications and/or non-drug treatments used during the study treatment 
period (except rescue medication) are these medications and/or non-drug treatments that 
were administered not for fever reduction at any time point from the administration of 
study medication up to the time of end of study (Section 3).   
 
 Concomitant medications and/or non-drug treatments used post the study are these 
medications and/or non-drug treatments that were administered after the time of end of 
study.   


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 17 
 
TMF Doc ID: 98.03 
 
 Concomitant medications and/or non-drug treatments used during the Endotoxin 
administration period are these medications and/or non-drug treatments that were 
administered at any time point from the first administration of Endotoxin up to study 
medication dose.   
 
Concomitant medications will be coded using the WHO Drug Dictionary.  Concomitant non-drug 
treatments will be coded using MedDRA preferred term.  Concomitant medications and/or non-
drug treatments will be summarized as described in Section 6.5.4. 
 
3.4.6. Rescue Medication 
Rescue medication will be the medications that are administered for fever reduction such as 
acetaminophen and ibuprofen at any time point from the administration of study medication  to 
the end of study (Section 3).   Rescue medication will be summarized as described in Section 
6.5.5. 
 
 
3.5. Safety Endpoints 
3.5.1. Adverse Events 
Adverse event (AE) analyses will include all events which initially occurred, or worsened 
following treatment (i.e., treatment-emergent).  Adverse events will be summarized by the medical 
dictionary for regulatory affairs (MedDRA) system organ class (SOC) and preferred term and 
classified according to their severity (mild, moderate, or severe) and relationship (related or not 
related) to study product.  For the summary by severity, subjects who have multiple occurrences 
of the same AE will be classified according to the worst reported severity of the AE.  Similarly, 
for the summary by relationship to the study product, the AE will be classified according to the 
worst relationship. 
 
In the study, adverse events (including serious adverse events [SAE] if any) will be collected after 
dosing of Endotoxin .  Subjects will be contacted 14 (±3) calendar days post end of the study to 
ascertain if any SAEs have occurred after end of the study.  
 
An AE is considered treatment emergent relative to the treatment (i.e., the study medication or 
Endotoxin, respectively) if: 
 the event occurs for the first time during the effective duration of the treatment and was 
not seen prior to the start of the treatment, or 
 the event was seen prior to the start of the treatment but increased in severity during 
treatment. 
 
Adverse events will be classified as study medication treatment-emergent, and Endotoxin 
treatment-emergent, respectively, according to their corresponding onset time.  Adverse events 
will also be classified  according to their causality with the relevant treatment, i.e. whether it is 
due to Endotoxin,  study medication, or other reasons, based on the study case report form. 


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Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 19 
 
TMF Doc ID: 98.03 
After the administration of study medication till the end of study, vital signs will be considered as 
out of normal range per the following criteria (Protocol Appendix 3):   
 
Pulse Rate 
Supine/Sitting: <40 or >120 bpm;  Standing: <40 or >140 bpm 
Systolic Blood Pressure: 
≥30 mmHg for change from baseline in same posture; or <90 mmHg 
Diastolic Blood Pressure: 
≥20 mmHg for change from baseline in same posture; or <50 mmHg 
Respiratory Rate: 
<12 bmp or >25 bpm 
Refer to Protocol Appendix 3.  
 
Changes from baseline in vital signs will be calculated at each post-baseline scheduled hour till 
the end of study, and at mostly prior to RSE full dose time, as post baseline value minus baseline 
value based on non-missing data of both baseline and post-baseline.    
 
Post-treatment vital signs and their change from baseline values will be summarized by treatment 
groups.   
 
Vital signs will be taken at the following scheduled time points: 1, 2, 3, 4, 5, 6, 7, and 8 hours 
post study treatment, at unscheduled time points, and prior to the Endotoxin full dose 
administration.  For all these, if vital signs assessment is performed within 25 minutes around a 
schedule post-treatment hour, the corresponding value will be assigned to that hour, regardless of 
the specific scheduled time. If more than one value falls within the 25 minutes window, a simple 
average of the values will be used. For the summary of vital signs that are assessed at 
unscheduled time points within 1 hour post study treatment such as 6 minutes post study 
treatment, a 5 minutes time window may be applied.  Vital signs assessed at early termination 
will be included in a scheduled time window according to the vital sign assessment time. Any 
missing vital sign measurements will be kept as missing.   
 
All these vital signs variables will be summarized as described in Section 6.6.3. Any abnormal 
vital signs will be presented in data listings . 
 
3.5.4. Electrocardiogram 
Electrocardiogram (ECG) will be measured at screening,  prior to Endotoxin test dose (baseline), 
at 8 hours post administration of study medication or early termination, or at any unscheduled 
additional times the investigator feels necessary (such as unscheduled taken prior to RSE full 
dose, prior to or after  dose of study medication, etc.).   The general abnormality of ECG will be 
assessed by Investigator and collected into study database as  ‘Normal’, ‘Abnormal, Not 
Clinically Significant’, ‘Abnormal, Clinically Significant’, and ‘Not Evaluable’.   The ECG 
component of QTcF interval (msec) assessed at each of these time points will be collected into 
study database.  
 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 20 
 
TMF Doc ID: 98.03 
As noted above, baseline QTcF Interval (msec) will be the one assessed  prior to the Endotoxin 
test dose.  However,  if  this QTcF interval data is missing, then the QTcF interval assessed at 
screening period will be used.   
 
Per Protocol,  it will be considered as ‘abnormal’ if the QTc interval is increased by ≥45 msec 
from the baseline, or an absolute QTc value is ≥500 msec.  Therefore: 
 
 If baseline QTcF Interval ≥ 500 msec, then  the QTcF interval of the subject at baseline 
will be counted as ‘Abnormal’.  Otherwise it will be counted as ‘Normal’;  
 
 If  a subject has at least one QTcF Interval ≥ 500 msec at any time after study medication 
dose, or has a value of ≥45 msec increase from the baseline,  then  the QTcF interval of 
the subject during the study treatment period will be counted as ‘Abnormal’.  Otherwise it 
will be counted as ‘Normal’.    
 
Number and percent of subjects with an abnormal ECG exam at the end of the study will be 
summarized by treatment groups.  Specifically: 
 
 The number and percent of subjects with abnormal QTcF Interval (msec) at end of the 
study (as defined above) will be summarized by treatment groups as described in Section 
6.6.4.    
 
 The number and percent of subject with ECG exam of ‘Normal’, ‘Abnormal, Not 
Clinically Significant’, ‘Abnormal, Clinically Significant’, and “Not Evaluable’ at end of 
the study will be summarized by treatment groups as described in Section 6.6.4.    
 
QTcF Interval (msec) at end of study will be the QTcF Interval assessed at schedule time of 8 
hours post study treatment if subject completes the study, or at time close to the time of early 
termination (see Section 3) for early terminated subjects. 
Unscheduled QTcF Interval (msec) includes:    
 QTcF interval (msec)  taken prior to RSE first full dose;  
 QTcF interval (msec)  taken after RSE first full dose and prior to study medication;     
 QTcF interval (msec)  taken post study treatment but not at scheduled 8 hours. 
 
Change from baseline QTcF Interval will be calculated as post baseline value minus baseline 
value based on non-missing data of both baseline and post-baseline values.    
 
If QTcF Interval (msec) assessment is performed within 25 minutes around schedule 8 hours 
post-treatment time point, the corresponding value will be assigned to that time point.  If more 
than one value falls within  25 minutes window, a simple average of the values will be used.   
Any missing post-baseline  QTcF Interval (msec) measurements will  be kept as missing.   
 


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Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 23 
 
TMF Doc ID: 98.03 
 
5.2. General Methods  
All computations will be performed using SAS® version 9.2 or higher (SAS Institute, Cary, NC). 
Statistically significant treatment differences will be declared if the probability of random 
occurrence among or between treatments, p, is ≤0.05 (two-sided).  Treatment differences will be 
considered marginally significant if 0.05<p 0.10.  All tests will be two sided. 
 
5.2.1. Analyses for Continuous Data 
All analyses of efficacy endpoints with continuous data will use analysis of covariance 
(ANCOVA) model with treatment group term and covariates time from the first RSE full dose to 
randomization and baseline temperature.  Pairwise treatment differences will be tested using least-
squares means (LSM) estimated from the ANCOVA models. Difference between least squares 
means for each pair of comparison, its standard error, and  two-sided 95% confidence interval will 
be presented. 
 
5.2.2. Analyses for Time to Event Data 
Time to event endpoints such as time to rescue medication will be analyzed using a proportional 
hazards model with treatment group term in the model. Pairwise treatment differences will be 
estimated by the hazard ratio (HR), associated two-sided 95% confidence interval for HR, and p-
value derived from the proportional hazard model using SAS software procedure PROC PHREG. 
Time when at least 25% subjects (25% quartile) reach the event by each treatment group, and its 
95% confidence interval may be obtained from estimated survival function based on LIFETEST 
procedure.  
 
In addition, time to event endpoints will be displayed graphically by treatment using the survival 
curves (with estimated probability of zero representing no event) based on the Kaplan-Meier 
estimates.   
 
5.2.3. Analysis of Interval-Censored Time to Event Data 
Time to interval-censored event endpoint will be analyzed using interval-censored survival 
analysis approach by the nonparametric survival method of Peto (1973) and Turnbull (1976). The 
SAS software procedure PROC ICLIFETEST (C. Guo, Y. So, and G. Johnston) which 
implements the method of Peto and Turnbull will be used to obtain p-values for the generalized 
log-rank tests on the interval-censored data (Section 3.2), testing the overall treatment effect and 
the difference between each pair of treatments.  The time when at least 25% subjects (25% 
quartile)  first return to “normal temperature” by each treatment group, and its 95% confidence 
interval will be obtained from estimated survival function using the ICLIFETEST procedure. A 
stratification variable defined by number of RSE full doses taken or by categorized time from first 
RSE full dose to randomization may be considered.  


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Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 29 
 
TMF Doc ID: 98.03 
6.4. Subset Analyses  
No subset analyses are planned. 
 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
6.5.1.1. Demographics 
Demographic data of race, ethnicity and age will be summarized by treatment group and overall 
for the mITT, and for the safety analysis sets. 
Continuous demographic variables of age and body weight will be summarized using sample size, 
mean, median, standard deviation, and range by treatment groups and overall.  Categorical 
demographic variables of sex, race, and ethnicity will be summarized using frequencies and 
percentages.  No statistical tests will be conducted. 
 
6.5.1.2. Baseline Temperature 
Baseline temperature will be summarized by treatment groups and overall for both mITT and ITT 
analysis sets. 
Continuous baseline temperature will be summarized using sample size, mean, median, standard 
deviation, and range by treatment group and overall. 
 
6.5.1.3. Baseline Vital Signs and Baseline QTcF Interval (msec) 
Baseline vital signs and baseline QTcF interval (msec) will be summarized by treatment group 
and overall for safety and the exposure to Endotoxin analysis sets (Section 4.4.2). 
These continuous baseline variables will be summarized using sample size, mean, median, 
standard deviation, and range by treatment group and overall. 
 
6.5.1.4. Prior Medical Conditions and Medical History 
Frequency and percentage of subjects with prior medical conditions and medical history will be 
tabulated by treatment group and overall for the safety set based on the MedDRA preferred term.   
 
 
6.5.2. Study Conduct and Subject Disposition 
6.5.2.1.  All Subjects Dosed with Endotoxin 
Endotoxin administration data (Section 3.4.2) will be summarized by treatment group and overall 
for the mITT and for the safety analysis sets . Similar summary will be done for the subject 
exposure to Endotoxin analysis set (Section 4.4.2), in which subjects who dosed with Endotoxin 
but not randomized will be summarized in the “non-randomized” group. 


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Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 31 
 
TMF Doc ID: 98.03 
6.6.1. Adverse Events 
Adverse event (AE) analyses will include all events which initially occurred, or worsened 
following treatment (i.e., treatment-emergent).  Adverse events will be summarized by the 
MedDRA system organ class (SOC) and preferred term and classified according to their severity 
(mild, moderate, or severe) and relationship (related or not related) to study product.  For the 
summary by severity, subjects who have multiple occurrences of the same AE will be classified 
according to the worst reported severity of the AE.  Similarly, for the summary by relationship to 
the study product, the AE will be classified according to the worst relationship. 
Treatment emergent adverse events will be presented by overall incidence of at least one event, 
incidence within system organ class (SOC) only, and incidence by SOC and preferred term (PT). 
 
Treatment emergent adverse events will be summarized as follows:  
 Study Period Treatment-Emergent Adverse Events which occurred only after subjects 
received a study medication or occurred before but got worse will be summarized by 
incidence within SOC and preferred term, and tabulated by study treatment , and 
selectively, by Endotoxin exposure subgroups using the safety analysis set. These AEs 
will also be included in Tier-1 and Tier-2 events (see Section 3.5.1) summaries. Summary 
tables will be presented mainly by causality categories. 
 Endotoxin Period Treatment-Emergent Adverse Events which occurred after subjects 
received at least one dose of Endotoxin but before they took the study medication, or 
occurred before receiving an Endotoxin dose but got worse during the Endotoxin period 
will be summarized by incidence within SOC and preferred term, and tabulated by study 
treatment groups and the additional group of non-randomized subjects, using the exposure 
to endotoxin analysis set. These AEs will also be summarized by study treatment and 
causality using the safety analysis set. Additional summaries may be conducted by the 
endotoxin exposure subgroups, using the Exposure to Endotoxin analysis set. In any of the 
scenarios discussed here, all events will be listed.  However, only a smaller set of 
summaries (selected from a standard set of AE tables) will be performed and presented. 
 
 
Serious adverse events (SAE) occurred within 24 hours after dosing of study medication will be 
listed as in study treatment period. SAE reported after 24 hours till 14 calendar days post-
treatment via follow up telephone call will be listed as in study follow up period if applicable. 
Non-treatment emergent AEs (i.e., adverse events occurred before subject took any dose of study 
medication or Endotoxin) will be summarized by incidence within SOC and preferred term and 
tabulated by study treatment . 
 
All adverse events data will be listed for subjects who were enrolled into the study and received at 
least one dose of Endotoxin.   
 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 32 
 
TMF Doc ID: 98.03 
6.6.2. Laboratory Data 
Laboratory data as stated in Section 3.5.2  is considered source data and will not be entered into 
the study database.  Therefore these data will not be analyzed unless otherwise noted.  
 
6.6.3. Vital Signs 
All vital signs data will be summarized by treatment group and overall for the safety analysis set.  
No statistical tests will be conducted. The following will be produced (Section 3.5.3): 
 Baseline (i.e. assessed  prior to the Endotoxin test dose) and post baseline (i.e.,  prior to full 
dose of Endotoxin, and at each schedule hour from 1 hour till 8 hours post-treatment) vital 
signs for systolic and diastolic blood pressures, pulse rate and respiratory rate will be 
summarized using sample size, mean, median, standard deviation, and range by treatment 
group and overall, and data will be tabulated and presented graphically over time.  
All vital sign data will be listed for subjects who were enrolled into the study and received at least 
one dose of Endotoxin.   
 
6.6.4. Electrocardiogram 
The end of study QTcF interval (msec) and  change from baseline values (Section 3.5.4) will be 
summarized by treatment group and overall for the safety analysis set. No statistical test will be 
performed. 
Number and percent of subjects with abnormal (clinically significant or not) ECG at the end of  
study (and at baseline) will be summarized by treatment groups and overall for the safety analysis 
set. No statistical test will be conducted. 
Number and percent of subjects with normal/abnormal QTcF interval (msec) at the end of study 
(Section 3.5.4) will be summarized by treatment groups and overall for the safety analysis set. No 
statistical test will be conducted.  Baseline and at the end of study QTcF interval (msec)  (Section 
3.5.4) will be summarized using sample size, mean, median, standard deviation, and range by 
treatment group and overall. No statistical test will be conducted. 
 
All ECG data will be listed for subjects who were enrolled into the study and received at least one 
dose of Endotoxin.   
 
6.6.5. Physical Examination 
All physical exam data will be listed for subjects who were enrolled into the study and received at 
least one dose of Endotoxin.   
 


Protocol B5061002  (Compound Number- PF-06438867)  
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015 
 
 
Page 33 
 
TMF Doc ID: 98.03 
7. INTERIM ANALYSES 
No interim analysis is planned. 
 
8. REFERENCES  
Peto, R. (1973), “Experimental Survival Curves for Interval-Censored Data,”  Applied Statistics, 
22, 86–91. 
Turnbull, B. W. (1976), “The Empirical Distribution Function with Arbitrarily Grouped, 
Censored and Truncated Data,” Journal of the Royal Statistical Society, Series B, 38, 290–295. 
Guo C., So Y., Johnston G. (2014), “Analyzing Interval-Censored Data with the ICLIFETEST 
Procedure,” Paper SAS279-2014, Cary, NC: SAS Institute Inc. 
SAS Institute Inc. (2013), “SAS/STAT® 13.1 User’s Guide: The ICLIFETEST Procedure,” Cary, 
NC: SAS Institute Inc. 
SAS Institute Inc. (2008), “SAS/STAT® 9.2 User’s Guide: The PHREG Procedure,” Cary, NC: 
SAS Institute Inc. 
SAS Institute Inc. (2012), “SAS/STAT® 12.1 User’s Guide: The LIFETEST Procedure,” Cary, 
NC: SAS Institute Inc. 


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